Cav1.2 L-type calcium channels regulate stress coping behavior via serotonin neurons

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.

Phenotypic expansion of CACNA1C-associated disorders to include isolated neurological manifestations

“…In the central nervous system, CACNA1C shows the highest expression in the cerebral cortex, hippocampi, thalami, cerebellum, and suprachiasmatic nucleus 5 . It has also been implicated in the development of the serotonergic system 21 . These neuroanatomic substrates can account for the reported neurological phenotypes in our cohort.…”

“…1 Title: Phenotypic expansion of CACNA1C-associated disorders to include isolated neurological manifestations Lance H. Rodan MD, 1,2 Rebecca C. Spillmann MS CGC, 3 Harley T. Kurata PhD, 4 Shawn M. Lamothe PhD, 4 Jasmine Maghera BS, 4 Rami Abou Jamra MD, 5 Anna Alkelai PhD, 6 Stylianos E. Antonarakis MD, DSc, 7 Isis Atallah MD, 8 Omer Bar-Yosef MD, PhD, 9,10 Frédéric Bilan PhD, 11 Kathrine Bjorgo MD, 12 Xavier Blanc PhD, 7 Patrick Van Bogaert MD, PhD, 13 Yoav Bolkier MD, 10,14 Lindsay C. Burrage MD, PhD, 15 Björn U. Christ MA, 16 Jorge L. Granadillo MD, 17 Patricia Dickson MD, 17 Kirsten A. Donald MBChB, PhD, 16 Christèle Dubourg PhD, 18,19 Aviva Eliyahu MD, 10,20,21 Lisa Emrick MD, 15 Kendra Engleman MS, CGC, 22 Michaela Veronika Gonfiantini MD, 23 Jean-Marc Good MD, PhD, 24 Judith Kalser MD, 25 Chiara Kloeckner CM, 5 Guus Lachmeijer MD, PhD, 26 Marina Macchiaiolo MD, 23 Francesco Nicita MD, 27 Sylvie Odent MD, 28 Emily O'Heir BS, 1,29 Xilma Ortiz-Gonzalez MD, PhD, 30 Marta Pacio-Miguez MS, 31 María Palomares-Bralo MSc, PhD, 31…”

Targeting microglia L‐type voltage‐dependent calcium channels for the treatment of central nervous system disorders

“…anxiety during the open field test (Ehlinger & Commons, 2019). Like the data with CACNA1C-lacking mice, homozygous loss of CACNA1D also appears to induce an antidepressant and anxiolytic phenotype (Busquet et al, 2010).…”

Regulation of neuronal excitation–transcription coupling by Kv2.1-induced clustering of somatic L-type Ca 2+ channels at ER-PM junctions

“…calcium signaling j membrane contact sites j excitation-transcription coupling j voltage-gated calcium channels j voltage-gated potassium channels I n brain neurons, Ca 2+ influx through L-type voltage-gated Ca 2+ channels (LTCCs) initiates diverse physiological responses, including the regulation of membrane potential, release of intercellular signaling molecules, and changes in gene expression (1)(2)(3). Cav1.2 is the major LTCC principal α 1 subunit expressed in hippocampal neurons (4)(5)(6)(7)(8), and Cav1.2 knockout mice have deficits in hippocampal long-term potentiation, memory, and related behaviors (6,(9)(10)(11). Neurons organize Cav1.2-containing LTCCs into microdomains containing different effectors that enable Ca 2+ influx through these channels to activate specific Ca 2+ signaling pathways (12)(13)(14).…”