Until recently, the study of plasticity of neural circuits focused almost exclusively on potentiation and depression at excitatory synapses on principal cells. Other elements in the neural circuitry, such as inhibitory synapses on principal cells and the synapses recruiting interneurons, were assumed to be relatively inflexible, as befits a role of inhibition in maintaining stable levels and accurate timing of neuronal activity. It is now evident that inhibition is highly plastic, with multiple underlying cellular mechanisms. This Review considers these recent developments, focusing mainly on functional and structural changes in GABAergic inhibition of principal cells and long-term plasticity of glutamateric recruitment of inhibitory interneurons in the mammalian forebrain. A major challenge is to identify the adaptive roles of these different forms of plasticity, taking into account the roles of inhibition in the regulation of excitability, generation of population oscillations, and precise timing of neuronal firing.

Focal epilepsy is commonly pharmacoresistant, and resective surgery is often contraindicated by proximity to eloquent cortex. Many patients have no effective treatment options. Gene therapy allows cell-type specific inhibition of neuronal excitability, but on-demand seizure suppression has only been achieved with optogenetics, which requires invasive light delivery. Here we test a combined chemical–genetic approach to achieve localized suppression of neuronal excitability in a seizure focus, using viral expression of the modified muscarinic receptor hM4Di. hM4Di has no effect in the absence of its selective, normally inactive and orally bioavailable agonist clozapine-N-oxide (CNO). Systemic administration of CNO suppresses focal seizures evoked by two different chemoconvulsants, pilocarpine and picrotoxin. CNO also has a robust anti-seizure effect in a chronic model of focal neocortical epilepsy. Chemical–genetic seizure attenuation holds promise as a novel approach to treat intractable focal epilepsy while minimizing disruption of normal circuit function in untransduced brain regions or in the absence of the specific ligand.

It has been suggested that a functional deficit in NMDA-receptors (NMDARs) on parvalbumin (PV)-positive interneurons (PV-NMDARs) is central to the pathophysiology of schizophrenia. Supportive evidence come from examination of genetically modified mice where the obligatory NMDAR-subunit GluN1 (also known as NR1) has been deleted from PV interneurons by Cre-mediated knockout of the corresponding gene Grin1 (Grin1ΔPV mice). Notably, such PV-specific GluN1 ablation has been reported to blunt the induction of hyperlocomotion (a surrogate for psychosis) by pharmacological NMDAR blockade with the non-competitive antagonist MK-801. This suggests PV-NMDARs as the site of the psychosis-inducing action of MK-801. In contrast to this hypothesis, we show here that Grin1ΔPV mice are not protected against the effects of MK-801, but are in fact sensitized to many of them. Compared with control animals, Grin1ΔPVmice injected with MK-801 show increased stereotypy and pronounced catalepsy, which confound the locomotor readout. Furthermore, in Grin1ΔPVmice, MK-801 induced medial-prefrontal delta (4 Hz) oscillations, and impaired performance on tests of motor coordination, working memory and sucrose preference, even at lower doses than in wild-type controls. We also found that untreated Grin1ΔPVmice are largely normal across a wide range of cognitive functions, including attention, cognitive flexibility and various forms of short-term memory. Taken together these results argue against PV-specific NMDAR hypofunction as a key starting point of schizophrenia pathophysiology, but support a model where NMDAR hypofunction in multiple cell types contribute to the disease.

Synaptotagmin 1 (Syt1) synchronizes neurotransmitter release to action potentials (APs) acting as the fast Ca 2+ release sensor and as the inhibitor (clamp) of spontaneous and delayed asynchronous release. While the Syt1 Ca 2+ activation mechanism has been wellcharacterized, how Syt1 clamps transmitter release remains enigmatic. Here we show that C2B domain-dependent oligomerization provides the molecular basis for the Syt1 clamping function. This follows from the investigation of a designed mutation (F349A), which selectively destabilizes Syt1 oligomerization. Using a combination of fluorescence imaging and electrophysiology in neocortical synapses, we show that Syt1 F349A is more efficient than wild-type Syt1 (Syt1 WT ) in triggering synchronous transmitter release but fails to clamp spontaneous and synaptotagmin 7 (Syt7)-mediated asynchronous release components both in rescue (Syt1 −/− knockout background) and dominant-interference (Syt1 +/+ background) conditions. Thus, we conclude that Ca 2+ -sensitive Syt1 oligomers, acting as an exocytosis clamp, are critical for maintaining the balance among the different modes of neurotransmitter release. synaptic transmission | synaptotagmin | C2B domain | fusion clamp T ightly regulated synaptic release of neurotransmitters forms the basis of neuronal communication in the brain. Synaptotagmin 1 (Syt1) plays a key role in this process, both as the major Ca 2+ sensor for fast synchronous action potential (AP)-evoked transmitter release and as an inhibitor of spontaneous and delayed evoked asynchronous release. Syt1 is an integral membrane protein of synaptic vesicles containing a large cytosolic part composed of 2 tandemly arranged Ca 2+ -binding C2 domains (C2A and C2B). The C2B domain also binds SNARE (soluble Nethylmaleimide-sensitive factor attachment protein receptor) complexes and acidic lipids on the presynaptic membrane, and thus supports the generation and maintenance of the readily releasable pool (RRP) of vesicles docked at the synaptic active zone (1-3). Action potential-evoked depolarization triggers opening of presynaptic voltage-gated Ca 2+ channels, resulting in a transient and spatially restricted increase of [Ca 2+ ] at the vesicular release sites. Upon Ca 2+ binding, the adjacent aliphatic loops on Syt1 C2 domains insert into the presynaptic membrane and this triggers rapid (submillisecond timescale) fusion of RRP vesicles (4, 5).In physiological conditions, Syt1 also acts as a suppressor (or "clamp") of spontaneous transmitter release (that occurs in the absence of neuronal spiking) and of the delayed lasting increase in vesicular exocytosis that follows APs (asynchronous release). Indeed, at many synapses, genetic deletion of Syt1 not only abolishes the fast synchronous release component but also leads to a severalfold enhancement of spontaneous and asynchronous release (6-8). Similarly, deletion of the SNARE-binding presynaptic protein complexin partially abrogates the clamping phenotype, suggesting that a synergistic action of both Syt1 and complex...

