Elite Pharmaceuticals Inc (ELTP)

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Autism Spectrum Disorders and calcium channels... hmmmmm

RESEARCH ARTICLE
NEUROPHYSIOLOGY

Cav1.3 calcium channels are full-range linear amplifiers of firing frequencies in lateral DA SN neurons

JOSEF SHIN et al
SCIENCE ADVANCES
8 Jun 2022
Vol 8, Issue 23
https://www.science.org/doi/10.1126/sciadv.abm4560

Abstract
The low-threshold L-type calcium channel Cav1.3 accelerates the pacemaker rate in the heart, but its functional role for the extended dynamic range of neuronal firing is still unresolved. Here, we show that Cav1.3 calcium channels act as unexpectedly simple, full-range linear amplifiers of firing rates for lateral dopamine substantia nigra (DA SN) neurons in mice. This means that they boost in vitro or in vivo firing frequencies between 2 and 50 hertz by about 30%. Furthermore, we demonstrate that clinically relevant, low nanomolar concentrations of the L-type channel inhibitor isradipine selectively reduce the in vivo firing activity of these nigrostriatal DA SN neurons at therapeutic plasma concentrations. Thus, our study identifies the pacemaker function of neuronal Cav1.3 channels and provides direct evidence that repurposing dihydropyridines such as isradipine is feasible to selectively modulate the in vivo activity of highly vulnerable DA SN subpopulations in Parkinson’s disease.

Not only is DA burst firing known to have essential functions in reward prediction error signaling, reinforcement learning, and initiation of voluntary movement (22–27) but also recently found de novo gain-of-function mutations in CACNA1D (coding for Cav1.3 a1 subunits) lead to neurodevelopmental disorders, including autism spectrum disorders (28, 29). Last, DHPs such as isradipine have been tested for modulation of DA neurons for potential neuroprotection in Parkinson’s disease (PD) [reviewed in (7)]. In summary, there is great interest in identifying the functional roles of Cav1.3 channels in the DA system.

Good stuff.

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