Ca_v3 T-Type Voltage-Gated Ca²⁺ Channels and the Amyloidogenic Environment: Pathophysiology and Implications on...

Voltage-gated Ca²⁺ channels (VGCCs) were reported to play a crucial role in neurotransmitter release, dendritic resonance phenomena and integration, and the regulation of gene expression. In the septohippocampal system, high- and low-voltage-activated (HVA, LVA) Ca²⁺ channels were shown to be involved in theta genesis, learning, and memory processes. In particular, HVA Ca_v2.3 R-type and LVA Ca_v3 T-type Ca²⁺ channels are expressed in the medial septum-diagonal band of Broca (MS-DBB), hippocampal interneurons, and pyramidal cells, and ablation of both channels was proven to severely modulate theta activity. Importantly, Ca_v3 Ca²⁺ channels contribute to rebound burst firing in septal interneurons. Consequently, functional impairment of T-type Ca²⁺ channels, e.g., in null mutant mouse models, caused tonic disinhibition of the septohippocampal pathway and subsequent enhancement of hippocampal theta activity. In addition, impairment of GABA A/B receptor transcription, trafficking, and membrane translocation was observed within the septohippocampal system. Given the recent findings that amyloid precursor protein (APP) forms complexes with GABA B receptors (GBRs), it is hypothesized that T-type Ca²⁺ current reduction, decrease in GABA receptors, and APP destabilization generate complex functional interdependence that can constitute a sophisticated proamyloidogenic environment, which could be of potential relevance in the etiopathogenesis of Alzheimer's disease (AD). The age-related downregulation of T-type Ca²⁺ channels in humans goes together with increased Aβ levels that could further inhibit T-type channels and aggravate the proamyloidogenic environment. The mechanistic model presented here sheds new light on recent reports about the potential risks of T-type Ca²⁺ channel blockers (CCBs) in dementia, as observed upon antiepileptic drug application in the elderly.