Synaptotagmin1 (Syt1) synchronises neurotransmitter release to action potentials acting as the fast Ca 2+ release sensor and as the inhibitor (clamp) of spontaneous and delayed asynchronous release. Whilst the Syt1 Ca 2+ activation mechanism has been well characterised, how Syt1 clamps transmitter release remains enigmatic. Here we show that C2B domain-dependent oligomerisation provides the molecular basis for the Syt1 clamping function. This follows from the investigation of a designed mutation (F349A), which selectively destabilises Syt1 oligomerisation. Using combination of fluorescence imaging and electrophysiology in neocortical synapses we show that Syt1 F349A is more efficient than wild type Syt1 (Syt1 WT ) in triggering synchronous transmitter release but fails to clamp spontaneous and Synaptotagmin7 (Syt7)-mediated asynchronous release components both in rescue (Syt1 -/knock-out background) and dominant-interference (Syt1 +/+ background) conditions. Thus we conclude that Ca 2+ -sensitive Syt1 oligomers, acting as an exocytosis clamp, are critical for maintaining the balance among the different modes of neurotransmitter release.

Several types of hippocampal interneurons exhibit a form of long-term potentiation (LTP) that depends on Ca2+-permeable AMPA receptors and group I metabotropic glutamate receptors. Several sources of evidence point to a presynaptic locus of LTP maintenance. The retrograde factor that triggers the expression of LTP remains unidentified. Here, we show that trains of action potentials in putative oriens-lacunosum-moleculare interneurons of the mouse CA1 region can induce long-lasting potentiation of stimulus-evoked excitatory postsynaptic currents that mimics LTP elicited by high-frequency afferent stimulation. We further report that blockers of nitric oxide production or TRPV1 receptors failed to prevent LTP induction. The present results add to the evidence that retrograde signalling underlies N-methyl-d-aspartate (NMDA) receptor-independent LTP in oriens interneurons, mediated by an unidentified factor.

Key points Regular‐spiking interneurons in the hippocampal stratum oriens exhibit a form of long‐term potentiation of excitatory transmission that is independent of NMDA receptors but requires co‐activation of Ca2+‐permeable AMPA receptors and group I metabotropic glutamate receptors.We show that T‐type Ca2+ channels are present in such interneurons.Blockade of T‐type currents prevents the induction of long‐term potentiation, and also interferes with long‐lasting potentiation induced either by postsynaptic trains of action potentials or by pairing postsynaptic hyperpolarization with activation of group I metabotropic receptors.Several Ca2+ sources thus converge on the induction of NMDA receptor independent synaptic plasticity. AbstractNMDA receptor independent long‐term potentiation (LTP) in hippocampal stratum oriens‐alveus (O/A) interneurons requires co‐activation of postsynaptic group I metabotropic glutamate receptors (mGluRs) and Ca2+‐permeable AMPA receptors. The rectification properties of such AMPA receptors contribute to the preferential induction of LTP at hyperpolarized potentials. A persistent increase in excitatory transmission can also be triggered by exogenous activation of group I mGluRs at the same time as the interneuron is hyperpolarized, or by postsynaptic trains of action potentials in the absence of presynaptic stimulation. In the present study, we identify low‐threshold transient (T‐type) channels as a further source of Ca2+ that contributes to synaptic plasticity. T‐type Ca2+ currents were detected in mouse regular‐spiking O/A interneurons. Blocking T‐type currents pharmacologically prevented LTP induced by high‐frequency stimulation of glutamatergic axons, or by application of the group I mGluR agonist dihydroxyphenylglycine, paired with postsynaptic hyperpolarization. T‐type current blockade also prevented synaptic potentiation induced by postsynaptic action potential trains. Several sources of Ca2+ thus converge on NMDA receptor independent LTP induction in O/A interneurons.

Switches between global sleep and wakefulness states are believed to be dictated by top-down influences arising from subcortical nuclei. Using forward genetics and in vivo electrophysiology, we identified a recessive mouse mutant line characterized by a substantially reduced propensity to transition between wake and sleep states with an especially pronounced deficit in initiating rapid eye movement (REM) sleep episodes. The causative mutation, an Ile102Asn substitution in the synaptic vesicular protein, VAMP2, was associated with morphological synaptic changes and specific behavioral deficits, while in vitro electrophysiological investigations with fluorescence imaging revealed a markedly diminished probability of vesicular release in mutants. Our data show that global shifts in the synaptic efficiency across brain-wide networks leads to an altered probability of vigilance state transitions, possibly as a result of an altered excitability balance within local circuits controlling sleep-wake architecture.