Du gène au comportement: les mécanismes du canal calcium du type L sous jacent aux symptômes neuropsychiatriques

Aperçu: G.M.

Les canaux de calcium de type L (CTRL) Cav1.2 et Cav1.3, codés par les gènes CACNA1C et CACNA1D, respectivement, sont des régulateurs importants de l'afflux de calcium dans les cellules et sont essentiels au développement normal du cerveau et à la plasticité. Chez les humains, CACNA1C est apparu comme l'un des gènes de risque candidats les plus avancés et les plus avancés pour une gamme de troubles neuropsychiatriques, y compris le trouble bipolaire (BD), la schizophrénie (SCZ), le trouble dépressif majeur, le trouble du spectre de l'autisme et le trouble déficitaire de l'attention et hyperactivité .

Neurotherapeutics. 2017 May 11. doi: 10.1007/s13311-017-0532-0.

From Gene to Behavior: L-Type Calcium Channel Mechanisms Underlying Neuropsychiatric Symptoms

Kabir ZD^1,2, Martínez-Rivera A^1,2, Rajadhyaksha AM^3,4,5.

Author information

1

Pediatric Neurology, Pediatrics, Weill Cornell Medicine, New York, NY, USA.

2

Weill Cornell Autism Research Program, Weill Cornell Medicine, New York, NY, USA.

3

Pediatric Neurology, Pediatrics, Weill Cornell Medicine, New York, NY, USA. amr2011@med.cornell.edu

4

Weill Cornell Autism Research Program, Weill Cornell Medicine, New York, NY, USA. amr2011@med.cornell.edu.

5

Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA. amr2011@med.cornell.edu.

Abstract

The L-type calcium channels (LTCCs) Ca_v1.2 and Ca_v1.3, encoded by the CACNA1C and CACNA1D genes, respectively, are important regulators of calcium influx into cells and are critical for normal brain development and plasticity. In humans, CACNA1C has emerged as one of the most widely reproduced and prominent candidate risk genes for a range of neuropsychiatric disorders, including bipolar disorder (BD), schizophrenia (SCZ), major depressive disorder, autism spectrum disorder, and attention deficit hyperactivity disorder. Separately, CACNA1D has been found to be associated with BD and autism spectrum disorder, as well as cocaine dependence, a comorbid feature associated with psychiatric disorders. Despite growing evidence of a significant link between CACNA1C and CACNA1D and psychiatric disorders, our understanding of the biological mechanisms by which these LTCCs mediate neuropsychiatric-associated endophenotypes, many of which are shared across the different disorders, remains rudimentary. Clinical studies with LTCC blockers testing their efficacy to alleviate symptoms associated with BD, SCZ, and drug dependence have provided mixed results, underscoring the importance of further exploring the neurobiological consequences of dysregulated Ca_v1.2 and Ca_v1.3. Here, we provide a review of clinical studies that have evaluated LTCC blockers for BD, SCZ, and drug dependence-associated symptoms, as well as rodent studies that have identified Ca_v1.2- and Ca_v1.3-specific molecular and cellular cascades that underlie mood (anxiety, depression), social behavior, cognition, and addiction.

PMID: 28497380

DOI: 10.1007/s13311-017-0532-0