Abstract
Cav1.3 has been suggested to mediate hippocampal neurogenesis of adult mice and contribute to hippocampal-dependent learning and memory processes. However, the mechanism of Cav1.3 contribution in these processes is unclear. Here, roles of Cav1.3 of mouse dorsal hippocampus during newborn cell development were examined. We find that knock-out (KO) of Cav1.3 resulted in the reduction of survival of newborn neurons at 28 days old after mitosis. The retroviral eGFP expression showed that both dendritic complexity and the number and length of mossy fiber bouton (MFB) filopodia of newborn neurons at ≥ 14 days old were significantly reduced in KO mice. Both contextual fear conditioning (CFC) and object-location recognition tasks were impaired in recent (1 day) memory test while passive avoidance task was impaired only in remote (≥ 20 days) memory in KO mice. Results using adeno-associated virus (AAV)-mediated Cav1.3 knock-down (KD) or retrovirus-mediated KD in dorsal hippocampal DG area showed that the recent memory of CFC was impaired in both KD mice but the remote memory was impaired only in AAV KD mice, suggesting that Cav1.3 of mature neurons play important roles in both recent and remote CFC memory while Cav1.3 in newborn neurons is selectively involved in the recent CFC memory process. Meanwhile, AAV KD of Cav1.3 in ventral hippocampal area has no effect on the recent CFC memory. In conclusion, the results suggest that Cav1.3 in newborn neurons of dorsal hippocampus is involved in the survival of newborn neurons while mediating developments of dendritic and axonal processes of newborn cells and plays a role in the memory process differentially depending on the stage of maturation and the type of learning task.
Highlights
L-type calcium channels (LTCCs) are formed by the Cav1 family, which comprise isoforms of Cav1.1–4 [1]
Immunohistochemistry of Cav1.3 showed the strong expression in cell body regions compared to dendritic and axonal regions of neurons in Cornu Ammonis 1 (CA1), CA3 and DG of dorsal hippocampus and cortex of adult mice (Fig 1A and S1B Fig), which is consistent with Veng and Browning (2002) [41]
The results suggest that Cav1.3 in mature neurons of dorsal hippocampus is important for both recent and remote memories of contextual fear conditioning (CFC) learning and Cav1.3 activity from some group of neurons is enough for maintaining these CFC memories
Summary
L-type calcium channels (LTCCs) are formed by the Cav family, which comprise isoforms of Cav1.1–4 [1] In neurons, both Cav1.2 and Cav1.3 are expressed [2] and are known to regulate neuronal excitability [3, 4], gene expression [5, 6], synaptic plasticity [3, 7,8,9], and learning and memory [10]. Null Cav1.3 KO mice showed impairment in the recent memory of object location recognition (OLR) task [21] and CFC though there were no effects in extinctions at 2 to 3 days after training and in the recent memory of water-maze learning [16] These genetic studies suggest differential roles of Cav1.2 and Cav1.3 even in hippocampal-dependent learning and memory tasks. It is still unclear how hippocampal Cav1.3 contributes to CFC learning and memory and whether the remote memory of CFC is affected or not in Cav1.3 KO mice
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