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Additionally, a gain\u2010of\u2010function mutation in<jats:italic><jats:styled-content style=\"fixed-case\">CACNA<\/jats:styled-content>1C<\/jats:italic>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 (<jats:styled-content style=\"fixed-case\">TS<\/jats:styled-content>2\u2010neo) mouse, which displays behavioral features consistent with the core triad of<jats:styled-content style=\"fixed-case\">ASD<\/jats:styled-content>. We find that<jats:styled-content style=\"fixed-case\">TS<\/jats:styled-content>2\u2010neo 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\u2010dependent feedback inhibition of the rostral dorsal raphe nuclei. Collectively, these results suggest that the global gain\u2010of\u2010function 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<jats:styled-content style=\"fixed-case\">ASD<\/jats:styled-content>mouse models, and the capacity for Cav1.2 L\u2010type calcium channels to impact both serotonin structure and function has important implications for several neuropsychiatric conditions.<\/jats:p>","DOI":"10.1111\/ejn.13707","type":"journal-article","created":{"date-parts":[[2017,9,18]],"date-time":"2017-09-18T14:11:27Z","timestamp":1505743887000},"page":"2416-2425","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Altered Cav1.2 function in the Timothy syndrome mouse model produces ascending serotonergic abnormalities"],"prefix":"10.1111","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9116-3996","authenticated-orcid":false,"given":"Daniel G.","family":"Ehlinger","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, Perioperative and Pain Medicine Boston Children's Hospital Boston MA USA"},{"name":"Department of Anesthesia Harvard Medical School 300 Longwood Ave Boston MA 02115 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathryn G.","family":"Commons","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Perioperative and Pain Medicine Boston Children's Hospital Boston MA USA"},{"name":"Department of Anesthesia Harvard Medical School 300 Longwood Ave Boston MA 02115 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2017,10,5]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2217-15.2015"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neubiorev.2005.07.002"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1112667108"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ynstr.2014.10.004"},{"key":"e_1_2_10_6_1","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","article-title":"Controlling the false discovery rate: a practical and powerful approach to multiple testing","volume":"57","author":"Benjamini Y.","year":"1995","journal-title":"J. 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