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The GABAa receptor is a ligand-gated ion channel that mediates the vast majority of fast inhibitory transmission in the brain GABAa receptors are involved in the pathophysiology of epileptic and psychiatric disorders, cognitive deficits, substance abuse, and many other CNS diseases. These receptors are also the main drug target of anticonvulsive, anxiolytic, and sedative medications GABAa receptors are heteropentamers consisting of five homologous subunits forming the channel pore.
The syndrome of children and adults harboring high-titer serum and CSF antibodies against any of the indicated subunits is mainly characterized by treatment-refractory seizures, epilepsia partialis continua, and status epilepticus , Together with epileptic activity, patients show signs of encephalopathy with changes in behavior, cognition, or consciousness including coma. Some patients also develop focal neurological signs, such as hemiparesis, dyskinesias, aphasia, or oculomotor disturbances.
CSF findings are variable and abnormal in most cases and include pleocytosis, elevated protein concentration, or oligoconal bands Coexistence of other autoantibodies occurs in some patients including thyroid peroxidase, GAD65, and GABAb receptor antibodies , This finding is highly unusual in other AE and provides a clue towards the identity of the disorder. In rare instances, GABAa receptor autoantibodies are triggered by HSE; these patients develop relapsing neurological symptoms a few weeks after recovering from the viral infection Treatment with anticonvulsants is frequently ineffective, and pharmacologically induced coma barbiturates can be necessary to control seizure activity.
The reactivity of the antibodies with live cultured neurons and the type of subunit targets suggests a specific interaction of the antibodies with synaptic GABAa receptors , However, interaction with other subunits of the GABAa receptor cannot be excluded, since this has not been investigated in detail. Given the rarity of the syndrome, availability of patient material especially CSF is a critical issue that limits experimental approaches to investigate potential effects of the antibodies in a passive-transfer animal model.
In cultured primary neurons, application of patients' antibodies led to a reduction of synaptic and extrasynaptic density of GABAa receptors , In animal models with experimental status epilepticus, the continuous epileptic activity leads to a downregulation of synaptic GABAa receptors More detailed investigations of how antibodies interact with the different subunits of the GABAa receptor, the consequences of antibody binding on the interaction with anchoring molecules and synaptic delocalization of the receptor, and the effects on GABAergic signaling in intact neuronal networks are exciting topics for future research.
Dipeptidyl-peptidase-like protein-6 DPPX is a membrane glycoprotein that has an important role in tuning up the voltage-gated A-type Kv4. These channels operate in the subthreshold range of membrane potentials and are critical to ensemble voltage-gated ion currents that determine somatodendritic signal integration Autoantibodies to DPPX associate with cognitive dysfunction, memory deficits, hyperekplexia, myoclonus, tremor, and seizures.
Overall, the clinical picture of most patients is compatible with a nonspecific syndrome with a variety of manifestations indicating CNS hyperexcitability. Different from other AE, the symptom presentation of these patients can be insidious causing a diagnostic delay of many months. Infrequently, some patients may develop a clinical picture resembling a variant of stiff-person syndrome named progressive encephalomyelitis with rigidity and myoclonus PERM, discussed later Most patients show partial or complete neurological response to immunotherapy, accompanied also by resolution of gastrointestinal symptoms 33 , The antibodies also show intense reactivity with neurons of the myenteric plexus, likely explaining the frequent and severe gastrointestinal problems In preparations of guinea pig myenteric and human submucous plexus, patients' antibodies caused an increase of the excitability and action potential frequency In addition, incubation of hippocampal neurons with patients' antibodies caused a decrease of DPPX and Kv4.
The findings support a pathogenic role of the antibodies, although an animal model of the disorder has not yet been developed. Dopamine signaling is mediated through dopamine receptors, which are a family of G protein-coupled seven transmembrane domains receptors.
Both classes of receptors are highly expressed in the striatum caudate-putamen and also in cortex, hippocampus, and substantia nigra D2R is a therapeutic target of Parkinson's disease, Tourette's syndrome, and schizophrenia Antibodies to D2R have been demonstrated in patients, mostly children, with basal ganglia encephalitis manifesting with abnormal movements e. The disorder is rare; for example, in a study including 17 patients with basal ganglia encephalitis identified during 11 yr in a referral institution, 12 had these antibodies.
A potential explanation for this discrepancy is the location and type of epitopes, which appear to be extracellular and conformational in cases of basal ganglia encephalitis 55 , whereas in cases of PANDAS, the location of the epitope is unknown and the antibody reactivity does not depend on the conformation of the antigen Given the extracellular location of the D2R epitopes in cases of basal ganglia encephalitis, it is likely that the antibodies have pathogenic effects, but studies are not yet available.
However, the exact targets of these antibodies are unknown. Autoantibodies to cell surface epitopes of the D2R have also been described in some patients who develop autoimmune encephalitis after HSE, usually accompanied by NMDA receptor antibodies Figure 4 , and in a subgroup of children who develop isolated symptoms of psychosis It is unclear whether these antibodies also occur in the CSF or their presence in serum represents a secondary phenomenon of a neurological disease without pathogenic implications.
Studies comparing serum and CSF antibody titers and investigations with cultured neurons and in vivo models are needed to establish the role of D2R antibodies in human disease. Among eight mammalian mGluR receptors, the two of group 1 mGluR1 and mGluR5 are targets of autoantibodies that associate with human autoimmune CNS disorders, mGluR1 with cerebellar ataxia and motor incoordination see sect.
Interestingly, the two disorders associated with antibodies against mGluR1 and mGluR5 occur with frequent association with Hodgkin's lymphoma the reason for the association with this specific tumor is unknown , , The two receptors have a similar structure consisting of homodimers with a large extracellular domain and seven transmembrane domains The mGluR5 is particularly important for long-term depression LTD and regulates rapid synaptic transmission in the hippocampus In several human disorders, such as Huntington's disease , Alzheimer's disease , depression , and Fragile X syndrome , mGluR5 is being considered as a potential therapeutic target.
The term Ophelia syndrome was used in the description of the first patient reported with AE associated with Hodgkin's lymphoma likely representing a case of mGluR5 antibody-mediated symptoms Since then, several patients have been reported, all with a clinical picture that included confusion, agitation, memory loss, delusions, paranoid ideation, hallucinations, psychosis, or seizures , Patients' antibodies show intense reactivity with brain predominantly hippocampus, striatum, and cortex of wild-type mice but no reactivity with mGluR5 -null mice brain.
The importance of recognizing this disorder is that it is remarkably responsive to immunotherapy , There are no studies investigating the effects of mGluR5 antibodies on the receptor. The accessibility of the epitopes to circulating antibodies and the rapid response of the disease to immunotherapy suggest pathogenicity of the antibodies.
