Cav1.2 L-type calcium channels regulate stress coping behavior via serotonin neurons. (January 2019)

• Record Type: Journal Article
• Authors: Ehlinger, Daniel G.; Commons, Kathryn G.
• Is Part Of: Neuropharmacology. Volume 144(2019)
• Page Start: 282
• Page End: 290
• Publication Date: 2019-01
• Subjects: Serotonin -- Dorsal raphe -- Cacna1c -- L-type calcium channels -- Cav1.2 -- Psychiatric disorders; 5-HT Serotonin -- 5-HT1A Serotonin type 1A receptor -- DR Dorsal raphe -- LTCC L-type calcium channel; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2018.08.033
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: Human genetic variation in the gene CACNA1C, which codes for the alpha-1c subunit of Cav1.2 L-type calcium channels (LTCCs), has been broadly associated with enhanced risk for neuropsychiatric disorders including major depression, bipolar and schizophrenia. Little is known about the specific neural circuits through which CACNA1C and Cav1.2 LTCCs impact disease etiology. However, serotonin (5-HT) neurotransmission has been consistently implicated in these neuropsychiatric disorders and Cav1.2 LTCCs may influence 5-HT neuron activity during relevant behavioral states such as stress. We utilized a temporally controlled and 5-HT neuron specific Cacna1c knockout mouse model to assess stress-coping behavior using the forced swim test and dorsal raphe (DR) 5-HT neuron Fos activation. Furthermore, we assessed 5-HT1A receptor function and feedback inhibition of the DR following administration of the 5-HT1A antagonist WAY-100635. We find that 5-HT neuron Cacna1c knockout disrupts active-coping behavior in the forced swim test and that this behavioral effect is rescued by blocking 5-HT1A receptors. Moreover, Cacna1c knockout mice display enhanced Fos expression in caudal DR 5-HT neurons and an enhanced response to a 5-HT1A receptor antagonist in rostral DR 5-HT neurons, indicating that loss of Cacna1c disrupts both 5-HT neuron activation and 5-HT1A dependent feedback inhibition across the caudal to rostral DR. Collectively, these results reveal an important role for 5-HT neuron Cav1.2 LTCCs in stress-coping behavior and 5-HT1A receptor function. This suggests that alterations in CACNA1C function or expression could influence the development or treatment of neuropsychiatric disorder through serotonergic mechanisms. Highlights: Loss of the L-type calcium channel subunit Cav1.2 selectively in serotonin neurons disrupts normal behavioral response to stress. Blocking 5-HT1A receptors restores normal behavior. There is evidence for altered balance of activation and feedback inhibition between different subgroups of serotonin neurons when Cav1.2 is lacking.