Presynaptic P/Q calcium channel deficit promotes postsynaptic excitability remodeling and neurogenesis in developing thalamic circuitry

Abstract

Inherited ion channel gene mutations cause network synchronization disorders, but their early impact on circuit development is less understood. Childhood absence epilepsy features cortical spike-wave discharges driven by thalamocortical rebound bursting. Loss-of-function mutations in P/Q-type calcium channels impair neurotransmitter release yet paradoxically increase thalamic excitability. In tottering mice, global P/Q deficiency elevates T-type calcium and big potassium (BK) channel transcripts in thalamic relay neurons, increasing excitability before seizure onset and coincident with the N-to-P/Q exocytosis switch. Selective P/Q deletion in cortical L6 pyramidal presynaptic input to thalamus reproduced the coordinate transcript elevation, indicating a transsynaptic mechanism. Unexpectedly, tottering, but not L6 mutants, showed increased thalamic neurogenesis and β-catenin/Lef1 upregulation, linking intrinsic thalamic P/Q channel function to early structural brain development. These findings reveal that subtle inherited changes in P/Q-mediated transmitter release and postsynaptic membrane calcium dynamics disrupt a previously unrecognized embryonic homeostatic pathway regulating growth, plasticity, and excitability in thalamocortical circuits.

Keywords: Cacna1g; Kcnma1; WNT signaling; absence epilepsy; attention deficit disorder; homeostasis; nanodomain; thalamic hypertrophy; transcriptome.