Altered Cav1.2 function in the Timothy syndrome mouse model produces ascending serotonergic abnormalities. (5th October 2017)

• Record Type: Journal Article
• Authors: Ehlinger, Daniel G.; Commons, Kathryn G.
• Is Part Of: European journal of neuroscience. Volume 46:Number 8(2017)
• Page Start: 2416
• Page End: 2425
• Publication Date: 2017-10-05
• Subjects: 5‐hydroxytryptamine‐type 1A receptor -- autism -- dorsal raphe nucleus -- neurodevelopment -- serotonin; Nervous system -- Periodicals; 612.8
• DOI: 10.1111/ejn.13707
• Languages: English
• ISSNs: 0953-816X

Abstract

Abstract: Polymorphism in the gene CACNA1C, encoding the pore‐forming subunit of Cav1.2 L‐type calcium channels, has one of the strongest genetic linkages to schizophrenia, bipolar disorder and major depressive disorder: psychopathologies in which serotonin signaling has been implicated. Additionally, a gain‐of‐function mutation in CACNA1C is responsible for the neurodevelopmental disorder Timothy syndrome that presents with prominent behavioral features on the autism spectrum. Given an emerging role for serotonin in the etiology of autism spectrum disorders (ASD), we investigate the relationship between Cav1.2 and the ascending serotonin system in the Timothy syndrome type 2 (TS2‐neo) mouse, which displays behavioral features consistent with the core triad of ASD. We find that TS2‐neo mice exhibit enhanced serotonin tissue content and axon innervation of the dorsal striatum, as well as decreased serotonin turnover in the amygdala. These regionally specific alterations are accompanied by an enhanced active coping response during acute stress (forced swim), serotonin neuron Fos activity in the caudal dorsal raphe, and serotonin type 1A receptor‐dependent feedback inhibition of the rostral dorsal raphe nuclei. Collectively, these results suggest that the global gain‐of‐function Cav1.2 mutation associated with Timothy syndrome has pleiotropic effects on the ascending serotonin system including neuroanatomical changes, regional differences in forebrain serotonin metabolism and feedback regulatory control mechanisms within the dorsal raphe. Altered activity of the ascending serotonin system continues to emerge as a common neural signature across several ASD mouse models, and the capacity for Cav1.2 L‐type calcium channels to impact both serotonin structure and function has important implications for several neuropsychiatric conditions. Abstract : The Timothy Syndrome mouse carries a mutation in Cacna1c that encodes Cav1.2 L‐type calcium channels. We reveal enhanced serotonin axon innervation of the dorsal striatum, decreased turnover in the amygdala, and disrupted dorsal raphe serotonin neuron activity/feedback‐inhibition in this model. This represents an important step in understanding serotonin dysfunction in autism, and the impact of Cav1.2 on the serotonin system has important implications for several neuropsychiatric conditions.