Calsequestrin Deletion Facilitates Hippocampal Synaptic Plasticity and Spatial Learning in Post-Natal Development

Experimental evidence highlights the involvement of the endoplasmic reticulum (ER)-mediated Ca(2+) signals in modulating synaptic plasticity and spatial memory formation in the hippocampus. Ca(2+) release from the ER mainly occurs through two classes of Ca(2+) channels, inositol 1,4,5-trisphosphate receptors (InsP3Rs) and ryanodine receptors (RyRs). Calsequestrin (CASQ) and calreticulin (CR) are the most abundant Ca(2+)-binding proteins allowing ER Ca(2+) storage. The hippocampus is one of the brain regions expressing CASQ, but its role in neuronal activity, plasticity, and the learning processes is poorly investigated. Here, we used knockout mice lacking both CASQ type-1 and type-2 isoforms (double (d)CASQ-null mice) to: a) evaluate in adulthood the neuronal electrophysiological properties and synaptic plasticity in the hippocampal Cornu Ammonis 1 (CA1) field and b) study the performance of knockout mice in spatial learning tasks. The ablation of CASQ increased the CA1 neuron excitability and improved the long-term potentiation (LTP) maintenance. Consistently, (d)CASQ-null mice performed significantly better than controls in the Morris Water Maze task, needing a shorter time to develop a spatial preference for the goal. The Ca(2+) handling analysis in CA1 pyramidal cells showed a decrement of Ca(2+) transient amplitude in (d)CASQ-null mouse neurons, which is consistent with a decrease in afterhyperpolarization improving LTP. Altogether, our findings suggest that CASQ deletion affects activity-dependent ER Ca(2+) release, thus facilitating synaptic plasticity and spatial learning in post-natal development.