Sex-dependent effects of Cacna1c haploinsufficiency on behavioral inhibition evoked by conspecific alarm signals in rats.

Markus Wöhr, Maria Willadsen, Theresa M Kisko, Rainer K W Schwarting, Markus Fendt

Progress in neuro-psychopharmacology & biological psychiatry 2020 Apr 20

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Deficits in processing social signals leads to reduced social functioning and is typically associated with neuropsychiatric disorders, including autism spectrum disorder, schizophrenia, and major depressive disorder. The cross-disorder risk gene CACNA1C is implicated in the etiology of all of these disorders and single-nucleotide polymorphisms within CACNA1C are ranked among the best replicated and most robust genetic findings from genome-wide association studies in psychiatry. Rats are highly social, live in large social groups, and communicate through ultrasonic vocalizations (USV), with low-frequency 22-kHz USV emitted in dangerous and often life-threating situations, such as predator exposure, serving an alarming function. In the present study, we applied an alarm 22-kHz USV playback paradigm to investigate the role of Cacna1c in socio-affective information processing in rats. Specifically, we assessed behavioral inhibition evoked by 22-kHz USV in constitutive heterozygous Cacna1c+/- females and males, as compared to wildtype Cacna1c+/+ littermate controls. To probe specificity, two sets of alarm 22-kHz USV were presented, i.e. 22-kHz USV elicited by predator urine exposure and 22-kHz USV emitted during a retention test on learned fear, together with acoustic control stimuli. Our results show that behavioral inhibition evoked by playback of alarm 22-kHz USV is robust and occurs in response to both sets, yet is modulated by Cacna1c in a sex-dependent manner. In male but not female rats, Cacna1c haploinsufficiency led to less pronounced and less specific behavioral inhibition, supporting the idea that Cacna1c haploinsufficiency results in a lower motivation and/or diminished capability to display appropriate responses to important socio-affective communication signals. Copyright © 2019 Elsevier Inc. All rights reserved.

Citation

Markus Wöhr, Maria Willadsen, Theresa M Kisko, Rainer K W Schwarting, Markus Fendt. Sex-dependent effects of Cacna1c haploinsufficiency on behavioral inhibition evoked by conspecific alarm signals in rats. Progress in neuro-psychopharmacology & biological psychiatry. 2020 Apr 20;99:109849