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

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 (IP₃ R2) is the main isoform expressed by astrocytes. The complete lack of IP₃ R2 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 IP₃ R2-mediated signaling did not disrupt normal learning or recent (24-48 h) memory. Contrary to expectations, however, mice lacking IP₃ R2 exhibited remote (2-4 weeks) memory deficits. Not only did the lack of IP₃ R2 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 IP₃ R2-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 IP₃ R2 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.

KEYWORDS: {{ getKeywords(articleDetailText.words) }}