Hippocampal neurophysiology during exploratory behaviour and sleep in rats heterozygous for the psychiatric risk gene cacna1c

Morrell, Edward 2020. Hippocampal neurophysiology during exploratory behaviour and sleep in rats heterozygous for the psychiatric risk gene cacna1c. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Genome-wide association studies reveal that calcium channel gene variants confer risk for psychiatric disorders across diagnostic categories. One consistently implicated gene is CACNA1C, a gene encoding the α1 pore-forming subunit of the L-type calcium channel. Recent rodent research highlights an important role for Cacna1c in hippocampal synaptic plasticity and related cognition, yet little is known about the effects of reduced Cacna1c gene dosage on hippocampal neurophysiology in vivo. Using tetrodes targeted to the dorsal CA1 I recorded single unit and local field potential activity in rats heterozygous for Cacna1c during free exploration and rest. Cacna1c heterozygous rats displayed enlarged place-fields and an associated reduction in place-cell spatial information content during runs on a linear track in a familiar and novel orientation, while place-cell activity during exploration of a novel open-field was intact. In addition, while 6-10Hz theta and 25-140Hz gamma rhythms were comparable in frequency and power in heterozygotes, their dependence on locomotion was compromised. Phase-amplitude coupling between theta and slow-gamma was also attenuated in Cacna1c heterozygous rats running on the track in a novel orientation. Hippocampal recordings at rest revealed intact 120-250Hz sharp-wave ripple oscillations, yet an enhanced participation of individual neurons in sharp-wave ripple events in Cacna1c heterozygotes. Despite the elevation in ripple-associated activity, coactivity between cell pairs during sharp-wave ripple events was markedly impaired. Changes to neurophysiology during sleep-associated oscillations appeared independent of global sleep architecture, since Cacna1c heterozygotes showed normal circadian activity patterns. Finally, combining genetic L-type calcium channel hypofunction with NMDA receptor blockade using systemic ketamine administration, did not exacerbate hippocampal deficits in Cacna1c heterozygotes, indicating a divergence of these biological pathways. This research reveals an important role for CACNA1C in hippocampal neurophysiology that may contribute to cognitive deficits associated with psychiatric risk

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Psychology
Subjects:	B Philosophy. Psychology. Religion > BF Psychology
Date of First Compliant Deposit:	1 June 2021
Date of Acceptance:	1 June 2021
Last Modified:	06 Jan 2022 02:15
URI:	https://orca.cardiff.ac.uk/id/eprint/141675

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