title: Impaired spatial memory and enhanced long-term potentiation in mice with forebrain-specific ablation of the Stim genes.
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 Ca(2+) 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.
authors.affiliation: Program in Neuroscience and Behavioral Disorders, Duke-NUS Graduate Medical School Singapore, Singapore.
authors.forename: Gisela
authors.initials: G
authors.lastname: Garcia-Alvarez
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore Singapore, Singapore.
authors.forename: Mahesh S
authors.initials: MS
authors.lastname: Shetty
authors.affiliation: Program in Neuroscience and Behavioral Disorders, Duke-NUS Graduate Medical School Singapore, Singapore.
authors.forename: Bo
authors.initials: B
authors.lastname: Lu
authors.affiliation: Program in Neuroscience and Behavioral Disorders, Duke-NUS Graduate Medical School Singapore, Singapore.
authors.forename: Kenrick An Fu
authors.initials: KA
authors.lastname: Yap
authors.affiliation: Division of Molecular Immunology, Medical Institute of Bioregulation, Kyushu University Higashi-ku, Japan.
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Oh-Hora
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore Singapore, Singapore.
authors.forename: Sreedharan
authors.initials: S
authors.lastname: Sajikumar
authors.affiliation: Program in Neuroscience and Behavioral Disorders, Duke-NUS Graduate Medical School Singapore, Singapore ; Behavioral Neuroscience Laboratory, National Neuroscience Institute Singapore, Singapore.
authors.forename: Zoë
authors.initials: Z
authors.lastname: Bichler
authors.affiliation: Program in Neuroscience and Behavioral Disorders, Duke-NUS Graduate Medical School Singapore, Singapore ; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore Singapore, Singapore.
authors.forename: Marc
authors.initials: M
authors.lastname: Fivaz
keywords: AMPA receptor; PKA; STIM1 and STIM2; endoplasmic reticulum; excitatory synapse; long-term potentiation; spatial memory