In line with the symptoms described by patients with mGluR antibodies, genetic disruption of mGluR5 impairs behavioral learning, particularly those involving extinction of non-reinforced behaviors. Neurexins act as a link between pre- and postsynaptic compartments, with the intracellular domain interacting with the presynaptic machinery for neurotransmitter release, and the extracellular domain binding to postsynaptic cell adhesion molecules such as neuroligins, cerebellins, and leucine-rich repeat transmembrane neuronal proteins LRRTMs 10 , , , Mutations in the neurexin genes have been associated with schizophrenia 99 , , and autism 83 , 99 , , Ablation of neurexin-3 demonstrates different brain region-specific pre- and postsynaptic functions; in the hippocampus, extracellular sequences of presynaptic neurexin-3 mediate trans-synaptic regulation of postsynaptic AMPA receptors, whereas in the olfactory bulb, intracellular sequences of neurexin-3 are required for GABA release 9.
In addition, two patients developed facial dyskinesias, and three needed ventilatory support. Three partially recovered with immunotherapy, one had a fulminant progression to death due to seizures, and the other died of sepsis after partial response to immunotherapy. The findings are in accord with studies showing that disruption of endogenous neurexin-neuroligin interaction by recombinant neurexin reduces the number of presynaptic terminals and inhibitory and excitatory synapses , Although no animal models are available, these preliminary studies support the pathogenicity of the antibodies.
The IgLON5 gene was identified during the sequencing of human chromosome 19 and is predominantly expressed in the nervous system IgLON5 is the most recently identified member of a family of proteins that belongs to the immunoglobulin superfamily of cell adhesion molecules IgLON proteins are highly glycosylated, contain three immunoglobulin-like domains, and are attached to the plasma membrane through a glycosylphosphatidylinositol GPI anchor The family of IgLON proteins has important functions in neuronal pathfinding and synaptic formation during brain development The exact function of IgLON5 protein is unknown; preliminary studies indicate that it is expressed in the neuronal membrane including the synapse and is widely distributed throughout the brain Patients with IgLON5 autoantibodies develop an intriguing disorder that reinforces the links between autoimmunity and neurodegeneration.
The syndrome was originally identified in a Sleep Disease Center in three patients who showed a disrupted pattern of sleep with some features resembling agrypnia excitata along with gait instability and dysautonomia Investigations for Caspr2 autoantibodies which often occur with agrypnia excitata were negative, but the studies revealed a novel autoantibody that reacted with brain Figure 3 and precipitated IgLON5.
Most patients develop sleep apneas and abnormal movements that predominate in the first part of the night. These symptoms do not improve with continuous positive airway pressure CPAP therapy, and sleep studies with video-polysomnograpy show a unique temporal sequence of sleep stages and behaviors, transitioning from very abnormal at the beginning of the night to close to normal by the end.
The initiation and reentering of sleep after awakening are characterized by undifferentiated non-rapid-eye-movement NREM sleep and poorly structured N2 phase with frequent vocalizations, stereotyped upper limb movements, and finalistic behaviors parasomnias.
In addition, most patients have a sleep breathing disorder characterized by stridor and obstructive sleep apnea , , In addition to the sleep disorder, other symptoms may include gait instability, frequent falls, supranuclear gaze palsy, dysphagia, dysautonomia, chorea, and cognitive decline. These symptoms can evolve over several years, sometimes preceding the sleep disorder and leading to consideration of other diagnoses such as progressive supranuclear palsy or multiple system atrophy.
Life-threatening complications include acute respiratory distress requiring tracheostomy and intensive care support, and dysautonomia that likely was responsible from the sudden death while awake of some patients Two immunological features suggest the disorder is immune mediated.
The frequency of these alleles among the normal population is 1. Studies with cultures of dissociated rat hippocampal neurons show that patients' antibodies cause a decrease of clusters of cell surface IgLON5 which is long-lasting or only partially reversible ; the pathogenic implication of this finding is currently unknown. Autopsy studies showed a novel neuronal tauopathy without evidence of inflammatory infiltrates or complement.
Deposits of phosphorylated tau including 3R and 4R tau isoforms were found highly restricted to neurons Figure 12 , predominantly involving the hypothalamus, brain stem tegmentum, and upper spinal cord In retrospect, patients with this disorder may have previously been described as atypical cases of progressive supranuclear palsy , , A pathologically based set of diagnostic criteria have been recently proposed Table 3 Neuropathology of the IgLON5 syndrome.
Autopsy studies of the brain of a patient with the IgLON5 syndrome demonstrating absence of inflammatory infiltrates A and C , a neurofibrillary tangle B , and neuronal deposits of hyperphosphorylated tau D. At present, it is unclear if the anti-IgLON5 syndrome is a primary tauopathy that results in a secondary immune response against IgLON5 or a primary autoimmune disorder that through unknown mechanisms leads to abnormal tau phosphorylation and deposition in neurons.
In favor of the first is the chronic symptom progression and poor response to immunotherapy. However, this hypothesis does not explain the specific presence of IgLON5 autoantibodies and the association to an uncommon HLA haplotype. The cerebellum, and in particular the Purkinje cells, are frequent targets of autoimmunity.
Autoimmune cerebellar ataxia may occur without autoantibodies such as post-varicella cerebellitis 3 or in association with antibodies against intracellular or cell surface neuronal antigens Most intracellular or onconeuronal antigens are expressed by Purkinje cells and other neurons and can be used as biomarkers of paraneoplastic e. Regardless of the type of antibody, patients with autoimmune cerebellar dysfunction usually develop rapid progression, over weeks or less commonly months, of truncal wide-based gait and limb ataxia associated with dysarthria, nystagmus, vertigo, and diplopia.
Symptoms often stabilize within 6 mo of disease onset, leaving the patient physically dependent in most cases. In rare instances, there is increased signal of the cerebellar white matter on T2-weighted images and transient contrast enhancement of cerebellar folia that may suggest leptomeningeal inflammation or tumor infiltration A common feature of the cerebellar syndromes associated with antibodies against cell surface antigens is that symptoms are less responsive to immunotherapy than those related to limbic and other types of encephalitis 66 , MRI of a patient with cerebellar ataxia associated with DNER antibodies; the arrow points to the cerebellum that shows prominent atrophy A.
The CSF of the patient showed robust reactivity with rodent cerebellum B , including the Purkinje cells inset and molecular layer in a characteristic fine dotlike pattern representing the labeling of Purkinje cell dendrites. The pathological hallmark of autoimmune cerebellar ataxia is a widespread loss of Purkinje cells 47 , Other findings may include thinning of the molecular and granular layers of the cerebellar cortex without marked cell loss, and proliferation of Bergmann astrocytes.
