D M Kullmann

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..As new forms of LTP are discovered at different synapses, a simple resolution of the pre- versus postsynaptic debate seems increasingly remote...

..This review examines recent progress in understanding how different hippocampal interneuron networks contribute to feedback and feed-forward inhibition at different timescales...

..This constitutes a mechanism for flexible signal routing in neural circuits, which exploits sparsely synchronized network oscillations and temporal filtering by feed-forward inhibition...

..Tonic signalling appears to be mediated by extrasynaptic receptors. The adaptive significance of this form of signalling remains poorly understood...

..This review summarises the clinical features of the known neurological channelopathies, within the context of the functions of the individual ion channels...

..The next decade will likely reveal whether these or related genes also act as susceptibility factors for sporadic epilepsy...

..This article is part of a Special Issue entitled 'Synaptic Plasticity & Interneurons'...

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..Some aspects of the early stages of LTP expression remain open to alternative explanations...

..Here we highlight some unanswered questions, and some promising areas for research that will likely lead to a fuller understanding of the link from molecular lesion to disease...

..This study addresses the modulation of GABA release from interneuron terminals by presynaptic glutamate receptors...

..Future developments are likely to include the discovery of other ion channel genes associated with inherited and sporadic CNS disorders. The full range of manifestations of inherited ion channel mutations remains to be established...

..As for group I metabotropic glutamate receptors, their role in anti-Hebbian LTP is permissive at the very least in some interneuron types, although an instructive role has been suggested in other forms of activity-dependent plasticity...

..Because synaptically released glutamate mimics many of the actions of exogenous agonists, presynaptic kainate receptors potentially play an extensive role in hippocampal signaling...

..We further discuss how the remarkable plasticity of glutamatergic synapses on interneurons greatly enhances the computational capacity of the cortical microcircuit...

..Thus, KAR-Ca(2+) store coupling acts as a synapse-specific, short-range autoreceptor mechanism...

..Anti-Hebbian LTP may occur in interneurons that are silent during periods of intense pyramidal cell firing, such as sharp waves, and lead to their altered activation during theta activity...

..The presence of relatively picrotoxin-resistant GABA(A) receptors in interneurons provides a potential target for agents to modulate the activity of sub-populations of hippocampal neurons...

..One of the mutations was also found in a distantly related family, providing evidence of the influence of genetic background on the EA1 phenotype...

..GABAergic transmission from the dentate gyrus to CA3 has major implications not only for information flow into the hippocampus but also for developmental and pathological processes involving the hippocampus...

..The relative contribution of these components changes after the induction of epilepsy, implying an adaptive plasticity of the tonic current in the presence of spontaneous seizures...

..Axonal receptors are thus important in initiating the intense interneuronal activity triggered by kainate, which in turn influences inhibitory signaling to principal cells...

..Glutamatergic synapses on O-LM cells thus behave in a homogeneous manner and exhibit LTP dependent on Ca(2+)-permeable AMPA receptors...

..Reducing the tonic conductance in interneurons enhanced their excitability and the inhibitory drive to pyramidal cells. These results point to a role for cell type-dependent tonic inhibition in regulating cortical excitability...

..These NMDAR isoforms thus play complementary roles in sensing global and local glutamate signals, respectively...

..Failure of GABA(B) receptor-mediated modulation of mossy fiber transmission at mossy fibers may contribute to the development of spontaneous seizures after status epilepticus...

..We propose that Hebbian LTP at synapses driving disynaptic inhibition is necessary to maintain information processing without degradation during memory encoding...

..Enhanced glutamatergic transmission and the emergence of cross-talk among perforant path-dentate granule cell synapses may contribute to lowering seizure threshold...

..Voltage-dependent temporal tuning of excitatory synaptic responses may thus contribute to signal integration in neural circuits...

..Antibodies against the alpha2 subunit of GABAA receptors stain mossy fibers. Axonal GABAA receptors thus play a potentially important role in tonic and activity-dependent heterosynaptic modulation of information flow to the hippocampus...

..Standard DNA sequencing methods may miss large scale genetic rearrangements such as deletions and duplications. The authors investigated whether large scale genetic rearrangements in CACNA1A can cause EA2 and FHM1...

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..Our data suggest that functional stratification of all variants, including common polymorphisms, rare variants and novel mutations, may provide new insights into the mechanisms of channelopathies...

