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Sex-Specific Effects of Cacna1c Haploinsufficiency on Social Behavior, Ultrasonic Communication, and Cognition in Rats
The risk gene CACNA1C encodes for the α1C subunit of the L-type voltage-gated Ca2+ channel, known as Cav1.2. Genome wide association studies have implicated CACNA1C in neuropsychiatric disorders, such as major depression, bipolar disorder, schizophrenia, and autism spectrum disorder. Importantly,...
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| Format: | Dissertation |
| Sprache: | Englisch |
| Veröffentlicht: |
Philipps-Universität Marburg
2018
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| Online Zugang: | PDF-Volltext |
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| Zusammenfassung: | The risk gene CACNA1C encodes for the α1C subunit of the L-type voltage-gated Ca2+
channel, known as Cav1.2. Genome wide association studies have implicated CACNA1C in
neuropsychiatric disorders, such as major depression, bipolar disorder, schizophrenia, and
autism spectrum disorder. Importantly, social behavior and communication deficits are
persistent in each disorder with added cognitive impairments similarly being present. Several
studies in humans and mouse models have indicated that Cav1.2 expression levels are
associated with alterations in sociability and cognition. Rat models provide an ideal
translational tool to determine underlying disease pathomechanisms, due in part to their highly
gregarious nature emerging early in life, thus, creating a practical means to study the
development of social behavior and communication. Using a newly developed Cacna1c rat
model, this dissertation aimed at exploring the role Cacna1c plays in social behavior and
communication in juvenile rats, as well as the association with cognitive impairments in
adulthood. Detailed practical assessment for juvenile behavior and ultrasonic vocalizations
(USV) outline social play (Review I) and USV playback (Review II) as pertinent paradigms to
assess alterations in social behavior and communication with relevance to neuropsychiatric
disorders. Results indicate that deficits in 50-kHz USV were evident in male haploinsufficient
Cacna1c rats in the sender and receiver (Study I). Cacna1c haploinsufficiency in females
resulted in abnormal social play behaviour and minor deficits in response to 50-kHz USV
playback (Study II). Moreover, Cacna1c rats appear to show normal, and in some cases above
normal, cognitive abilities, albeit with a slight reduction in cognitive flexibility in
haploinsufficient Cacna1c males (Study III). Together, these findings further extend the notion
that Cav1.2 expression levels may be associated with alterations in social behavior,
communication, and cognitive abilities in a sex-dependent manner, with important bearings on
neuropsychiatric disorders. |
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| Umfang: | 282 Seiten |
| DOI: | 10.17192/z2018.0235 |