The deep cerebellar nuclei are usually well preserved, inflammatory infiltrates are rarely present, and there is microglial proliferation in the white matter Patients with this antibody usually present with rapidly progressive cerebellar ataxia and have an underlying Hodgkin's lymphoma. The target antigen of Tr antibodies was identified as DNER, a transmembrane protein containing 10 epidermal growth factor-like repeats 66 , This protein is strongly expressed by Purkinje cells of the cerebellum Figure 13 B and is essential for the normal development of these neurons and Bergmann glia, which express one or more Notch receptors , DNER is located in the plasma membrane and endosomes of the dendrites but not in the axons.
Tr antibodies recognize glycosylated epitopes located in the extracellular domain of DNER between the second and third epidermal growth factor EGF -like repeats Interestingly, the first two EGF domains of DNER are sufficient and necessary to bind Notch 78 ; this region does not contain the immunodominant epitope or the glycosylation sites Bergmann glial cells are intimately associated with Purkinje cells throughout development , so an immune disruption of the signaling between Bergmann glia and Purkinje neurons by patients' antibodies may have profound effects on cerebellar function.
Unlike other antigens in paraneoplastic cerebellar ataxia, DNER has not been found expressed in the tumor tissue of the patients, suggesting that the immune response is not triggered by the tumor expression of the antigen, but likely results from an immune dysregulation caused by the tumor 27 , However, these antibodies also occur in some patients with SCLC and paraneoplastic cerebellar ataxia without clinical or electrophysiological evidence of LEMS , To test this hypothesis, one study showed that passive transfer of IgG from a patient with cerebellar ataxia and LEMS into the cerebellar subarachnoid space of mice caused reversible ataxia, whereas this effect was not observed when the IgG came from a patient with LEMS without ataxia, or from a normal subject This receptor and the mGluR5 see sect.
IV G belong to group 1 of metabotropic glutamate receptors The mGluR1 is highly expressed by cerebellar Purkinje neurons and modulates rapid calcium signaling in the dendritic spines of these neurons Mice with genetic deletion of mGluR1 have ataxia, abnormal innervation of Purkinje neurons, and impaired LTD at parallel fiber synapses of Purkinje neurons , The cerebellar ataxia with autoantibodies against mGluR1 was identified in in two patients with cerebellar ataxia and serum and CSF antibodies that showed a similar pattern of reactivity with mice brain and cerebellum Figure 3 Both patients had past history of Hodgkin's lymphoma 2 yr and 9 yr before neurological symptom onset , but no tumor recurrence was identified.
One of the patients was diagnosed and treated early, and improved with immunotherapy; the other patient was treated 1 yr after symptom onset and did not improve Injection of the antibodies in the subarachnoid space of mice, near the cerebellum, resulted in progressive ataxia with wide gait and severe difficulty in walking.
In another study, the application of patients' antibodies to cerebellar slices of mice decreased the basal activity of Purkinje cells, whereas in vivo application to the flocculus of mice evoked acute disturbances in the performance of compensatory eye movements In cultured mouse Purkinje cells, the same antibodies blocked the induction of LTD. Consistent with the prominent antibody-induced dysfunction of Purkinje cells, the autopsy of a patient who for 5 yr had mGluR1 antibodies showed substantial loss of Purkinje cells Since the above cases were reported, we and others have identified 18 additional patients , 4 not reported , all with cerebellar ataxia, but most of them without tumors.
Stiff-person syndrome is characterized by muscle stiffness, rigidity, and painful spams predominantly involving the paraspinal, abdominal, and lower extremity muscles. The arms, neck, and face are less commonly involved.
The spasms can be spontaneous or triggered by movement or sensory tactile, auditory and emotional stimuli. Electrophysiological studies show sustained motor unit activity leading to cocontraction of agonist and antagonist muscles. Symptoms improve during sleep and with diazepam and other GABAergic drugs The resulting clinical syndrome has been known since and is easy to recognize on clinical grounds There are several variants of the disorder including stiff-limb syndrome predominant or isolated involvement of one extremity , and PERM PERM has a more aggressive clinical course compared with stiff-person syndrome.
In addition to encephalomyelitis with rigidity and myoclonus, other symptoms of PERM include sensory problems pruritus and neuropathic pain , brain stem dysfunction nystagmus, ophthalmoparesis, dysphagia, trismus , and dysautonomia profuse sweating, dry mouth, bladder dysfunction. Postmortem examination demonstrates degeneration of long tracts and widespread neuronal loss and inflammatory infiltrates in the brain stem and spinal cord.
The pathological findings are particularly severe in the central grey matter of the spinal cord that contains inhibitory interneurons accounting for the muscle spasms and rigidity. These findings contrast with those of classical stiff-person syndrome which usually shows no pathological abnormalities.
The antibodies more frequently encountered in patients with PERM are directed against the alpha subunit of the GlyR Autoantibodies in stiff-person spectrum disorders. Schematic representation of an inhibitory synapse including the three main targets of autoantibodies in patients with stiff-person spectrum disorders: the presynaptic proteins GAD and amphiphysin and the postsynaptic glycine receptor GlyR.
Although autoantibodies to any of these proteins can result in a similar syndrome [stiff-person, stiff-limb, or progressive encephalomyelitis with rigidity and myoclonus PERM ], GAD autoantibodies predominantly associate with nonparaneoplastic stiff-person syndrome, GlyR antibodies occur more frequently with nonparaneoplastic PERM, and amphiphysin antibodies usually associate with cancer-related stiff-person syndrome or PERM.
A series of patients with stiff-person syndrome and related disorders showed that the outcome was more dependent on the severity of the symptoms and type of autoimmunity than on the syndrome In cases of stiff-person syndrome or PERM where the antibodies are directed against cell surface antigens e. There is controversy on whether GAD65 antibodies have a direct pathogenic effect. Investigations similar to those used for antibodies against cell surface proteins showed no reactivity of patients GAD65 antibodies with cultured live neurons and no antibody internalization In passive-transfer experiments, intrathecal application of patients IgG fractions containing GAD65 antibodies induced disease signs that resembled those of the donor patients, but results were inconsistent between different IgG preparations , Accordingly, depletion of GAD65 antibodies from total IgG of patients with stiff-person syndrome did not alter the effect of the IgG on presynaptic neuronal dysfunction, and did not abolish presynaptic IgG binding suggesting the co-existence of other, potentially pathogenic antibodies The glycine receptor GlyR is a chloride channel receptor that mediates inhibitory neurotransmission in the spinal cord and brain stem In these locations, the receptor is clustered at inhibitory synapses by the tubulin-binding protein gephyrin The receptor is selectively blocked by the high-affinity competitive antagonist strychnine ; strychnine poisoning results in severe muscle spasms, opisthotonic posturing, and convulsions which are triggered by minimal stimuli.
