Control of aversion by glycine-gated GluN1/GluN3A NMDA receptors in the adult medial habenula.

The unconventional N-methyl-d-aspartate (NMDA) receptor subunits GluN3A and GluN3B can, when associated with the other glycine-binding subunit GluN1, generate excitatory conductances purely activated by glycine. However, functional GluN1/GluN3 receptors have not been identified in native adult tissues. We discovered that GluN1/GluN3A receptors are operational in neurons of the mouse adult medial habenula (MHb), an epithalamic area controlling aversive physiological states. In the absence of glycinergic neuronal specializations in the MHb, glial cells tuned neuronal activity via GluN1/GluN3A receptors. Reducing GluN1/GluN3A receptor levels in the MHb prevented place-aversion conditioning. Our study extends the physiological and behavioral implications of glycine by demonstrating its control of negatively valued emotional associations via excitatory glycinergic NMDA receptors.

The properties of reticular thalamic neuron GABA(A) IPSCs of absence epilepsy rats lead to enhanced network excitability.

Both human investigations and studies in animal models have suggested that abnormalities in GABA(A) receptor function have a potential role in the pathophysiology of absence seizures. Recently we showed that, prior to seizure onset, GABA(A) IPSCs in thalamic reticular (NRT) neurons of genetic absence epilepsy rats from Strasbourg (GAERS) had a 25% larger amplitude, a 40% faster decay and a 45% smaller paired-pulse depression than those of nonepileptic control (NEC) rats. By means of a novel mathematical description, the properties of both GAERS and NEC GABAergic synapses can be mimicked. These model synapses were then used in an NRT network model in order to investigate their potential impact on the neuronal firing patterns. Compared to NEC, GAERS NRT neurons show an overall increase in excitability and a higher frequency and regularity of firing in response to periodic input signals. Moreover, in response to randomly distributed stimuli, the GAERS but not the NEC model produces resonance between 7 and 9 Hz, the frequency range of spike-wave discharges in GAERS. The implications of these results for the epileptogenesis of absence seizures are discussed.

Modulation of neuronal T-type calcium channels.

As T-type calcium channels open near resting membrane potential and markedly influence neuronal excitability their activity needs to be tightly regulated. Few neuronal T-current regulations have been described so far, but interestingly some of them involve unusual mechanisms like G protein-independent but receptor-coupled modulation, while the use of recombinant channels has established both a direct action of Gbetagamma subunits, anandamide, arachidonic acid and a phosphorylation process by CaMKII. Nearly all reported types of modulation involve Cav3.2 channels while no regulation of Cav3.1 has been reported, a difference that may originate from diversities in the intracellular loop connecting the II and III domains of the two isotypes. The search for T-current regulators requires taking into account their peculiar activation properties, since a close link may exist between the channel conformation and its modulation. Indeed, in thalamocortical neurons a phosphorylation-mediated regulation of the amplitude of the T-current has been shown to be highly dependent upon the state of the channel and only to become apparent when the channels are in the voltage range close to neuronal resting membrane potential.