Wednesday, February 5, 2025
2/5/2025
Project Summary Memories are essential for survival and contribute to numerous brain functions. The storage of long-term memories takes time: newly formed memories are initially labile, but over time stabilize and strengthen through a process known as memory consolidation. Defects in this process underlie many devastating conditions associated with cognitive impairment, including neurodevelopmental disorders and neurodegenerative diseases. Therefore, elucidating the molecular mechanisms underlying memory consolidation and strengthening is key to understanding how memories function and ultimately developing novel, effective therapies to treat cognitive impairments. Over 25 years of work in this field, our group has identified fundamental molecular mechanisms of memory consolidation in the rat and mouse hippocampus, a brain region critical for episodic and spatial memories. Among those mechanisms, the gene encoding insulin-like growth factor 2 (IGF-2 or IGF-II) emerged as a key target of the evolutionarily conserved CREB-C/EBP pathway. IGF-2 is necessary for memory consolidation and also strengthens memory. In fact, administering recombinant IGF-2 at the time of learning or memory retrieval significantly enhances and prolongs memory retention by preventing memory decay. These memory-enhancing effects are mediated selectively via a high- affinity receptor for IGF-2, known as IGF-2 receptor (IGF-2R). Another ligand of this receptor, mannose-6- phosphate (M6P), exerts similar effects, indicating that memory enhancement derives from IGF-2R activation, which itself is necessary for memory consolidation. In mouse models, both IGF-2 and M6P can reverse most core deficits of autism spectrum disorder and Angelman syndrome, as well as major problems associated with neurodegenerative diseases including Alzheimer’s and Huntington’s disease; these effects are mediated via IGF-2R. Despite these remarkable effects in both healthy and pathophysiological states, relatively little is known about the biology of the IGF-2/IGF-2R system in the brain. Based on strong preliminary data, in the proposed research we aim to significantly advance the cellular and molecular characterization of the IGF- 2/IGF-2R system. By employing state-of-the-art molecular techniques, including RNAscope, regulated mouse genetics, biochemistry, immunohistochemistry, proteomics, transmission electron microscopy, ribosomal profiling, RNA-seq, and hippocampus-dependent behavioral tasks in mice, we will accomplish the following Aims: 1) Determine which hippocampal cell types express and regulate IGF-2 and IGF-2R under basal conditions and during memory consolidation; 2) Identify the hippocampal cell types that require IGF-2 and/or IGF-2R to form long-term memory; and 3) Elucidate the mechanisms of action of IGF-2R in memory consolidation. The outcomes of the proposed studies will significantly advance our understanding of the roles of IGF-2 and IGF-2R in memory consolidation and enhancement.
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