In addition, he had symptoms of brain stem dysfunction and hyperekplexia, and improved with immunotherapy Subsequent studies have shown that these antibodies preferentially associate with PERM 42 but may also occur with stiff-person syndrome , , seizures, dysautonomia, opisthotonus, hypersomnia, limbic encephalitis, brain stem encephalitis, and pruritus caused by local involvement of the spinal cord 42 , In a series of 52 patients with GlyR antibodies, most responded to immunotherapy although 4 patients died in the acute stage of the disease , and after a median follow-up of 3 yr, 5 patients had relapses The study also confirmed a low frequency of tumors 3 of 45 patients had benign thymomas, 1 B-cell marginal zone lymphoma, and 1 metastatic breast cancer , and the coexistence in some patients of GlyR and GAD antibodies A pathogenic effect of the antibodies has been suggested by in vitro studies with HEK cells expressing GlyR.
In this setting, patients' antibodies which are of the IgG class cause internalization of the receptors and show complement fixation However, it is unclear whether these effects also occur in neurons or in the human disease. Antibodies to amphiphysin occur in the paraneoplastic variant of stiff person-syndrome, and less frequently with other syndromes such as PERM, encephalitis, or sensory neuronopathy 64 , The tumors more frequently involved are breast cancer and SCLC, and the neurological syndrome usually precedes the detection of the cancer , Compared with patients with GAD antibodies, those with amphiphysin antibodies are older, do not develop diabetes, and the pattern of stiffness is different with predominant involvement of neck and arm muscles.
Amphiphysin, first described in , exists as two splice variants amphiphysin 1 and 2 and is an abundant N-BAR domain protein enriched in the presynaptic nerve ending. In resting conditions amphiphysin is found associated with synaptic vesicles, and during high synaptic activity it localizes at the sites of endocytosis Together with binding partners, amphiphysin is an important regulatory endocytic protein involved in several steps of clathrin-mediated endocytosis.
With its clathrin binding domain CLAP , amphiphysin directly interacts with clathrin and AP2 which is important for presynaptic membrane invagination and clathrin coat assembly The carboxy-terminal src homology 3 SH3 domain of amphiphysin binds to the prolin-rich region of the GTPase dynamin that mediates clathrin-coated vesicle fission from the membrane 63 , , and to synaptojanin which in turn is a strong interacting partner of endophilin, both important for endocytic steps from membrane invagination to vesicle uncoating 23 , , The functional aspects of how autoantibodies to amphiphysin interfere with vesicle endocytosis and synaptic transmission and finally lead to characteristic disease symptoms in animal models are discussed in the next section.
These antibody-mediated effects have only recently started to be elucidated, and findings were briefly described above. However, two autoantibodies have been more extensively studied, including the antibodies against amphiphysin a presynaptic protein and those against the NMDA receptor a postsynaptic receptor. In this section we focus in these two models of antibody-mediated disorders of the synapse. As noted above, amphiphysin is an important regulatory endocytic protein involved in several steps of clathrin-mediated endocytosis.
Even though amphiphysin is not essential for vesicle recycling, amphiphysin knockout mice develop severe dysfunction in vesicle recycling and show reduced learning abilities and increased mortality due to irreversible seizures At the cellular level, neurons from these mice exhibit stimulus-dependent slower recycling time of synaptic vesicles and a reduced pool size of vesicles In comparison to the genetic deletion of amphiphysin, acute interference with amphiphysin function by specific antibodies or blocking peptides specifically targeting the SH3 domain in the lamprey giant synapse led to a more severe phenotype in endocytic dysfunction 70 , In these in vitro studies, it has been demonstrated that the SH3 domain but not the central CLAP domain is accessible to antibodies.
The amphiphysin SH3 domain is functionally important because it is the binding part for the interaction with dynamin which mediates the formation of clathrin-coated intermediates during vesicle endocytosis 79 , Interestingly, in patients with stiff-person syndrome, the autoantibodies also specifically target the SH3 domain Passive-transfer experiments with polyclonal IgG fractions and with affinity-purified antibodies from patients with stiff person-syndrome induced some of the characteristic symptoms of the disease in experimental animals , fulfilling the modified Koch-Witebsky postulates for antibody-mediated disease Motor hyperactivity, stiffness, and muscle spasms were observed after systemic administration of high titer amphiphysin antibodies after opening the BBB using a model of mild experimental autoimmune encephalomyelitis induced by adoptive transfer of encephalitogenic T-cells 32 , More specifically, symptoms of muscle hyperactivity along with increased anxiety-related behavior were also obtained in an animal model of repetitive intrathecal application of specific, affinity-purified IgG amphiphysin antibodies via implanted catheters , Super-resolution STED microscopy demonstrated human IgG in subcompartments of spinal presynaptic terminals at the site of vesicle endocytosis and in the vicinity of the active zone of vesicle release.
One of the most potent inhibitory mechanisms in the spinal cord is presynaptic inhibition caused by local GABAergic interneurons last-order GABAergic interneurons. These interneurons form axo-axonal synapses on the presynaptic endings of Ia afferent fibers that project to spinal motor neurons Activation of the GABAa receptors leads to opening of chloride channels and depolarization of the membrane, thereby blocking the invasion of action potentials into the nerve terminals or reducing its amplitude , resulting in a decrease of calcium influx and finally in a reduction of excitatory transmitter release from the Ia afferent terminal onto the motor neuron 76 , This depolarization can be measured by recording voltage changes in a dorsal root dorsal root potentials or indirectly by measuring changes in the modification of the monoynaptic Hoffmann H -reflex Figure In symptomatic animals after intrathecal passive transfer of pathogenic amphiphysin antibodies, in vivo H-reflex and dorsal root potential recording revealed markedly decreased presynaptic inhibition as a consequence of severely affected primary afferent depolarization due to disturbed GABAergic inhibition 77 , , Figure Interestingly, the function of spinal GABAergic interneurons and presynaptic inhibition has also been shown to be affected in patients with stiff-person syndrome examined with H-reflex recordings and reciprocal and vibration-induced modulation of the monosynaptic reflex arc In addition to reduced spinal GABAergic inhibition, there is evidence of decreased supraspinal inhibition as shown by neurophysiological studies including transcranial magnetic stimulation and blink reflex recordings , In vitro experiments with patch-clamp recordings and FM-dye imaging showed deficits in endocytic function in synapses of primary neurons after preincubation with purified human amphiphysin antibodies Figure These deficits were stimulus dependent and more pronounced in GABAergic compared with glutamatergic synapses This is compatible with a hypothesized interaction of autoantibodies with the amphiphysin SH3 domain and interference with amphiphysin binding to partners in the endocytic process that bind to the SH3 domain, such as dynamin In experiments using dynamin deficient neurons, synaptic function is severely impaired upon stimulation leading to an accumulation of plasma membrane invaginations and reduction of the presynaptic vesicle pool Comparing excitatory and inhibitory synapses by electron tomography, dynamin deficiency unmasks a striking heterogeneity between the synaptic subclasses where inhibitory synapses are primarily affected This indicates that inhibitory synapses may be exceptionally vulnerable to deficits in endocytic protein function which is likely due to their higher tonic activity and unmet need for continuous vesicle recycling to build up vesicle pools for proper exocytosis and neurotransmission 80 , Recently, it has been shown that presynaptic vesicle pools and clathrin-coated intermediates are markedly reduced in experimental rats after intrathecal passive-transfer of affinity-purified amphiphysin antibodies Figure 17 In analogy to the above-mentioned findings, neurons with genetic deficiency of endocytic proteins showed prominent defects in presynaptic vesicle endocytosis after sustained stimulation.
