Low-threshold (T-type) Ca2+ channels encoded by the Ca V 3 genes endow neurons with oscillatory properties that underlie slow waves characteristic of the non-rapid eye movement (NREM) sleep EEG. Three Ca V 3 channel subtypes are expressed in the thalamocortical (TC) system, but their respective roles for the sleep EEG are unclear. Ca V 3.3 protein is expressed abundantly in the nucleus reticularis thalami (nRt), an essential oscillatory burst generator. We report the characterization of a transgenic Ca V 3.3 −/− mouse line and demonstrate that Ca V 3.3 channels are indispensable for nRt function and for sleep spindles, a hallmark of natural sleep. The absence of Ca V 3.3 channels prevented oscillatory bursting in the lowfrequency (4-10 Hz) range in nRt cells but spared tonic discharge. In contrast, adjacent TC neurons expressing Ca V 3.1 channels retained low-threshold bursts. Nevertheless, the generation of synchronized thalamic network oscillations underlying sleep-spindle waves was weakened markedly because of the reduced inhibition of TC neurons via nRt cells. T currents in Ca V 3.3 −/− mice were <30% compared with those in WT mice, and the remaining current, carried by Ca V 3.2 channels, generated dendritic [Ca 2+ ] i signals insufficient to provoke oscillatory bursting that arises from interplay with Ca 2+ -dependent small conductance-type 2 K + channels. Finally, naturally sleeping Ca V 3.3 −/− mice showed a selective reduction in the power density of the σ frequency band (10-12 Hz) at transitions from NREM to REM sleep, with other EEG waves remaining unaltered. Together, these data identify a central role for Ca V 3.3 channels in the rhythmogenic properties of the sleep-spindle generator and provide a molecular target to elucidate the roles of sleep spindles for brain function and development.2+ channels encoded by the Ca V 3 genes activate near resting membrane potentials and generate low-threshold Ca 2+ spikes leading to burst firing and low-frequency oscillatory discharge that are prominent in some thalamic, olivary, and cerebellar neurons (1). Among the low-threshold Ca 2+ currents carried by Ca V 3 channels, those mediated by Ca V 3.3 channels are unique in that they display the slowest time course, the fastest recovery from inactivation, and often the most depolarized activation voltages (2, 3). Moreover, Ca V 3.3 mRNA is expressed predominantly in brain and shows highest regional specificity (3-5). To date, identification of specific physiological roles for Ca V 3.3 channels has been hampered for several reasons. First, these channels typically are coexpressed with Ca V 3.1 and/or Ca V 3.2 channels (4, 5), and specific pharmacological tools are not available (1). Second, Ca V 3.3 channels often are found in distal dendrites, limiting accessibility for electrophysiological characterization (6, 7). Finally, Ca V 3.3 −/− mice have not been reported, whereas Ca V 3.1 −/− and Ca V 3.2 knockdown mice have helped address the roles of Ca V 3.1 and Ca V 3.2 channels in sleep and pain, respectively (8-10)...

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Dual metabotropic glutamate 2/3 (mGlu2/3) receptor agonists have been examined with success in the clinic with positive proof of efficacy in several tests of anxiety and schizophrenia. Moreover, a large body of evidence has accumulated that these drugs have significant neuroprotective potential. An important discussion in the field deals with dissecting effects on mGlu2 versus effects on mGlu3 receptors, which is relevant for the potential use of subtype-selective agonists or allosteric activators. We addressed this issue using mGlu2 and mGlu3 receptor knock-out mice. We used mixed cultures of cortical cells in which astrocytes and neurons were plated at different times and could therefore originate from different mice. Cultures were challenged with NMDA for the induction of excitotoxic neuronal death. The mGlu2/3 receptor agonist, (Ϫ)-2-oxa-4-aminocyclo[3.1.0]hexane-4,6-dicarboxylic acid (LY379268), was equally neuroprotective in cultures containing neurons from wild-type, mGlu2 ؊/؊ , or mGlu3 ؊/؊ mice. Neuroprotection was instead abolished when astrocytes lacked mGlu3 receptors, unless neuronal mGlu2 receptors were also absent. The latter condition partially restored the protective activity of LY379268. Cultures in which neurons originated from mGlu2 ؊/؊ mice were also intrinsically resistant to NMDA toxicity. In in vivo experiments, systemic administration of LY379268 protected striatal neurons against NMDA toxicity in wild-type and mGlu2 Ϫ/Ϫ mice but not in mGlu3 ؊/؊ mice. In addition, LY379268 was protective against nigrostriatal degeneration induced by low doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine only in mice lacking mGlu2 receptors. We conclude that neuroprotection by mGlu2/3 receptor agonists requires the activation of astrocytic mGlu3 receptors, whereas, unexpectedly, activation of mGlu2 receptors might be harmful to neurons exposed to toxic insults.