Abstract
The fine-tuning of neuronal excitability relies on a tight control of Ca2+ homeostasis. The low voltage-activated (LVA) T-type calcium channels (Cav3.1, Cav3.2 and Cav3.3 isoforms) play a critical role in regulating these processes. Despite their wide expression throughout the central nervous system, the implication of T-type Cav3.2 isoform in brain functions is still poorly characterized. Here, we investigate the effect of genetic ablation of this isoform in affective disorders, including anxiety, cognitive functions as well as sensitivity to drugs of abuse. Using a wide range of behavioral assays we show that genetic ablation of the cacna1h gene results in an anxiety-like phenotype, whereas novelty-induced locomotor activity is unaffected. Deletion of the T-type channel Cav3.2 also triggers impairment of hippocampus-dependent recognition memories. Acute and sensitized hyperlocomotion induced by d-amphetamine and cocaine are dramatically reduced in T-type Cav3.2 deficient mice. In addition, the administration of the T-type blocker TTA-A2 prevented the expression of locomotor sensitization observed in wildtype mice. In conclusion, our data reveal that physiological activity of this specific Ca2+ channel is required for affective and cognitive behaviors. Moreover, our work highlights the interest of T-type channel blockers as therapeutic strategies to reverse drug-associated alterations.
Highlights
Affective and cognitive functions constitute a complex ensemble of behavioral skills strongly dependent on the fine regulation of intracellular homeostasis and neuronal excitability
Ca2+ is the most common signal transduction element in neurons and its entry is tightly regulated by two major classes of voltagegated calcium channels (VGCCs): the high-voltage activated (HVA) (L, P/Q and N-type) and the low-voltage activated (LVA) (T-type) calcium channels
To investigate whether the genetic ablation of Cacna1h gene might induce muscular alteration that can impact on the spontaneous behavior of mice, we assessed muscular strength using two essays: the grip-strength and the grid test
Summary
Affective and cognitive functions constitute a complex ensemble of behavioral skills strongly dependent on the fine regulation of intracellular homeostasis and neuronal excitability. Disruption of calcium-dependent low-threshold currents mediated by T-type calcium channels have been associated with a wide range of neurological and neuropsychiatric disorders including epilepsy, insomnia, Parkinson’s disease, depression and schizophrenia as well as chronic pain syndromes (Huguenard and Prince, 1994; Kim et al, 2001, 2003; Anderson et al, 2005; Bourinet et al, 2005; Choi et al, 2007; Llinas et al, 2007; Uebele et al, 2009; Miwa et al, 2011; Francois et al, 2013; Park et al, 2013). The novel and specific blocker of T-type channels TTA-A2 has been reported to efficiently alleviate psychomotor effects induced by MK-801 and amphetamine as well as conditioned avoidance responding (Kraus et al, 2010; Uslaner et al, 2012), strengthening the Frontiers in Behavioral Neuroscience www.frontiersin.org
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