In contrast to the depletion induced during sustained stimulation, vesicle pools were even enlarged compared with control animals at resting conditions This is suggestive of a compensatory mechanism to maintain a basal pool of releasable vesicles in vivo that is then exhausted under sustained stimulation and continued synaptic activity.
Supporting this hypothesis, the molecular composition of vesicular proteins is changed in primary GABAergic neurons following incubation with human amphiphyin antibodies Super-resolution direct stochastic optical reconstruction microscopy dSTORM revealed different composition of presynaptic vesicles with v-SNARE proteins, indicating changes in dynamic properties of vesicle pools with reduction of the resting pool vesicles revealed by the presence of synaptobrevin 7 Moreover, long-term application of amphiphysin antibodies to primary neurons over 24 h induced a switch of endocytic pathways from adaptor-protein AP 2-dependent clathrin-mediated endocytosis to the AP3-dependent pathway of vesicle formation from bulk endosomes.
This change in endocytic pathways could be reversed by the use of brefeldin A, a fungal inhibitor that blocks the AP3 dependent pathway , Effects of anti-amphiphysin antibodies on spinal inhibitory pathways. A : spinal reflex pathways of antagonistic muscle groups: afferent fibers project to Ia interneurons gray mediating disynaptic reciprocal inhibition recurrent inhibition by glycinergic transmission onto motor neurons MN supplying antagonistic muscle groups.
In addition, afferents also project to local interneurons via polysynaptic transmission. Last-order interneurons black mediate primary afferent depolarization PAD of afferent fibers by activation of GABAa receptors axo-axonal synapses; presynaptic inhibition. B : examples of Hofmann H -reflex recording at higher frequency 10 Hz after stimulation of a peripheral tibial nerve in rats. The first deflection is the anterograde muscle response M , the second response is the H-reflex after monosynaptic transmission in the spinal cord.
In normal conditions, the H-reflex is fully suppressed at high-frequency simulation green trace. Note that upon long-term intrathecal application of human anti-amphiphysin antibodies, the suppression of the H-reflex is insufficient red trace. C : H-reflex recordings after tibial nerve stimulation together with stimulation of a nerve supplying antagonistic muscles peroneal nerve. Top trace shows simultaneous stimulation, and bottom trace represents recordings with a 50 ms preceding volley of peroneal nerve stimulation resulting in reduction of H-reflex amplitude green traces.
In rats with intrathecal application of anti-amphiphysin antibodies red trace , GABAergic presynaptic inhibition is reduced as shown by absent H-reflex depression after heteronymous stimulation. D : time course of H-reflex inhibition after heteronymous stimulation. Depression of the H-reflex is most pronounced at interstimulus intervals delay of 25— ms demonstrating polysynaptic mechanisms of presynaptic inhibition.
In rats with application of anti-amphiphysin antibodies, H-reflex inhibition is absent. E and F : determination of presynaptic inhibition by in vivo recording of dorsal root potentials dorsal root L5 is cut on one side and afferent volleys are delivered by tibial nerve stimulation. Dorsal root potentials long-lasting upward deflection as shown in F are mediated by presynaptic GABAergic inhibition due to primary afferent depolarization.
Dorsal root potential amplitude is severely reduced in rats after intrathecal treatment with anti-amphiphysin antibodies. Anti-amphiphysin antibodies reduce vesicle release in GABAergic presynaptic terminals. A : vesicles in presynaptic terminals of primary neurons were loaded with FM-dyes white.
Subsequent stimulation results in reduction of fluorescence intensity indicating exocytosis of presynaptic vesicles. B : in control conditions, GABA and glutamatergic terminals of neurons preincubated with control IgG show regular patterns of vesicle release. In neurons pretreated with anti-amphiphysin antibodies, initial fluorescence intensity as a measure for vesicle content is reduced in GABAergic terminals and vesicle release is slowed.
Schematic depicts the situation of reduced vesicle loading in GABAergic synapses that result in reduced synaptic transmission upon stimulation. Proposed model of activity-induced synaptic dysfunction due to amphiphysin antibodies. Antibodies to amphiphysin interact with their target antigen at the step of vesicle recycling A. Binding of antibodies to the amphiphysin SH3 domain blocks the interaction with dynamin and other endocytic proteins right panel in A.
This leads to defective endocytosis with a reduction of clathrin-coated intermediates and subsequently to a reduced number of presynaptic vesicles filled with neurotransmitter and available for exocytosis. Blocking of endocytic function induces an accumulation of adaptor proteins AP2, AP at the cell membrane. B : electron microscopy images of spinal presynaptic boutons light blue of rats after intrathecal passive-transfer of IgG from a healthy subject normal or anti-amphiphysin antibodies and continuous stimulation of Ia afferent fibers.
Vesicle pool and GABA immunoreactivity postembedding immunogold stain, black dots are depleted in the synapse of an animal treated with pathogenic amphiphysin antibodies. Scale bar: nm. Together, the evidence of pathogenic interference of amphiphysin autoantibodies with endocytic function, the unique vulnerability of tonic GABAergic synapses to deficits in clathrin-mediated endocytosis, the transfer of symptoms of stiff-person syndrome upon application of patients' antibodies to experimental animals, and the clinical improvement in patients after antibody removal and immunotherapy , makes this rare enigmatic disease an example of AE likely mediated by autoantibodies against a presynaptic protein Figure Yet, there are several caveats that need to be taken into account when considering amphiphysin antibodies a potential cause of stiff-person syndrome.
First, it is not yet clear how systemic or intrathecal antibodies interact with a presumably intracellular antigen It is conceivable that coexisting neuronal antibodies except for anti-nuclear antibodies contribute to and determine clinical differences among patients.
Fourth, an active immunization model with production of autoantibodies and induction of disease has not yet been developed. The first evidence that intrasynaptically located amphiphysin can be accessed by autoantibodies comes from the observation that intrathecally administered affinity-purified antibodies can be detected in spinal synaptic nerve endings by super-resolution microscopy. These pathogenic IgG antibodies also appear to be internalized in primary neurons in an epitope-specific process as revealed by competition and preabsorption experiments One possible explanation for the ability of autoantibodies to access amphiphysin may be the transient exposure of amphiphysin to the extracellular compartment during the process of vesicle recycling.
