Aims: 

Activity-dependent Ca²⁺ entry into postsynaptic neurons is important for learning, synaptic plasticity, modulation of cellular excitability and transcription. We sought to elucidate the functional contribution of Ca²⁺ influx via Ca _v1.2 channels to these processes in the hippocampus using mice with the Ca _v1.2 gene inactivated in principal hippocampal neurons (Ca_v1.2 ^HKO).

Methods: 

Long-term potentiation (LTP) and cellular excitability were examined in the CA1 region of hippocampal slices from control and mutant mice using extracellular recording of excitatory postsynaptic potentials and current-clamp recording from individual pyramidal cells. Spatial learning was tested in a discriminatory water maze. Transcriptional activation through the extracellular signalling related kinase (ERK) – CREB – CRE pathway was assessed by immunoblotting and immunohistochemical analysis.

Results: 

Ca_v1.2^HKO mice displayed inferior performance in the discriminatory water maze. This deficit in spatial learning was paralleled by an impairment of protein synthesis-dependent NMDA receptor-independent LTP. CA1 pyramidal cells from mutant mice had normal resting membrane potential and input resistance, but showed attenuated excitability following somatic depolarisation (e.g. attenuation in spiking frequency). In addition, activation of the ERK pathway and CRE-dependent transcription by LTP-inducing stimuli was reduced in hippocampal neurons from Ca_v1.2^HKO mice. Conclusion: These results suggest a critical function of the Ca_v1.2 channel for hippocampal memory formation likely due to modulating intrinsic excitability, facilitating CRE-dependent gene expression and maintenance of LTP.