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Mounting evidence suggests that neuronal voltage-gated CaV1.2 and CaV1.3 L-type calcium channels (LTCCs) can modulate mood and anxiety behaviors. In CaV1.2 dihydropyridine (DHP)-insensitive mice (CaV1.2DHP-/- mice), systemic application of the DHP channel activator BAYK 8644 induced pro-depression-like behavior providing evidence for a possible role of CaV1.3 channels in mood behavior. We therefore explored the role of CaV1.3 LTCCs in depression- and anxiety-like behaviors using CaV1.3-deficient mice (CaV1.3-/-). However, CaV1.3-/- mice are congenitally deaf and it is so far unclear how deafness affects emotional behavior in mice. We therefore used another mouse model suffering from congenital deafness, claudin 14-deficient mice (Cldn14-/-) as a control to address this question. As CaV1.3 channels are expressed in the retina we also investigated CaV1.3-/- mice for possible disturbances in retinal morphology and visual function that could interfere with behavioral analysis.
Depression-like behavior was assessed using forced swim and tail suspension tests (FST and TST) whereas elevated plus maze (EPM) and stress-induced hyperthermia (SIH) were performed to test anxiety-like behavior. Morris water maze, electroretinography and immunofluorescence stainings were performed to evaluate the consequence on visual acuity and retinal morphology of CaV1.3 deletion in CaV1.3-/- mice.
We showed that CaV1.3-/- mice displayed less immobility in the FST as well as in the TST, indicating an antidepressant-like phenotype. In the EPM, CaV1.3-/- mice entered the open arms more frequently and spent more time there indicating an anxiolytic-like phenotype which was, however not supported in the SIH test. By performing parallel experiments in Cldn14-/- mice, an influence of deafness on the antidepressant-like phenotype could be ruled out. On the other hand, a similar EPM behavior indicative of an anxiolytic phenotype was also found in the Cldn14-/- animals. Using electroretinography and visual behavioral tasks we demonstrated that in mice, CaV1.3 channels do not significantly contribute to visual function. However, distinct morphological changes were revealed in synaptic ribbons in the outer plexiform layer of CaV1.3-/- retinas by immunohistochemistry. Although these changes have no major effects on visual function, they indicate a possible role of this channel type in structural plasticity at the ribbon synapse.
CaV1.3 LTCCs modulate depression-like behavior but are not essential for visual function. The findings raise the possibility that selective modulation of CaV1.3 channels could be a promising new therapeutic concept for the treatment of mood disorders.
Supported by the Austrian Science Fund (P-20670 and W11).