Supporting this hypothesis is the demonstration that the carboxy-terminal ending of the vesicular GABA transporter VGAT is facing the luminal side of synaptic vesicles and can be exposed to the extracellular space during vesicle recycling This short episode could be sufficient for specific antibodies to bind and subsequently be internalized in GABAergic nerve endings.
Moreover, this uptake is regulated by synaptic vesicle recycling, thus providing an epitope- and activity-dependent mechanism of specific antibody internalization in neurons. Alternatively, IgG and other macromolecules can also be taken up in a nonspecific manner e. One can also argue that these mechanisms of antibody uptake may be nonpathogenically relevant given that it is unclear how antibodies would avoid degradation in endosomes and lysosomes and reach their intracellular cognate antigen.
When the encephalitis associated with antibodies against NMDA receptor was first described in [GluN1 as the target was not recognized until 60 ], the prevailing concept about most neuronal autoantibodies related to human disease was that they were good biomarkers of the disease but had limited pathogenic relevance.
This idea was supported by multiple failed attempts to demonstrate the pathogenicity of some of these antibodies e. Thus the identification of autoantibodies reacting with the cell surface of live neurons e. Initial studies using dissociated rat hippocampal neurons incubated for 3—7 days with patients' antibodies showed a selective and reversible decrease of NMDA receptor surface density and synaptic localization that correlated with the titers of antibodies present in patients' serum or CSF samples 57 , a reproduction of these findings is shown in Figure These effects were not observed using Fab fragments derived from the autoantibodies, but subsequent crosslinking of the Fab fragments with Fab antibodies recapitulated the antibody-induced reduction of cell surface and synaptic NMDA receptors.
As a result, whole cell patch-clamp recordings of mEPSCs in cultured neurons showed that patients' antibodies specifically decreased synaptic NMDA receptor-mediated currents, without altering the AMPA receptor-mediated currents In contrast to the marked effects on the levels of NMDA receptors, patients' antibodies did not alter other synaptic proteins e.
To determine if the autoantibodies had effects in vivo also, CSF from patients with high-titer GluN1 antibodies or control CSF from individuals without these antibodies was infused directly into the hippocampus of adult rats for 2 wk, followed by analysis of tissue-bound human IgG and levels of NMDA receptors. This pattern was similar to that identified in the hippocampus of two patients who had died of anti-NMDA receptor encephalitis.
Moreover, no neuronal death or deposits of complement were observed, which is also similar to the autopsy findings of the patients even though the autoantibodies are predominantly IgG1 and potentially able to fix complement Overall, results from these studies provided a compelling link between the clinical syndrome and the presence of these antibodies, strongly suggesting they have a pathogenic role in the disease.
For additional information, see Refs. These findings led to the formulation of several interesting questions that were addressed by Moscato et al. For example, the potential different effects of patients' antibodies on inhibitory GAD positive and excitatory GAD negative neurons was investigated in cultured neurons showing that the autoantibodies caused a similar decrease of NMDA receptor density in both types of neurons However, these in vitro data did not rule out that at the circuitry level e.
This hypothesis was investigated in vivo using microdialysis and infusion of patients' antibodies in the CA1 region of hippocampus and premotor cortex of rats. Analysis of microdialysates showed that in the presence of patients' but not control IgG, very high concentrations of glutamate were found in the extracellular space during NMDA infusion This was consistent with dysfunction of the NMDA-related glutamatergic turnover or impaired turnover of receptors, resulting in NMDA-related excitotoxicity.
Concomitant administration of NMDA and AMPA induced a rise in extracellular concentrations of glutamate up to toxic levels, suggesting a potential mechanism of why patients' with persistent, very high levels of CSF antibodies refractory to immunotherapy may develop irreversible deficits or have a fatal outcome Data from these microdialysis studies support the concept that patients' antibodies decrease NMDA receptors and function not only at the postsynaptic level of the glutamatergic synapse but also at the level of inhibitory interneurons, contributing to the hyperglutamatergic state.
The dynamics of antibody-induced internalization of receptors were investigated in cultured neurons exposed for 15 min to 48 h to patients IgG Although a progressive decrease of NMDA receptor density started to be noted 2 h after exposure to the patients' antibodies, the most significant effects were noted at 12 h with no further reduction of NMDA receptors with longer treatment. In parallel, the internalized NMDA receptor clusters followed the same time course.
Similar studies using Fab fragments did not cause significant effects Given that a potential agonistic effect of patient's antibodies could induce internalization by mechanisms independent of crosslinking, similar experiments were conducted in the presence or absence of DLaminophosphonovaleric acid APV , an NMDA receptor blocker. The presence of the blocker did not attenuate the effects of the antibodies, suggesting that the main mechanism of NMDA receptor internalization was due to the effects of receptor crosslinking Further studies using colabeling of internalized antibody-bound NMDA receptors with recycling endosomal and lysosomal biomarkers Rab11, Lamp1 showed that a greater percentage of internalized receptors colocalized with recycling endosomes than lysosomes, similar to the trafficking observed in other conditions e.
Therefore, the postendocytic trafficking did not seem to be affected by antibody binding to the receptor. Another study confirming the antibody-mediated internalization of receptors showed a decrease of total GluN1, suggesting that the internalized receptors were more prone to degradation The hypothesis that patients' antibodies could potentially modulate receptor function independently of their ability to internalize NMDA receptors led to investigations using whole cell patch-clamp recordings of mEPSCs from primary neurons after short exposure 30 min to patients and control CSF.
These studies showed no significant differences between patients' and control CSF, suggesting that the reduction of mEPSCs after prolonged 24 h exposure to patients' antibodies is predominantly due to a decrease of synaptic NMDA receptor density rather than other potential modulatory changes of the receptor by patients' antibodies.
In contrast to these findings, single-channel recordings on HEK cells cotransfected with GluN1 mutants and GluN2B showed that patients' antibodies bound more robustly to GluN1 ATD forms that are prone to more frequent channel opening The data led to studies to explore whether patients' antibodies had an effect on receptor function. No consistent effects on receptor closed time were observed, suggesting that patients' antibodies bind to a receptor that is prone to opening and probably stabilizes the open state Overall, these data suggest that although the main pathogenic effect of patients' antibodies is receptor internalization, these antibodies may also directly affect receptor function.
The question of whether patients' NMDA receptor antibodies caused homeostatic plasticity or synaptic scaling was addressed in cultures of primary neurons determining first a possible upregulation of NMDA receptor transcription after antibody-induced internalization.
Homeostatic plasticity was also assayed in inhibitory synapses in response to NMDA receptor hypofunction caused by patients' antibodies. However, the amplitude and inter-event interval of miniature inhibitory postsynaptic currents mIPSCs were unchanged in cultured neurons treated for 24 h with patients' antibodies, and the gene expression of GAD1 and GAD2 enzymes involved in the synthesis of GABA by inhibitory neurons was also unchanged In contrast, patients' antibodies caused a significant decrease in inhibitory synapse density onto excitatory neurons [demonstrated by a decrease of vesicular GABA transporter VGAT stained presynaptic terminals] Overall, results from these studies suggested a mechanism of synaptic scaling whereby neurons were able to partially adjust their inhibitory tone in a compensatory direction.
