γ-Band deficiency and abnormal thalamocortical activity in P/Q-type channel mutant mice

Abstract

Thalamocortical in vivo and in vitro function was studied in mice lacking P/Q-type calcium channels (Ca V 2.1), in which N-type calcium channels (Ca V 2.2) supported central synaptic transmission. Unexpectedly, in vitro patch recordings from thalamic neurons demonstrated no γ-band subthreshold oscillation, and voltage-sensitive dye imaging demonstrated an absence of cortical γ-band-dependent columnar activation involving cortical inhibitory interneuron activity. In vivo electroencephalogram recordings showed persistent absence status and a dramatic reduction of γ-band activity. Pharmacological block of T-type calcium channels (Ca V 3), although not noticeably affecting normal control animals, left the knockout mice in a coma-like state. Hence, although N-type calcium channels can rescue P/Q-dependent synaptic transmission, P/Q calcium channels are essential in the generation of γ-band activity and resultant cognitive function.

Calcium channels in higher-level brain function

“…P/Q channels (formally named Ca v 2.1 channels) belong to the Ca v 2 superfamily of voltage-gated calcium channels and are distinguished from other voltage-gated calcium channels by the presence of an ␣ 1A subunit. As we see in the article by Llinás et al (1), these channels are selectively blocked by a spider venom, -agatoxin, a useful tool for experimental studies. In the normal central nervous system, P/Q channels, when activated by strong depolarization, support Ca 2ϩ -dependent synaptic transmission between neurons at many sites, including the thalamus, which is the brain region at the heart of the investigation by Llinás et al…”

“…During the postnatal period, as shown by Llinás et al (1), compensatory expression of N-type (Ca v 2.2) channels in thalamic and cortical neurons can support a small complement of highthreshold current in thalamic neurons, serving to maintain excitatory synaptic transmission between the thalamus and cortex and supporting activation of the cortex by the thalamus. These compensatory effects of N-type channels were insufficient, however, to maintain the subthreshold Ϸ40-Hz membrane oscillations observed in depolarizing thalamic neurons from normal mice.…”

“…Product (µM) N ature has a habit of using relatively simple cellular mechanisms in the service of the higher-level integrative functions of multicellular organ systems. In the article by Llinás et al (1), published in a recent issue of PNAS, we can see an example of how a mechanism that probably evolved for maintaining the integrity of the excitable membranes of nerve, heart, glandular, and muscle cells, when placed in the context of a highly interconnected network of neurons, is recruited as a fundamental component of brain mechanisms that underlie states of consciousness and that are also involved in those of perception and cognition.…”

CACNA1A haploinsufficiency causes cognitive impairment, autism and epileptic encephalopathy with mild cerebellar symptoms

“…[59][60][61][62][63] In the neocortex and hippocampus, Ca V 2.1 channels have been demonstrated to mediate GABA release and synaptic efficiency from cortical GABAergic parvalbumin-positive fast-spiking interneurons (FS-INs) 15,42,43,47 as well as from cortical pyramidal cells. 15 We recently demonstrated that a selective deletion of Cacna1a from cortical and hippocampal GABAergic interneurons, while sparing the thalamus and cerebellum, selectively impairs GABA release from FS-INs, despite an upregulation of N-type channels, and that this is sufficient to cause generalized epilepsy in conditional mutant mice.…”

Altered thalamocortical rhythmicity and connectivity in mice lacking Ca V 3.1 T-type Ca 2+ channels in unconsciousness

“…Indeed, highfrequency oscillations in thalamic neurons have been associated with the generation of high-frequency oscillatory properties in thalamocortical network supported by the activation of dendritic P/Q-type Ca 2+ channels (27). Previous studies have shown that abnormally large T-type Ca 2+ currents were encountered with genetic deletion or alteration of the P/Q-type calcium channel (12,28). Thus, the converse situation, where increased P/Q-type Ca 2+ channel mediated activities in the absence of T-type Ca 2+ channels, could also be supported through the compensatory alterations in Ca V 3.1 KO mice.…”