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Garcia-Alvarez G, Shetty MS, Lu B, et al. Impaired spatial memory and enhanced long-term potentiation in mice with forebrain-specific ablation of the Stim genes. Front Behav Neurosci. 2015;9:180doi: 10.3389/fnbeh.2015.00180.
Garcia-Alvarez, G., Shetty, M. S., Lu, B., Yap, K. A., Oh-Hora, M., Sajikumar, S., Bichler, Z., & Fivaz, M. (2015). Impaired spatial memory and enhanced long-term potentiation in mice with forebrain-specific ablation of the Stim genes. Frontiers in behavioral neuroscience, 9180. https://doi.org/10.3389/fnbeh.2015.00180
Garcia-Alvarez, Gisela, et al. "Impaired spatial memory and enhanced long-term potentiation in mice with forebrain-specific ablation of the Stim genes." Frontiers in behavioral neuroscience vol. 9 (2015): 180. doi: https://doi.org/10.3389/fnbeh.2015.00180
Garcia-Alvarez G, Shetty MS, Lu B, Yap KA, Oh-Hora M, Sajikumar S, Bichler Z, Fivaz M. Impaired spatial memory and enhanced long-term potentiation in mice with forebrain-specific ablation of the Stim genes. Front Behav Neurosci. 2015 Jul 14;9:180. doi: 10.3389/fnbeh.2015.00180. eCollection 2015. PMID: 26236206; PMCID: PMC4500926.
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Front Behav Neurosci. 2015 Jul 14;9:180. doi: 10.3389/fnbeh.2015.00180. eCollection 2015.

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

Frontiers in behavioral neuroscience

Gisela Garcia-Alvarez, Mahesh S Shetty, Bo Lu, Kenrick An Fu Yap, Masatsugu Oh-Hora, Sreedharan Sajikumar, Zoë Bichler, Marc Fivaz

Affiliations

  1. Program in Neuroscience and Behavioral Disorders, Duke-NUS Graduate Medical School Singapore, Singapore.
  2. Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore Singapore, Singapore.
  3. Division of Molecular Immunology, Medical Institute of Bioregulation, Kyushu University Higashi-ku, Japan.
  4. Program in Neuroscience and Behavioral Disorders, Duke-NUS Graduate Medical School Singapore, Singapore ; Behavioral Neuroscience Laboratory, National Neuroscience Institute Singapore, Singapore.
  5. 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.

PMID: 26236206 PMCID: PMC4500926 DOI: 10.3389/fnbeh.2015.00180

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.

Keywords: AMPA receptor; PKA; STIM1 and STIM2; endoplasmic reticulum; excitatory synapse; long-term potentiation; spatial memory

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