AUTHOR=Garcia-Alvarez Gisela , Shetty Mahesh S., Lu Bo , Yap Kenrick A., Oh-Hora Masatsugu , Sajikumar Sreedharan , Bichler Zoe , Fivaz Marc 

TITLE=Impaired spatial memory and enhanced long-term potentiation in mice with forebrain-specific ablation of the Stim genes

JOURNAL=Frontiers in Behavioral Neuroscience

VOLUME=9

YEAR=2015

URL=https://www.frontiersin.org/journals/behavioral-neuroscience/articles/10.3389/fnbeh.2015.00180

DOI=10.3389/fnbeh.2015.00180

ISSN=1662-5153

ABSTRACT=<p>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 <italic>Stim</italic> genes on cognitive functions remains, however, poorly understood. To explore the function of the <italic>Stim</italic> genes in learning and memory, we generated three mouse strains with conditional deletion (cKO) of <italic>Stim1</italic> and/or <italic>Stim2</italic> in the forebrain. <italic>Stim1</italic>, <italic>Stim2</italic>, and double <italic>Stim1/Stim2</italic> 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 <italic>Stim1</italic> cKO mice, while learning and memory in <italic>Stim2</italic> cKO mice was indistinguishable from their control littermates. Deletion of both <italic>Stim</italic> genes in the forebrain resulted, however, in a pronounced impairment in spatial learning and memory reflecting a synergistic effect of the <italic>Stim</italic> genes on the underlying neural circuits. Notably, long-term potentiation (LTP) at CA3-CA1 hippocampal synapses was markedly enhanced in <italic>Stim1/Stim2</italic> cKO mice and was associated with increased phosphorylation of the AMPA receptor subunit GluA1, the transcriptional regulator CREB and the L-type Voltage-dependent Ca<sup>2+</sup> 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.</p>