Abstract
Recent findings point to a central role of the endoplasmic reticulum-resident STIM (Stromal Interaction Molecule) proteins in shaping the structure and function of excitatory synapses in the mammalian brain. The impact of the Stim genes on cognitive functions remains, however, poorly understood. To explore the function of the Stim genes in learning and memory, we generated three mouse strains with conditional deletion (cKO) of Stim1 and/or Stim2 in the forebrain. Stim1, Stim2, and double Stim1/Stim2 cKO mice show no obvious brain structural defects or locomotor impairment. Analysis of spatial reference memory in the Morris water maze revealed a mild learning delay in Stim1 cKO mice, while learning and memory in Stim2 cKO mice was indistinguishable from their control littermates. Deletion of both Stim genes in the forebrain resulted, however, in a pronounced impairment in spatial learning and memory reflecting a synergistic effect of the Stim genes on the underlying neural circuits. Notably, long-term potentiation (LTP) at CA3-CA1 hippocampal synapses was markedly enhanced in Stim1/Stim2 cKO mice and was associated with increased phosphorylation of the AMPA receptor subunit GluA1, the transcriptional regulator CREB and the L-type Voltage-dependent Ca2+ channel Cav1.2 on protein kinase A (PKA) sites. We conclude that STIM1 and STIM2 are key regulators of PKA signaling and synaptic plasticity in neural circuits encoding spatial memory. Our findings also reveal an inverse correlation between LTP and spatial learning/memory and suggest that abnormal enhancement of cAMP/PKA signaling and synaptic efficacy disrupts the formation of new memories.
Highlights
STIM1 and STIM2 are endoplasmic reticulum (ER)-resident Ca2+ sensors that regulate store-operated Ca2+ entry (SOCE), the major Ca2+ influx pathway in non-excitable cells (Liou et al, 2005; Roos et al, 2005)
Both Stromal Interaction Molecule (STIM) isoforms are expressed throughout the nervous system, STIM1 is more abundant in the cerebellum (SkibinskaKijek et al, 2009; Hartmann et al, 2014), while STIM2 is the predominant isoform in the hippocampus (Berna-Erro et al, 2009; Skibinska-Kijek et al, 2009; Sun et al, 2014; Garcia-Alvarez et al, 2015), an expression pattern which is consistent with the reported functions of these isoforms in the brain
The Stim Genes are Required for a Specific form of Long-term Spatial Memory We report here the first behavioral analysis of mutant mice with conditional deletion of the Stim genes in the forebrain
Summary
STIM1 and STIM2 are endoplasmic reticulum (ER)-resident Ca2+ sensors that regulate store-operated Ca2+ entry (SOCE), the major Ca2+ influx pathway in non-excitable cells (Liou et al, 2005; Roos et al, 2005). A recent body of evidence indicates that STIMs function in the brain and shape synaptic transmission and architecture (Gruszczynska-Biegala et al, 2011; Hartmann et al, 2014; Sun et al, 2014; Garcia-Alvarez et al, 2015) Both STIM isoforms are expressed throughout the nervous system, STIM1 is more abundant in the cerebellum (SkibinskaKijek et al, 2009; Hartmann et al, 2014), while STIM2 is the predominant isoform in the hippocampus (Berna-Erro et al, 2009; Skibinska-Kijek et al, 2009; Sun et al, 2014; Garcia-Alvarez et al, 2015), an expression pattern which is consistent with the reported functions of these isoforms in the brain. Systemic ablation of the Stim gene protects against hypoxic neuronal cell death (Berna-Erro et al, 2009) and reduced levels of STIM2 in a presenilin-1 mouse model of Alzheimer’s disease accounts for a decrease in the fraction of mature (mushroom) dendritic spines in hippocampal neurons (Sun et al, 2014)
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