Long-term potentiation (LTP) of synaptic strength at Schaffer collateral synapses has largely been attributed to changes in the number and biophysical properties of AMPA receptors (AMPARs). Small-conductance Ca 2+ -activated K + channels (SK2 channels) are functionally coupled with NMDA receptors (NMDARs) in CA1 spines such that their activity modulates the shape of excitatory postsynaptic potentials (EPSPs) and increases the threshold for induction of LTP. Here we show that LTP induction in mouse hippocampus abolishes SK2 channel activity in the potentiated synapses. This effect is due to SK2 channel internalization from the postsynaptic density (PSD) into the spine. Blocking PKA or cell dialysis with a peptide representing the C-terminal domain of SK2 that contains three known PKA phosphorylation sites blocks the internalization of SK2 channels after LTP induction. Thus the increase in AMPARs and the decrease in SK2 channels combine to produce the increased EPSP underlying LTP.Activity-dependent changes in synaptic strength are widely believed to underlie the cellular mechanisms of learning and memory. This view has gained significant support from recent studies showing that learning induces long-lasting changes in synaptic strength 1-3 . At Schaffer collateral-to-CA1 synapses in the hippocampus, stimulation protocols that coordinate presynaptic and postsynaptic activity to induce LTP affect the postsynaptic cell through a process that is dependent upon NMDAR activity and Ca 2+ influx into the stimulated dendritic spine 4-6 . LTP inducing protocols act through PKA and calcium/calmodulin-dependent kinase II (CaMKII) to alter the biophysical properties 7-9 and increase the number of AMPARs in the PSD 10-14 .SK2 channels are activated solely by intracellular Ca 2+ ions, with submicromolar Ca 2+ affinity 15 , and are selectively blocked by the peptide toxin apamin. SK2 channels are expressed throughout the dendritic arbor of CA1 neurons and in dendritic spines 16,17 . Whole-cell current-clamp recordings and Ca 2+ imaging revealed that spine SK2 channels are activated by synaptically driven Ca 2+ influx 16 . The repolarizing effect of SK2 channel activity opposes the depolarizing effect of AMPAR activity, reducing the EPSP, favoring Mg 2+ reblocking of NIH Public Access Author ManuscriptNat Neurosci. Author manuscript; available in PMC 2009 January 5. Published in final edited form as:Nat Neurosci. 2008 February ; 11(2): 170-177. doi:10.1038/nn2041. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptNMDARs and reducing the Ca 2+ transient 16 . SK2 channels are therefore ideally suited to modulate the induction of synaptic plasticity. Indeed, field recordings in area CA1 showed that blocking SK2 channels facilitates the induction of synaptic plasticity. In addition, administration of apamin to mice facilitates hippocampal-dependent memory encoding 18 . In contrast, overexpression of SK2 channels in transgenic mice impairs the induction of synaptic plasticity and severely impairs hippoc...

Vitamin D deficiency is associated with muscle weakness, pain, and atrophy. Serum vitamin D predicts muscle strength and age-related muscle changes. However, precise mechanisms by which vitamin D affects skeletal muscle are unclear. To address this question, this study characterizes the muscle phenotype and gene expression of mice with deletion of vitamin D receptor (VDRKO) or diet-induced vitamin D deficiency. VDRKO and vitamin D-deficient mice had significantly weaker grip strength than their controls. Weakness progressed with age and duration of vitamin D deficiency, respectively. Histological assessment showed that VDRKO mice had muscle fibers that were significantly smaller in size and displayed hyper-nuclearity. Real-time PCR also indicated muscle developmental changes in VDRKO mice with dysregulation of myogenic regulatory factors (MRFs) and increased myostatin in quadriceps muscle (>2-fold). Vitamin D-deficient mice also showed increases in myostatin and the atrophy marker E3-ubiqutin ligase MuRF1. As a potential explanation for grip strength weakness, both groups of mice had down-regulation of genes encoding calcium-handling and sarco-endoplasmic reticulum calcium transport ATPase (Serca) channels. This is the first report of reduced strength, morphological, and gene expression changes in VDRKO and vitamin D-deficient mice where confounding by calcium, magnesium, and phosphate have been excluded by direct testing. Although suggested in earlier in vitro work, this study is the first to report an in vivo association between vitamin D, myostatin, and the regulation of muscle mass. These findings support a direct role for vitamin D in muscle function and corroborate earlier work on the presence of VDR in this tissue.

SUMMARY Ca2+-activated SK channels and voltage-gated A-type Kv4 channels shape dendritic excitatory postsynaptic potentials (EPSPs) in hippocampal CA1 pyramidal neurons. Synaptically evoked Ca2+ influx through N-methyl-D-aspartate receptors (NMDARs) activates spine SK channels, reducing EPSPs and the associated spine head Ca2+ transient. However, results using glutamate uncaging implicated Ca2+ influx through SNX-482 (SNX) sensitive Cav2.3 (R-type) Ca2+ channels as the Ca2+ source for SK channel activation. The present findings show that using Schaffer collateral stimulation the effects of SNX and apamin are not mutually exclusive and SNX increases EPSPs independent of SK channel activity. Dialysis with 1,2-bis(o-aminophenoxy)ethane-N’N’N’-tetraacetic acid (BAPTA), application of 4-Aminopyridine (4-AP), expression of a Kv4.2 dominant negative subunit, and dialysis with a KChIPs antibody occluded the SNX-induced increase of EPSPs. The results suggest two distinct Ca2+ signaling pathways within dendritic spines, that links Ca2+ influx through NMDARs to SK channels and Ca2+ influx through R-type Ca2+ channels to Kv4.2-containing channels.

No abstract