Role of Hippocampal Ca_v1.2 Ca²⁺Channels in NMDA Receptor-Independent Synaptic Plasticity and Spatial Memory

TLDR

NMDA receptor‑independent long‑term potentiation in the hippocampal CA1 region is poorly understood, and its underlying L‑type Ca²⁺ channel isoform has not been identified. The study aimed to determine whether hippocampal Ca_v1.2 channels are required for spatial learning, synaptic plasticity, and associated biochemical signaling. Using a hippocampal‑neocortical Ca_v1.2 conditional knockout mouse, the authors assessed spatial memory, late‑phase LTP, and MAPK/CREB pathway activation. The Ca_v1.2 HCKO mice exhibited selective loss of protein‑synthesis‑dependent NMDAR‑independent late‑phase LTP, severe spatial memory deficits, and reduced MAPK/CREB signaling, demonstrating that Ca_v1.2‑mediated Ca²⁺ influx is essential for hippocampal L‑LTP and spatial memory.

Abstract

Current knowledge about the molecular mechanisms of NMDA receptor (NMDAR)-independent long-term potentiation (LTP) in the hippocampus and its function for memory formation in the behaving animal is limited. NMDAR-independent LTP in the CA1 region is thought to require activity of postsynaptic L-type voltage-dependent Ca 2+ channels (Ca v 1.x), but the underlying channel isoform remains unknown. We evaluated the function of the Ca v 1.2 L-type Ca 2+ channel for spatial learning, synaptic plasticity, and triggering of learning-associated biochemical processes using a mouse line with an inactivation of the CACNA1C (Ca v 1.2) gene in the hippocampus and neocortex (Ca v 1.2 HCKO ). This model shows (1) a selective loss of protein synthesis-dependent NMDAR-independent Schaffer collateral/CA1 late-phase LTP (L-LTP), (2) a severe impairment of hippocampus-dependent spatial memory, and (3) decreased activation of the mitogen-activated protein kinase (MAPK) pathway and reduced cAMP response element (CRE)-dependent transcription in CA1 pyramidal neurons. Our results provide strong evidence for a role of L-type Ca 2+ channel-dependent, NMDAR-independent hippocampal L-LTP in the formation of spatial memory in the behaving animal and for a function of the MAPK/CREB (CRE-binding protein) signaling cascade in linking Ca v 1.2 channel-mediated Ca 2+ influx to either process.