Abstract
Experimental evidence highlights the involvement of the endoplasmic reticulum (ER)-mediated Ca2+ signals in modulating synaptic plasticity and spatial memory formation in the hippocampus. Ca2+ release from the ER mainly occurs through two classes of Ca2+ channels, inositol 1,4,5-trisphosphate receptors (InsP3Rs) and ryanodine receptors (RyRs). Calsequestrin (CASQ) and calreticulin (CR) are the most abundant Ca2+-binding proteins allowing ER Ca2+ 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 Ca2+ handling analysis in CA1 pyramidal cells showed a decrement of Ca2+ 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 Ca2+ release, thus facilitating synaptic plasticity and spatial learning in post-natal development.
Highlights
Calcium ions (Ca2+) play a crucial role as second messengers in all cell types [1]
We mainly found that CASQ2 is the isoform expressed in the hippocampus, and that the lack of this protein results in synaptic plasticity enhancement and spatial learning improvement, possibly by affecting the Ca2+ dynamics
The quantification of CASQ1 and CASQ2 mRNA was carried out using extensor digitorum longus (EDL) skeletal muscle as reference tissue (Figure 1A,B)
Summary
Transient elevations of intracellular Ca2+ concentration ([Ca2+]i) are pivotal for many cellular functions [2]. The rise of cytosolic Ca2+ concentration triggers the release of neurotransmitter at the synaptic junction, contributes to action potential, and regulates the activity-dependent changes in gene expression [3,4]. Ca2+ signals are critical for cellular and molecular mechanisms underlying synaptic plasticity [4,5,6], crucial in physiological brain functions, such as learning and memory [7]. Neuronal Ca2+ signals arise either from Ca2+ entry, mostly via voltage-gated or receptor-operated Ca2+ channels; via store-operated Ca2+ entry (SOCE) [8]; and/or from Ca2+ release from intracellular stores (i.e., endoplasmic reticulum, ER). Ca2+ release from the ER may occur via the inositol 1,4,5-trisphosphate receptor (InsP3R) or the ryanodine receptor (RyR) Ca2+
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