Cacna1c Hemizygosity Results in Aberrant Fear Conditioning to Neutral Stimuli.

Anna L Moon,Nichola M Brydges,Jeremy Hall,Lawrence S Wilkinson,Kerrie L Thomas

doi:10.1093/schbul/sbz127

Abstract

CACNA1C, a gene that encodes an alpha-1 subunit of L-type voltage-gated calcium channels, has been strongly associated with psychiatric disorders including schizophrenia and bipolar disorder. An important objective is to understand how variation in this gene can lead to an increased risk of psychopathology. Altered associative learning has also been implicated in the pathology of psychiatric disorders, particularly in the manifestation of psychotic symptoms. In this study, we utilize auditory-cued fear memory paradigms in order to investigate whether associative learning is altered in rats hemizygous for the Cacna1c gene. Cacna1c hemizygous (Cacna1c+/−) rats and their wild-type littermates were exposed to either delay, trace, or unpaired auditory fear conditioning. All rats received a Context Recall (24 h post-conditioning) and a Cue Recall (48 h post-conditioning) to test their fear responses. In the delay condition, which results in strong conditioning to the cue in wild-type animals, Cacna1c+/− rats showed increased fear responses to the context. In the trace condition, which results in strong conditioning to the context in wild-type animals, Cacna1c+/− rats showed increased fear responses to the cue. Finally, in the unpaired condition, Cacna1c+/− rats showed increased fear responses to both context and cue. These results indicate that Cacna1c heterozygous rats show aberrantly enhanced fear responses to inappropriate cues, consistent with key models of psychosis.

Highlights

Genetic variation in CACNA1C, a gene that encodes the pore-forming alpha-1 subunit of CaV1.2 L-type voltagegated calcium channels (LTCCs), has been strongly and consistently linked to both schizophrenia and bipolar disorder, among other psychiatric disorders.[1–3] While schizophrenia and bipolar disorder can present very differently in the clinic, both are associated with a psychosis phenotype,[4] and several studies have indicated that there is a shared genetic architecture between the two disorders,[5,6] including in CACNA1C.7Studies have shown the altered expression of CACNA1C in individuals with CACNA1C common risk variants, mostly decreased expression,[8–10] some studies have indicated an increased expression in certain brain regions.[11]
We investigate the responses of Cacna1c hemizygous rats after delay, trace, and unpaired contextual fear conditioning in order to determine the role of dosage of Cav1.2 on associative fear memory
The Cacna1c+/− rats were able to discriminate between the conditioned and nonconditioned context as no freezing was seen in the novel context (Novel Baseline) during Cue Recall

Summary

Introduction

Genetic variation in CACNA1C, a gene that encodes the pore-forming alpha-1 subunit of CaV1.2 L-type voltagegated calcium channels (LTCCs), has been strongly and consistently linked to both schizophrenia and bipolar disorder, among other psychiatric disorders.[1–3] While schizophrenia and bipolar disorder can present very differently in the clinic, both are associated with a psychosis phenotype,[4] and several studies have indicated that there is a shared genetic architecture between the two disorders,[5,6] including in CACNA1C.7Studies have shown the altered expression of CACNA1C in individuals with CACNA1C common risk variants, mostly decreased expression,[8–10] some studies have indicated an increased expression in certain brain regions.[11]. Genetic variation in CACNA1C, a gene that encodes the pore-forming alpha-1 subunit of CaV1.2 L-type voltagegated calcium channels (LTCCs), has been strongly and consistently linked to both schizophrenia and bipolar disorder, among other psychiatric disorders.[1–3]. While schizophrenia and bipolar disorder can present very differently in the clinic, both are associated with a psychosis phenotype,[4] and several studies have indicated that there is a shared genetic architecture between the two disorders,[5,6] including in CACNA1C.7. Studies have shown the altered expression of CACNA1C in individuals with CACNA1C common risk variants, mostly decreased expression,[8–10] some studies have indicated an increased expression in certain brain regions.[11]. Most studies have concentrated on common variations, rare variants in CACNA1C have been implicated in psychiatric disorders.[12,13]. There is evidence at a genomic level that these learning processes are implicated in risk for schizophrenia.[13,22,23]

Methods

Results

Conclusion