The impact of a CACNA1C gene polymorphism on learning and hippocampal formation in healthy individuals: A diffusion tensor imaging study

Dietsche, Bruno; Backes, Heidelore; Laneri, Davide; Weikert, Thomas; Witt, Stephanie H.; Rietschel, Marcella; Sommer, Jens; Kircher, Tilo; Krug, Axel

doi:10.1016/j.neuroimage.2013.11.030

Cited by 32 publications

(29 citation statements)

References 57 publications

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“…However, it is possible that the lack of a phenotype in cacna1c fbKO mice is due to a ceiling effect in freezing levels, a question that will be addressed in future studies using alternative fear conditioning protocols. Our behavioral findings in cacna1c fbKO mice are comparable to the low extraversion, a personality trait that is characterized by reduced social interactions 61 and poor learning performance 62 reported in human CACNA1C SNP carriers. Interestingly, while the cacna1c fbKO mice displayed elevated anxiety, 28 the TS mouse did not, 60 suggesting that human CACNA1C SNPs that have been associated with increased anxiety 63,64 could possibly result from decreased cacna1c levels in the PFC.…”

Section: Discussionsupporting

confidence: 84%

Rescue of impaired sociability and anxiety-like behavior in adult cacna1c-deficient mice by pharmacologically targeting eIF2α

et al. 2017

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CACNA1C, encoding the Cav1.2 subunit of L-type Ca2+ channels, has emerged as one of the most prominent and highly replicable susceptibility genes for several neuropsychiatric disorders. Cav1.2 channels play a crucial role in calcium-mediated processes involved in brain development and neuronal function. Within the CACNA1C gene, disease-associated single-nucleotide polymorphisms have been associated with impaired social and cognitive processing and altered prefrontal cortical (PFC) structure and activity. These findings suggest that aberrant Cav1.2 signaling may contribute to neuropsychiatric-related disease symptoms via impaired PFC function. Here, we show that mice harboring loss of cacna1c in excitatory glutamatergic neurons of the forebrain (fbKO) that we have previously reported to exhibit anxiety-like behavior, displayed a social behavioral deficit and impaired learning and memory. Furthermore, focal knockdown of cacna1c in the adult PFC recapitulated the social deficit and elevated anxiety-like behavior, but not the deficits in learning and memory. Electrophysiological and molecular studies in the PFC of cacna1c fbKO mice revealed higher E/I ratio in layer 5 pyramidal neurons and lower general protein synthesis. This was concurrent with reduced activity of mTORC1 and its downstream mRNA translation initiation factors eIF4B and 4EBP1, as well as elevated phosphorylation of eIF2α, an inhibitor of mRNA translation. Remarkably, systemic treatment with ISRIB, a small molecule inhibitor that suppresses the effects of phosphorylated eIF2α on mRNA translation, was sufficient to reverse the social deficit and elevated anxiety-like behavior in adult cacna1c fbKO mice. ISRIB additionally normalized the lower protein synthesis and higher E/I ratio in the PFC. Thus this study identifies a novel Cav1.2 mechanism in neuropsychiatric-related endophenotypes and a potential future therapeutic target to explore.

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Section: Discussionsupporting

confidence: 84%

Rescue of impaired sociability and anxiety-like behavior in adult cacna1c-deficient mice by pharmacologically targeting eIF2α

et al. 2017

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“…Although most of the imaging-genetics studies of this gene have used fMRI paradigms(Bigos et al, 2010), a recent DTI study showed that the CACNA1C SNP (rs1006737) was associated with FA in the right hippocampal formation using a hypothesis-driven approach(Dietsche et al, 2014). The neurogranin gene is another schizophrenia risk gene discovered by GWAS(Stefansson et al, 2009).…”

Section: 1 Introductionmentioning

confidence: 99%

Genetic underpinnings of white matter ‘connectivity’: Heritability, risk, and heterogeneity in schizophrenia

Voineskos

2015

Schizophrenia Research

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“…Recent research also suggests that allelic variation within the CACNA1C gene might be associated with psychopathology via modification of the brain's function and structure. For example, the rs1006737 risk allele (A) has been associated with altered behaviour [9][10][11], brain structure [12][13][14][15] as well as brain circuits involving working memory [7,16,17], episodic memory [18][19][20][21], learning [22,23] and emotion processing [15,24,25].…”

Section: Introductionmentioning

confidence: 99%

CACNA1C risk variant is associated with increased amygdala volume

Lancaster

Foley

Tansey

et al. 2015

Eur Arch Psychiatry Clin Neurosci

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Genome-wide association studies suggest that genetic variation within L-type calcium channel subunits confer risk to psychosis. The single nucleotide polymorphism at rs1006737 in CACNA1C has been associated with both schizophrenia and bipolar disorder and with several intermediate phenotypes that may serve as neurobiological antecedents, linking psychosis to genetic aetiology. Amongst others, it has been implicated in alterations in amygdala structure and function. In the present study, we show that the risk allele (A) is associated with increased amygdala volume in healthy individuals (n = 258). This observation reinforces a hypothesis that genetic variation may confer risk to psychosis via alterations in limbic structures. Further study of CACNA1C using intermediate phenotypes for psychosis will determine the mechanisms by which variation in this gene confers risk.

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The impact of a CACNA1C gene polymorphism on learning and hippocampal formation in healthy individuals: A diffusion tensor imaging study

Cited by 32 publications

References 57 publications

Rescue of impaired sociability and anxiety-like behavior in adult cacna1c-deficient mice by pharmacologically targeting eIF2α

Rescue of impaired sociability and anxiety-like behavior in adult cacna1c-deficient mice by pharmacologically targeting eIF2α

Genetic underpinnings of white matter ‘connectivity’: Heritability, risk, and heterogeneity in schizophrenia

CACNA1C risk variant is associated with increased amygdala volume

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