Hippocampus-related cognitive disorders develop in the absence of epilepsy and ataxia in the heterozygous Cacna1a mutant mice tottering.

CACNA1A-associated epilepsy and ataxia frequently accompany cognitive impairments as devastating co-morbidities. However, it is unclear whether the cognitive deficits are consequences secondary to the neurological symptoms elicited by CACNA1A mutations. To address this issue, Cacna1a mutant mice tottering (tg), and in particular tg/+ heterozygotes, serve as a suitable model system, given that tg/+ heterozygotes fail to display spontaneous absence epilepsy and ataxia typically observed in tg/tg homozygotes. Here, we examined hippocampus-dependent behaviors and hippocampal learning-related synaptic plasticity in tg mice. In behavioral analyses of tg/+ and tg/tg, acquisition and retention of spatial reference memory were characteristically impaired in the Morris water maze task, while working memory was intact in the eight-arm radial maze and T-maze tasks. tg/+ heterozygotes showed normal motor function in contrast to tg/tg homozygotes. In electrophysiological analyses, Schaffer collateral-CA1 synapses showed a deficit in the maintenance of long-term potentiation in tg/+ and tg/tg mice and an increased paired-pulse facilitation induced by paired pulses with 100 ms in tg/tg mice. Our results indicate that the tg mutation causes a dominant disorder of the hippocampus-related memory and synaptic plasticity, raising the possibility that in CACNA1A-associated human diseases, functionally aberrant CaV2.1 Ca2+ channels actively induce the observed cognitive deficits independently of the neurological symptoms.

Role of Oxidative Stress and Ca2+ Signaling in Psychiatric Disorders.

Psychiatric disorders are caused by complex and diverse factors, and numerous mechanisms have been proposed for the pathogenesis of these disorders. Accumulating evidence suggests that oxidative stress is one of the general factors involved in the pathogenesis/pathophysiology of major psychiatric disorders, including bipolar disorder, depression, anxiety disorder, and schizophrenia. Indeed, some clinical trials have shown improvement of the symptoms of these disorders by antioxidant supplementation. However, the molecular basis for the relationship between oxidative stress and the pathogenesis of psychiatric disorders remains largely unknown. In general, Ca2+ channels play central roles in neuronal functions, including neuronal excitability, neurotransmitter release, synaptic plasticity, and gene regulation, and genes that encode Ca2+ channels have been found to be associated with psychiatric disorders. Notably, a class of Ca2+-permeable transient receptor potential (TRP) cation channels is activated by changes in cellular redox status, whereby these TRP channels can link oxidative stress to Ca2+ signals. Given the unique characteristic of redox-sensitive TRP channels, these channels could be a target for delineating the pathogenesis or pathophysiology of psychiatric disorders. In this review, we summarize the outcomes of clinical trials for antioxidant treatment in patients with psychiatric disorders and the current insights into the physiological/pathological significance of redox-sensitive TRP channels in the light of neural functions, including behavioral phenotypes, and discuss the potential role of TRP channels in the pathogenesis of psychiatric disorders. Investigation of redox-sensitive TRP channels may lead to the development of novel therapeutic strategies for the treatment of psychiatric disorders.

Deficiency of the RIß subunit of protein kinase A causes body tremor and impaired fear conditioning memory in rats.

The RIß subunit of cAMP-dependent protein kinase (PKA), encoded by Prkar1b, is a neuronal isoform of the type I regulatory subunit of PKA. Mice lacking the RIß subunit exhibit normal long-term potentiation (LTP) in the Schaffer collateral pathway of the hippocampus and normal behavior in the open-field and fear conditioning tests. Here, we combined genetic, electrophysiological, and behavioral approaches to demonstrate that the RIß subunit was involved in body tremor, LTP in the Schaffer collateral pathway, and fear conditioning memory in rats. Genetic analysis of WTC-furue, a mutant strain with spontaneous tremors, revealed a deletion in the Prkar1b gene of the WTC-furue genome. Prkar1b-deficient rats created by the CRISPR/Cas9 system exhibited body tremor. Hippocampal slices from mutant rats showed deficient LTP in the Schaffer collateral-CA1 synapse. Mutant rats also exhibited decreased freezing time following contextual and cued fear conditioning, as well as increased exploratory behavior in the open field. These findings indicate the roles of the RIß subunit in tremor pathogenesis and contextual and cued fear memory, and suggest that the hippocampal and amygdala roles of this subunit differ between mice and rats and that rats are therefore beneficial for exploring RIß function.