Therefore, although a loss of glutamatergic drive to inhibitory GABAergic neurons has been postulated to lead to disinhibition in models of hypofunction of NMDA receptor [e. Other studies conducted by Mikasova et al. These changes were not caused by loss of synaptic contacts, since the overall number of glutamatergic synapses was not affected, consistent with the findings of Hughes et al.
In addition, neurons exposed to patients' CSF antibodies, but not control CSF for 20 h, failed to increase the synaptic content of GluA1-AMPA receptor after undergoing chemically induced LTP , suggesting that patients' antibodies reduced potentiation of glutamatergic synapses. It is interesting and necessary to further investigate how the neural correlation shapes the regulation of irregular neuronal firing by autaptic transmission.
Future work should explore the complicated combination roles of multiple autapses in the modulation of irregular neuronal firing. In conclusion, we have systematically performed mechanistic studies to investigate the functional importance of autaptic transmission in modulating neuronal firing irregularity. Our results showed that both excitatory and electrical autapses subserve the production of burst firing, thus contributing negatively to neuronal firing regularity.
Contrarily, the inhibitory autapse was found to suppress burst firing and therefore improve neuronal firing regularity. These observations established an insightful mechanistic understanding on how different types of autapses shape the irregular firing at the single-neuron level. Notably, we disclosed that these proposed autaptic modulation mechanisms on irregular neuronal firing are general principles, which are applicable to neurons operating in different modes.
Recent fast developments in high-resolution dynamic-clamp and voltage-clamp recording techniques could be utilized to validate testable predictions offered by our model. Finally, we note that as a promising tool the phase response curve can be used to further characterize the complicated dynamical responses of neurons with different types of autapses due to perturbations in future studies 59 , As schematically shown in Fig. The firing dynamics of the postsynaptic neuron is simulated by using the simple model neuron proposed recently by Izhikevich The subthreshold membrane potential of the Izhikevich model neuron obeys the following two differential equations 35 :.
This choice corresponds to a neuron working as integrator and exhibiting class I excitability Note that the main results shown in this study are obtained using the class I neuron. In additional simulations, we demonstrate the similar results can be also observed for class II resonator and class III coincidence detector neurons In our study, each presynaptic neuron is assumed to be a simple spike generator and emits spikes in an independent Poisson fashion with the same input rate f in in Hz.
Otherwise, these two parameters decay exponentially as follows:. Note that two synaptic variables W ex and W inh are relative peak conductances of excitatory and inhibitory presynapses that determine their coupling strengths. In the following simulations, we fix the value of W ex and set. Under this condition, the received excitation and inhibition of the postsynaptic neuron from its presynaptic neurons are theoretically perfect balanced. In the present study, we consider both chemical and electrical autaptic connections.
Depending on the type of postsynaptic neuron, the chemical autapse is either excitatory or inhibitory in our model. Moreover, the autapse might be mediated via gap junction electrical autapse for inhibitory postsynaptic neuron, modelled as follows:. We employ several data analysis techniques to quantitatively evaluate the spike trains generated by our model.
To characterize the temporal regularity of spike trains, the coefficient of variation CV of inter-spike intervals ISIs is utilized. Mathematically, the coefficient of variation of ISIs is defined as 36 :. By definition, increased CV ISI reflects an increased interval-to-interval variability and thus a decreased regularity of neuronal firing.
Throughout our studies, the reported CV ISI values are averaged over 50 independent trials with different random seeds. In some cases, we estimate the probability distribution curve of ISIs. For each experimental setting, the ISI distribution curve is obtained based on 10 5 firing events. Statistically, we note that burst firing can be well identified provided that a short and noticeable ISI peak appears in the ISI distribution curve.
To further evaluate the intrinsic properties of burst firing, we perform further statistical analysis on both burst frequency and size for several recording data. To evaluate the contribution of self-feedback input to the total synaptic current, we compute the contribution factors for both the excitatory and inhibitory autaptic currents in this study.
As a dimensionless measure, the contribution factor CF is calculated as follows:. A larger CF value corresponds to a greater contribution of self-feedback input to the total synaptic current. The chosen integration time step is demonstrated to be small enough to ensure an accurate simulation of the Izhikevich model neuron.
How to cite this article : Guo, D. Destexhe, A. Neuronal Noise Springer, Balenzuela, P. Role of chemical synapses in coupled neurons with noise. E 72, ADS Google Scholar. Zaikin, A. Doubly stochastic coherence via noise-induced symmetry in bistable neural models. Zhou, C. Noise-induced synchronization and coherence resonance of a Hodgkin-Huxley model of thermally sensitive neurons.
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Ozer, M. Controlling the spontaneous spiking regularity via channel blocking on Newman-Watts networks of Hodgkin-Huxley neurons. Kreuz, T. Double coherence resonance in neuron models driven by discrete correlated noise. Luccioli, S. Dynamical response of the Hodgkin-Huxley model in the high-input regime. E 73 4 , Manjarrez, E. Internal stochastic resonance in the coherence between spinal and cortical neuronal ensembles in the cat. Haider, B.
Neocortical network activity in vivo is generated through a dynamic balance of excitation and inhibition. Higley, M. Balanced excitation and inhibition determine spike timing during frequency adaptation. Marino, J. Invariant computations in local cortical networks with balanced excitation and inhibition. Shadlen, M. The variable discharge of cortical neurons: Implications for connectivity, computation and information Coding.
Self-Sustained irregular activity in 2-D small-world networks of excitatory and inhibitory neurons. IEEE Trans. Bacci, A. Functional autaptic neurotransmission in fast-spiking interneurons: A novel form of feedback inhibition in the neocortex. Massive autaptic self-innervation of GABAergic neurons in cat visual cortex. PubMed Google Scholar. Frequency and dendritic distribution of autapses established by layer 5 pyramidal neurons in the developing rat neocortex: comparison with synaptic innervation of adjacent neurons of the same class.
Park, M. Recurrent inhibition in the rat neostriatum. Brain Res. Karabelas, A. Evidence for autapses in the substantia nigra. Cobb, S. Synaptic effects of identified interneurons innervating both interneurons and pyramidal cells in the rat hippocampus. Yamaguchi, K. In Encyclopedia of Neuroscience eds Binder, M. Enhancement of spike-timing precision by autaptic transmission in neocortical inhibitory interneurons.
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Autapse-induced spiral wave in network of neurons under noise. Enhancement of synaptic transmission by HPC-1 antibody in the cultured hippocampal neuron. NeuroReport 8 16 , — Izhikevich, E. Simple model of spiking neurons. Koch, C. MIT Press, Stochastic resonance in Hodgkin-Huxley neuron induced by unreliable synaptic transmission.
