Ca V 3.2 T-type calcium channels, encoded by CACNA1H, are expressed throughout the brain, yet their general function remains unclear. We discovered that Ca V 3.2 channels control NMDA-sensitive glutamatergic receptor (NMDA-R)-mediated transmission and subsequent NMDA-R-dependent plasticity of AMPA-R-mediated transmission at rat central synapses. Interestingly, functional Ca V 3.2 channels primarily incorporate into synapses, replace existing Ca V 3.2 channels, and can induce local calcium influx to control NMDA transmission strength in an activitydependent manner. Moreover, human childhood absence epilepsy (CAE)-linked hCa V 3.2(C456S) mutant channels have a higher channel open probability, induce more calcium influx, and enhance glutamatergic transmission. Remarkably, cortical expression of hCa V 3.2(C456S) channels in rats induces 2-to 4-Hz spike and wave discharges and absence-like epilepsy characteristic of CAE patients, which can be suppressed by AMPA-R and NMDA-R antagonists but not T-type calcium channel antagonists. These results reveal an unexpected role of Ca V 3.2 channels in regulating NMDA-R-mediated transmission and a novel epileptogenic mechanism for human CAE.

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Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background Previous studies suggest that rapid eye movement sleep rebound and disruption of rapid eye movement sleep architecture occur during the first 24 h after general anesthesia with volatile anesthetics in adult rats. However, it is unknown whether rapid eye movement sleep alterations persist beyond the anesthetic recovery phase in neonatal rats. This study tested the hypothesis that rapid eye movement sleep disturbances would be present in adolescent rats treated with anesthesia on postnatal day 7. Methods Forty-four neonatal rats were randomly allocated to treatment with anesthesia consisting of midazolam, nitrous oxide, and isoflurane or control conditions for 2 h or 6 h. Electroencephalographic and electromyographic electrodes were implanted and recordings obtained between postnatal days 26 and 34. The primary outcome was time spent in rapid eye movement sleep. Data were analyzed using two-tailed unpaired t tests and two-way repeated measures analysis of variance. Results Rats treated with midazolam, nitrous oxide, and isoflurane exhibited a significant increase in rapid eye movement sleep three weeks later when compared with control rats, regardless of whether they were treated for 2 h (174.0 ± 7.2 min in anesthetized, 108.6 ± 5.3 in controls, P < 0.0001) or 6 h (151.6 ± 9.9 min in anesthetized, 108.8 ± 7.1 in controls, P = 0.002). Conclusions Treatment with midazolam, nitrous oxide, and isoflurane on postnatal day 7 increases rapid eye movement sleep three weeks later in rats.

Voluntary hyperventilation triggers seizures in the vast majority of people with absence epilepsy. The mechanisms that underlie this phenomenon remain unknown. Herein, we review observations - many made long ago - that provide insight into the relationship between breathing and absence seizures.