Enhanced long-term potentiation and impaired learning in mice lacking alternative exon 33 of CaV1.2 calcium channel

Sheeja Navakkode,Jing Zhai,Tuck Wah Soong,Guang Li,Yuk Peng Wong

doi:10.1038/s41398-021-01683-2

Abstract

The CACNA1C (calcium voltage-gated channel subunit alpha 1 C) gene that encodes the CaV1.2 channel is a prominent risk gene for neuropsychiatric and neurodegenerative disorders with cognitive and social impairments like schizophrenia, bipolar disorders, depression and autistic spectrum disorders (ASD). We have shown previously that mice with exon 33 deleted from CaV1.2 channel (CaV1.2-exon 33−/−) displayed increased CaV1.2 current density and single channel open probability in cardiomyocytes, and were prone to develop arrhythmia. As Ca2+ entry through CaV1.2 channels activates gene transcription in response to synaptic activity, we were intrigued to explore the possible role of Cav1.2Δ33 channels in synaptic plasticity and behaviour. Homozygous deletion of alternative exon 33 resulted in enhanced long-term potentiation (LTP), and lack of long- term depression (LTD), which did not correlate with enhanced learning. Exon 33 deletion also led to a decrease in social dominance, sociability and social novelty. Our findings shed light on the effect of gain-of-function of CaV1.2Δ33 signalling on synaptic plasticity and behaviour and provides evidence for a link between CaV1.2 and distinct cognitive and social behaviours associated with phenotypic features of psychiatric disorders like schizophrenia, bipolar disorder and ASD.

Highlights

Synaptic plasticity is thought to underlie mechanisms of learning and memory and impairments in plasticity mechanisms are implicated in various neurodegenerative disorders such as Alzheimer’s, Parkinson’s and Huntington’s disease and psychiatric disorders such as autistic spectrum disorders (ASD), schizophrenia and depression [1,2,3,4,5,6]
Study L-long-term potentiation (LTP), a stable baseline was recorded for a minimum of 30 min and a strong tetanus stimulation (STET) was applied to synaptic input S1, which resulted in a long-lasting LTP in WT mice
This could be attributed to enhanced Ca2+ release through the gain-offunction of CaV1.2 Δ33 channels, as we had shown earlier that in cardiomyocytes, exclusion of exon 33 resulted in larger current density due to increased open probability and shift of voltage dependent activation in the hyperpolarizing direction [45, 48]

Summary

Introduction

Synaptic plasticity is thought to underlie mechanisms of learning and memory and impairments in plasticity mechanisms are implicated in various neurodegenerative disorders such as Alzheimer’s, Parkinson’s and Huntington’s disease and psychiatric disorders such as ASD, schizophrenia and depression [1,2,3,4,5,6]. There was no difference in the post tetanic potentiation values of Exon 33−/− mice compared to the WT (U-test, 1 min, P = 0.17).

Results

Conclusion