CACNA1C codes for the alpha-1 subunit of Cav1.2 L-type voltage gated calcium channels (LVGCCs). Variation in CACNA1C has been reliably implicated in psychiatric illness, including schizophrenia and bipolar disorder. Analyses have indicated a convergence of genetic risk for schizophrenia on abnormalities in the synapse and in behaviours including associative learning. LVGCCs play a role in synaptic plasticity and learning, partly through regulation of gene transcription. Their role in specific aspects of associative learning that are relevant for symptoms of psychiatric illness is yet to be fully elucidated. A hippocampal-dependent fear conditioning paradigm was used to determine the role of Cacna1c and LVGCCs in specific aspects of associative learning in rats. Studies measured the activity-regulated expression of Cacna1c and the effect of inhibition of LVGCCs. A genetic Cacna1c knockdown rat model was used to investigate the effects of reduced expression on behaviour and the expression of brain derived neurotrophic factor (BDNF). This model was additionally tested on reward-based reversal-learning. Analyses were translated to humans, to assess whether disease relevant variation in CACNA1C was associated with similar deficits in reversal learning and expression. Inhibition of LVGCCs affected the consolidation, extinction and latent inhibition of contextual fear memory, whereas reduced expression of Cacan1c had a selective effect on latent inhibition. There were no effects on the acquisition of reward associations, but reversal learning was impaired. Similar deficits in reversal learning were associated with disease relevant variation in CACNA1C in humans. Reduced CACNA1C expression was found to be associated with changes in the expression of BDNF in both rats and humans. Results indicate a role for Cacna1c and LVGCCs in the appropriate formation and update of aversive and reward associations. Impairments in these processes can underlie specific symptoms of disease including emotion dysregulation and delusions. The cross-species effects on BDNF require further investigation.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:704954 |
| Date | January 2016 |
| Creators | Sykes, Lucy Helen |
| Publisher | Cardiff University |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://orca.cf.ac.uk/98747/ |
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