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E 82 5 , Perez Velazquez, J. Phase response curves in the characterization of epileptiform activity. E 76 6 , Download references. You can also search for this author in PubMed Google Scholar. This work is licensed under a Creative Commons Attribution 4. Reprints and Permissions. Sci Rep 6, Download citation. Received : 14 February Accepted : 27 April Published : 17 May Anyone you share the following link with will be able to read this content:.
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Download PDF. Subjects Biological physics Computational science Networks and systems biology Nonlinear phenomena. Abstract The importance of self-feedback autaptic transmission in modulating spike-time irregularity is still poorly understood. Introduction Without doubt cortical neurons operate in noisy environments 1. Figure 1. Schematic description of the computational model. Full size image. Results We firstly consider a single Izhikevich neuron with calss I excitability 35 and examine how purely presynaptic bombardment controls its firing irregularity.
Presynaptic bombardment controls irregular neuronal firing and triggers coherence resonance We begin by examining how the presynaptic bombardment modulates the firing regularity of the considered model neuron 15 , 16 , Figure 2. Presynaptic bombardment contributes to the modulation of neuronal firing irregularity. Figure 3. Roles of chemical autapses in modulating irregular neuronal firing. Figure 4. Figure 5. Figure 6. Effect of electrical autapse in modulating irregular neuronal firing.
Figure 7. Autaptic transmission delay participates into the modulation of irregular neuronal firing. Figure 8. Discussion Cortical neurons have been observed to discharge highly irregular, seemingly random, action potentials in vivo 6 , 7 , 8.
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The relationship between the level of stimulation and the production of a neural impulse is called the all or none principle. Once triggered, the action potential continues the length of the axon without diminishing because the action potential depends upon cell membrane permeability, a cell characteristic, and not upon the strength of the triggering stimulus.
After the action potential occurs, however, there is a short period of refractoriness , which affects neuron firing. During the first part of the refractory period the absolute refractory period , the neuron will not fire again no matter how great the stimulation. The absolute refractory period lasts for only a short time. It is followed by the relative refractory period , during which a stronger than usual stimulus is required to trigger the action potential before the neuron returns to resting state.
After the refractory period, the neuron will fire when the neural threshold is reached. Synaptic transmission. The synapse is the name given the junction between neurons where information is exchanged. The action potential causes information to be transmitted from the axon of the first neuron presynaptic neuron to the dendrites or cell body of the second neuron postsynaptic neuron by secretion of chemicals called neurotransmitters.
Neurotransmitters are stored in small containers vesicles located in knoblike structures terminal buttons on the axon tips. The axon of the presynaptic neuron does not actually touch the dendrites of the postsynaptic neuron and is separated from them by a space called the synaptic cleft.
Stimulation of the presynaptic neuron to produce an action potential causes the release of neurotransmitters into the synaptic cleft. Most of the released neurotransmitters bind with molecules at special sites, receptors , on the dendrites of the postsynaptic neuron. Molecules of the neurotransmitter that do not bind to receptors in the postsynaptic neuron are taken up again by the presynaptic neuron, a process called reuptake.
The combination of the neurotransmitter molecules to receptor cell molecules in the postsynaptic cell membrane produces a change of potential in the postsynaptic cell membrane called the postsynaptic potential PSP. The PSP allows ions to enter or leave the cell membrane of the postsynaptic neuron. The ionic movements increase or decrease the probability of a neural impulse occurring in the postsynaptic neuron.
Many drugs, both therapeutic and recreational, work by affecting the level of neurotransmitters the chemicals released at the axon terminal buttons of the presynaptic neuron , and some disorders are associated with neurotransmitter deficiencies or excesses. Neurotransmitters are of several types:. Acetylcholine occurs throughout the nervous system and is the only neurotransmitter found in synapses between motor neurons and voluntary muscle cells.
Degeneration of cells producing acetylcholine is associated with Alzheimer's disease. Biogenic amines include three neurotransmitters: norepinephrine, dopamine , and serotonin. Dopamine modulates release from corticostriatal terminals.
Journal of Neuroscience, 24 43 , Maejima, T. Presynaptic inhibition caused by retrograde signal from metabotropic glutamate to cannabinoid receptors. Neuron, 31 3 , Melis, M. Endocannabinoids mediate presynaptic inhibition of glutamatergic transmission in rat ventral tegmental area dopamine neurons through activation of CB1 receptors.
Journal of Neuroscience, 24 1 , Nadim, F. Neuromodulation of neurons and synapses. Current opinion in neurobiology, 29, Wu, L. Presynaptic inhibition of elicited neurotransmitter release. Trends in neurosciences, 20 5 , Sign up to join this community. The best answers are voted up and rise to the top. Stack Overflow for Teams — Start collaborating and sharing organizational knowledge. Create a free Team Why Teams? Learn more. Understanding presynaptic and postsynaptic inhibition Ask Question.
Asked 2 years, 10 months ago. Modified 2 years, 9 months ago. Viewed times. As far as I understand, the two different types of inhibition refer to the following: Presynaptic inhibition : A neuron N1 is inhibited "indirectly" insofar as the presynaptic excitatory neuron's action on it are dampened.
My questions: 1 When we speak of "inhibitory post-synaptic potentials" IPSPs , is this hence always in the context of post-synaptic inhibition? Improve this question. Pugl Pugl 1 1 silver badge 11 11 bronze badges. Add a comment. Sorted by: Reset to default. Highest score default Date modified newest first Date created oldest first. Interneurons vs inhibitory cells Inhibitory interneurons are a major class of interneuron in the neocortex, but not all interneurons are inhibitory layer 4 spiny stellate cells, for example, are excitatory interneurons.
Sources of pre-synaptic inhibition In general because there may be exceptions, and almost certainly are in invertebrates who have very "weird" nervous systems from my mammal-biased worldview , presynaptic inhibition arises from three places: autoreceptors self receptors , retrograde signalling from post-synaptic cells, and neuromodulation. One could fill textbooks with information on all the mechanisms, but I'll give one example of each of the three types: Autoreceptors Glutamatergic synapses, for example, can have pre-synaptic inhibitory metabotropic glutamate receptors.
Pre-synaptic inhibition by neuromodulators Pre-synaptic cells can also be affected by local concentrations of neuromodulators, like dopamine Bamford et al Improve this answer. In this manner, the postsynaptic neuron is stimulated less when its presynaptic excitatory neuron is inhibited, and the presynaptic inhibition is a network effect?
It's presynaptic to the final cell that you are calling "postsynaptic", but it's post-synaptic to your inhibitory neuron. And that's a great and very concise definition you gave. Sign up or log in Sign up using Google. Sign up using Facebook.
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