..This heterosynaptic modulation is amplified by blocking cholinesterases. These results reveal a novel mechanism by which cholinergic neurons modulate information processing in the hippocampus...

..Blocking GABA(A)Rs also interfered with the induction of long-term potentiation at mossy fiber-CA3 synapses. Presynaptic GABA(A)Rs therefore facilitate information flow to the hippocampus both directly and by enhancing LTP...

..INTERPRETATION: Human absence epilepsy can be associated with dysfunction of the brain P/Q-type voltage-gated Ca(2+) channel. The phenotype in this patient has striking parallels with the mouse absence epilepsy models...

..New data suggest that distinct effects on integration of excitatory inputs by cerebellar granule cells might result from different modes of signaling by individual interneurons...

..The clinical, genetic and electrophysiological features of EA1 and EA2 are outlined, and a protocol for the assessment of these patients is proposed...

..1 dysfunction in patients with episodic ataxia type 1. The simple 15 min test may be useful in diagnosis, since it can differentiate patients with episodic ataxia type 1 from normal controls with high sensitivity and specificity...

..The purpose of this review is to present physiologic evidence of GABA release by mossy fibers and its modulation by epileptic activity...

..granulosum of the dentate gyrus (to recruit mossy fibers). These results show for the first time that GABAergic IPSCs can be modulated by endogenous Zn(2+) and are consistent with GABA release at Zn(2+)-containing mossy fiber synapses...

..Glutamatergic modulation of GABA release from individual synapses thus depends on the co-occurrence of presynaptic N-type Ca2+ channels and the target cell-dependent expression of group III mGluRs...

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..The results suggest that non-alpha Ca(2+)/calmodulin-dependent kinases substitute for the alpha isoform in NMDA receptor-dependent LTP in interneurons...

..The relationship between this apparent depression and the interstimulus interval provides a window on the kinetics of state transitions of the release apparatus...

..Indeed, a resolution of the mechanisms by which both diseases occur will represent a major milestone in understanding diseases of the CNS, in addition to opening the way to novel possible treatments...

..Several missense mutations of CACNA1S and SCN4A genes occur in hypokalemic periodic paralysis. These mutations affect arginine residues in the S4 voltage sensors of the channel. Approximately 20% of cases remain genetically undefined...

..We conclude that depolarization-dependent modulation of transmission at these boutons does not rely on changes in presynaptic Ca2+...

..Two other mutations associated with a severe phenotype (T226R, A242P) yielded an intermediate result. The phenotypic variability of KCNA1 mutations is reflected in a wide range of disorders of channel assembly, trafficking and kinetics...

..Molecular expression revealed evidence of impaired calcium channel function, suggesting that genetically induced reduction in calcium channel function may associate with cases of late-onset EA2...

..The results provide direct evidence that EA1 mutations increase neurotransmitter release, and provide an insight into mechanisms underlying the phenotypic differences that are associated with different mutations...

..Thus, an effective loss of functional GlyRalpha1-mediated current underlies hyperekplexia in this family, whereas a partial loss is asymptomatic...

..The effects of sex hormones are likely to be non-genomic because of their speed of onset and reversibility. These results suggest a possible mechanism to explain how the severity of myotonia congenita can be modulated by sex hormones...

..1 may have a central role in the pathogenesis of certain cases of primary generalized epilepsy, particularly when associated with ataxia, which may be wrongly ascribed to anticonvulsant medication...

..Four patients, who only had temporal lobe epilepsy without oligoclonal bands, may represent restriction to the first stage...

..1-mediated current. Because these mutations do not affect the alternate exon 37B, these findings reveal unexpected dependence of cerebellar function on intact exon 37A-containing Ca(V)2.1 channels...

..This review examines our current understanding of episodic ataxia type 1, focusing on its clinical and genetic features, pathophysiology, and treatment...

..To report the occurrence of an unusual neurologic disorder requiring admission to the intensive care unit...

..These results provide further evidence for GABA and glutamate cotransmission at mossy fibre synapses, although paired pre- and post-synaptic recordings will be required to determine the role of GABA at this unusual synapse...

..Furthermore, EA1 mutations alter heteromeric channel availability which probably modifies the integration properties and firing patterns of neurones controlling cognitive processes and body movements...