Ca2+-Binding Protein 1 Regulates Hippocampal-dependent Memory and Synaptic Plasticity

Abstract

Ca-binding protein 1 (CaBP1) is a Ca-sensing protein similar to calmodulin that potently regulates voltage-gated Ca channels. Unlike calmodulin, however, CaBP1 is mainly expressed in neuronal cell-types and enriched in the hippocampus, where its function is unknown. Here, we investigated the role of CaBP1 in hippocampal-dependent behaviors using mice lacking expression of CaBP1 (C-KO). By western blot, the largest CaBP1 splice variant, caldendrin, was detected in hippocampal lysates from wild-type (WT) but not C-KO mice. Compared to WT mice, C-KO mice exhibited mild deficits in spatial learning and memory in both the Barnes maze and in Morris water maze reversal learning. In contextual but not cued fear-conditioning assays, C-KO mice showed greater freezing responses than WT mice. In addition, the number of adult-born neurons in the hippocampus of C-KO mice was ∼40% of that in WT mice, as measured by bromodeoxyuridine labeling. Moreover, hippocampal long-term potentiation was significantly reduced in C-KO mice. We conclude that CaBP1 is required for cellular mechanisms underlying optimal encoding of hippocampal-dependent spatial and fear-related memories.

Neuronal ensemble-specific DNA methylation strengthens engram stability

“…Here we found that the expression of Dnmt3a2 triggered by neuronal activity in primary hippocampal cultures leads to DNA methylation changes preferentially in genes that regulate synaptic strength and structure and learning and memory. Namely, genes involved in the modification of the postsynaptic membrane (Tiam1, Ctnnd2, Cabp1, Kalrn, Lrrtm1, Farp1) and in neurotransmitter receptor activity (Grin2b, Gabrg2), several of which have demonstrated roles in memory formation (Tiam1: [23][24][25][26] ; Cabp1: [27][28][29] ; Lrrtm1: 30,31 ). Thus, this observation suggests that the expression of Dnmt3a2 in behaviorally allocated neurons modulates functional and structural plasticity in neuronal ensembles during memory consolidation, which likely strengthens engram stability and determines the likelihood of their reactivation.…”

Calcium Sensors in Neuronal Function and Dysfunction

“…These findings are consistent with related studies highlighting a function for caldendrin in the hippocampus. It is required for efficient encoding of hippocampaldependent spatial and fear-based memory (Yang et al 2018a), and mice in which all CaBP1 isoforms are deleted, including caldendrin, exhibit defects in excitation/inhibition in hippocampal circuits (Nanou et al 2018;Yang et al 2018b).…”

Caldendrin and Calneurons—EF-Hand CaM-Like Calcium Sensors With Unique Features and Specialized Neuronal Functions

“…Accordingly, it was reported in a recent study (Yang et al, 2018) that caldendrin knock-out mice exhibit deficits in spatial learning and memory and also fear-related memories. Surprisingly, it was also found that adult neurogenesis in the hippocampus is severely impaired in knock-out animals by yet unknown mechanisms (Yang et al, 2018). It is likely that this impairment will also contribute to learning and memory deficits in these mice.…”

“…Importantly, Li et al (2009) could show that binding of CaBP1 to InsP 3 R is much stronger than those of CaM to InsP 3 Rs, indicating that the former interaction will easily dominate and is more significant for InsP 3 R function and given the abundance of Caldendrin in spines it will clearly outcompete CaM. Furthermore, the low expression of CaBP1 in the hippocampus makes it likely that caldendrin is the Ca 2+ sensor for regulating hippocampal InsP 3 Rs and might thereby play an important role in synapto-dendritic Ca 2+ signaling as a prominent inhibitor of InsP 3 Rs in the hippocampus, a prediction that can be easily tested now due to the existence of caldendrin/CaBP1 knockout mice models (Kim et al, 2014; Mikhaylova et al, 2018; Yang et al, 2018).…”

“…Caldendrin/CaBP1 knockout mice show a rapid depression at inhibitory presynaptic sites that is related to binding and inactivation of Ca V 2.1 calcium channels in control of short-term synaptic plasticity (Lee et al, 2002; Few et al, 2011; Leal et al, 2012; Nanou et al, 2018). Other potential binding partners where a cellular and in particular synaptic function is less well investigated include light chain 3 (Seidenbecher et al, 2004), myo1c (Tang et al, 2007), recoverin (Fries et al, 2010), metabotropic glutamate receptors (Nakajima, 2011), AKAP79/150 (Seeger et al, 2012) and Ca V 1.3 calcium channels (Findeisen et al, 2013; Yang et al, 2018).…”