Gene Expression in Long-Term Memory

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.

Grant Number: 5R01MH065635-25
NIH Institute/Center: NIH
Principal Investigator: CRISTINA ALBERINI