The voltage-gated Ca2+ channel subunit α2δ-4 regulates locomotor behavior and sensorimotor gating in mice

Abstract

Voltage-gated Ca2+ channels are critical for the development and mature function of the nervous system. Variants in the CACNA2D4 gene encoding the α2δ-4 auxiliary subunit of these channels are associated with neuropsychiatric and neurodevelopmental disorders. α2δ-4 is prominently expressed in the retina and is crucial for vision, but extra-retinal functions of α2δ-4 have not been investigated. Here, we sought to fill this gap by analyzing the behavioral phenotypes of α2δ-4 knockout (KO) mice. α2δ-4 KO mice (both males and females) exhibited significant impairments in prepulse inhibition that were unlikely to result from the modestly elevated auditory brainstem response thresholds. Whereas α2δ-4 KO mice of both sexes were hyperactive in various assays, only females showed impaired motor coordination in the rotarod assay. α2δ-4 KO mice exhibited anxiolytic and anti-depressive behaviors in the elevated plus maze and tail suspension tests, respectively. Our results reveal an unexpected role for α2δ-4 in sensorimotor gating and motor function and identify α2δ-4 KO mice as a novel model for studying the pathophysiology associated with CACNA2D4 variants.

α2δ-4 and Cachd1 Proteins Are Regulators of Presynaptic Functions

“…Remarkably, and like α 2 δ-2 [ 25 ], α 2 δ-4 showed a distinct peri-synaptic localization in the presynaptic membrane around the centrally located synapsin cluster ( Figure 2 , upper panel and linescan). Together, these data suggest that HA-tagged Cachd1 and α 2 δ-4 target presynaptic terminals upon expression in cultured hippocampal neurons, in line with previous suggestions of the CNS functions of both proteins [ 20 , 21 , 22 ].…”

“…However, mutations in CACNA2D4 in patients with neurodevelopmental disorders [ 34 , 35 , 36 ] and increased α 2 δ-4 mRNA expression levels in the hippocampus after status epilepticus [ 20 ] suggest previously unrecognized functions in the brain. This is further supported by the fact that α 2 δ-4 knockout mice exhibit behavioral impairments in terms of cognitive and motor functions [ 21 ]. Given the extremely low expression of α 2 δ-4 in the hippocampus [ 15 ], α 2 δ-4 might be restricted to a specific and very small subpopulation of neurons in the brain [ 5 ].…”

“…Recent studies also suggested a functional role of lowly expressed α 2 δ-4 in the brain. mRNA levels of α 2 δ-4 were increased in human hippocampal biopsies obtained from epileptic patients [ 20 ], and a recent study on knockout mice identified a role for α 2 δ-4 in cognitive and motor behavior [ 21 ].…”

Bilirubin-Induced Transcriptomic Imprinting in Neonatal Hyperbilirubinemia

“…The marker identifies the neurons whose activity is calcium-dependent, a type of neuron that has been associated with cognitive and behavioral processes [ 16 , 113 , 114 ]. Noteworthy, the only gene permanently altered in all the regions under investigation in this work is Grm1 , a metabotropic glutamate receptor involved in neurite outgrowth and post-synaptic activity [ 28 , 38 , 40 , 62 , 63 , 115 ]. Those also altered are Cacng8 (promoting the targeting to the cell membrane and synapses of AMPA-selective glutamate receptors and modulating their gating properties [ 28 , 38 ]), and Cacna2d4 (a voltage-gated calcium channel; with the α2δ subunits as important regulators of synapse formation [ 28 , 38 , 116 ]).…”

Neuronal deletion of CaV1.2 is associated with sex-specific behavioral phenotypes in mice

“…Prepulse inhibition. This protocol has been described previously 38 . In short, mice were placed in an isolation cabinet (width: 38.1 cm × diameter: 35.6 cm × height: 45.7 cm), restrained in a clear acrylic cylinder (length: 12.7 cm × inner diameter: 3.8 cm), and the tremble response of the animal was measured via an accelerometer underneath the chamber.…”