Impairments in remote memory caused by the lack of Type 2 IP3 receptors

TitleImpairments in remote memory caused by the lack of Type 2 IP3 receptors
Publication TypeJournal Article
Year of Publication2019
AuthorsPinto-Duarte A, Roberts AJ, Ouyang K, Sejnowski TJ
Keywordsastrocyte, Behavior, Ca2+ signaling, long-term memory, synaptic plasticity

Abstract The second messenger inositol 1,4,5-trisphosphate (IP3) is paramount for signal transduction in biological cells, mediating Ca2+ release from the endoplasmic reticulum. Of the three isoforms of IP3 receptors identified in the nervous system, Type 2 (IP3R2) is the main isoform expressed by astrocytes. The complete lack of IP3R2 in transgenic mice was shown to significantly disrupt Ca2+ signaling in astrocytes, while leaving neuronal intracellular pathways virtually unperturbed. Whether and how this predominantly nonneuronal receptor might affect long-term memory function has been a matter of intense debate. In this work, we found that the absence of IP3R2-mediated signaling did not disrupt normal learning or recent (24–48 h) memory. Contrary to expectations, however, mice lacking IP3R2 exhibited remote (2–4 weeks) memory deficits. Not only did the lack of IP3R2 impair remote recognition, fear, and spatial memories, but it also prevented naturally occurring post-encoding memory enhancements consequent to memory consolidation. Consistent with the key role played by the downscaling of synaptic transmission in memory consolidation, we found that NMDAR-dependent long-term depression was abnormal in ex vivo hippocampal slices acutely prepared from IP3R2-deficient mice, a deficit that could be prevented upon supplementation with D-serine - an NMDA-receptor co-agonist whose synthesis depends upon astrocytes' activity. Our results reveal that IP3R2 activation, which in the brain is paramount for Ca2+ signaling in astrocytes, but not in neurons, can help shape brain plasticity by enhancing the consolidation of newly acquired information into long-term memories that can guide remote cognitive behaviors.

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