Abstract
N-Methyl-D-Aspartate Receptor 1 (NMDAR)-linked Ca++ current represents a significant percentage of post-synaptic transient that modulates synaptic strength and is pertinent to dendritic spine plasticity. In the hippocampus, Ca++ transient produced by glutamatergic ionotropic neurotransmission facilitates Ca++-Calmodulin-dependent kinase 2 (CaMKII) Thr286 phosphorylation and promote long-term potentiation (LTP) expression. At CA1 post-synaptic densities, Ca++ transients equally activate small conductance (SK2) channel which regulates excitability by suppressing Ca++ movement. Here, we demonstrate that upstream attenuation of GluN1 function in the hippocampus led to a decrease in Thr286 CaMKIIα phosphorylation, and increased SK2 expression. Consistent with the loss of GluN1 function, potentiation of SK channel in wild type hippocampus reduced CaMKIIα expression and abrogate synaptic localization of T286 pCaMKIIα. Our results demonstrate that positive modulation of SK channel at hippocampal synapses likely refine GluN1-linked plasticity by tuning dendritic localization of CaMKIIα.
Highlights
The hippocampus is the center for processing of spatial working memory
We reported that the pharmacologically-induced N-Methyl-D-Aspartate Receptor 1 (NMDAR) hypofunction suppressed CaMKII expression, and increased SK2 expression in the hippocampus of wild type (WT) mice (Ogundele and Lee, 2018)
Three weeks after hippocampal associated virus (AAV) injection, transfection was verified by fluorescence imaging of the reporter protein harbored by the AAV constructs
Summary
The hippocampus is the center for processing of spatial working memory. At hippocampal synapses, synaptic long-term potentiation (LTP) is dependent on glutamatergic neurotransmission (Cacucci et al, 2007; Allen et al, 2016). SK Channel Regulation of Synaptic Potentiation (González Burgos et al, 2012; Bosch et al, 2014; Chazeau and Giannone, 2016; Bustos et al, 2017; Frangeul et al, 2017; Forrest et al, 2018) To this effect, synaptic perturbations in the cognitive centers translate into impairment of neural encoding of instantaneous (working) memory. High-frequency spiking events involve the transient surge of postsynaptic Ca++ current that is mediated by NMDAR-linked ionotropic neurotransmission (Xia et al, 1996; Coultrap and Bayer, 2012). We reported that the pharmacologically-induced NMDAR hypofunction suppressed CaMKII expression, and increased SK2 expression in the hippocampus of WT mice (Ogundele and Lee, 2018) This outcome suggests that T286 phosphorylation of CaMKIIα and expression of SK2 may be inversely related in NMDAR hypofunction. Our results suggest that SK2 regulate hippocampal excitability—in part—by modulating dendritic localization of CaMKII
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