Cavallaro S, D'Agata V, Manickam P, Dufour F, Alkon DL.
Memory-specific temporal profiles of gene expression in the hippocampus.
Proc Natl Acad Sci U S A. 2002 Dec 10;99(25):16279-84.
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A compelling report by Cavallaro et al. demonstrates expression level changes within the hippocampus of rats using a conventional spatial learning task combined with Affymetrix U34 rat neurobiology gene chips. This group has a distinguished track record in expression profiling analysis following learning and memory paradigms (Cavallaro et al., 1997; 2001; 2002), and the genome-wide scan is a natural extension of their developing body of work. In brief, total hippocampal RNA is accessed at one, six, and 24 hours after Morris water maze training to assay gene expression changes relevant to long-term memory. One of the important distinctions the authors provide is that changes in genes related to the physical activity of the task and potential stress of the behavioral training therein (termed PARGs—physical activity-related genes) differ from bona fide memory-related genes (MRGs). Genes are classified by comparing naïve animals and swimming controls (PARGs) and comparing swimming controls with water maze trained subjects (MRGs). Interestingly, the authors report approximately 27 percent (345/1,200) genes sampled are differentially expressed as PARGs, whereas fewer than half that number (11 percent) (140/1,200) are determined to be MRGs. Subsequent clustering analysis demonstrates a different expression profile in terms of relative abundance and temporal regulation for swimming controls and Morris water maze trained rats. Proof-of-concept experiments of expression level changes are performed utilizing qPCR as well as a behavioral pharmacology experiment using one of the more promising candidate genes—a member of the fibroblast growth factor family termed fibroblast growth factor (FGF)-18 (Ohbayashi et al., 1998). Moreover, following identification of an upregulation of FGF-18 on the cDNA microarray platform in the water maze trained subjects, infusion of FGF-18 peptide into the lateral ventricles enhanced memory by reducing latency to find the submerged platform.
Only a brief description of the results is outlined in this synopsis; the report is extremely well-written, with a terse Discussion section outlining several classes of genes pertinent to learning and memory, and to neurobiology as a whole. cDNA microarray experiments were performed using RNA extracted from the entire hippocampal formation, and it is tempting to speculate what gene changes would occur if subregions (e.g., CA3, CA1, and the granule cell layer of the dentate gyrus) were analyzed in this paradigm.
In terms of relevance to aging and Alzheimer’s disease (AD), an analogy can be drawn between expression profiling for PARGs versus MRGs in the learning and memory paradigm with genes related to senescence versus pathological aging such as mild cognitive impairment (MCI) and AD. Specifically, a goal is to identify the constellation of alterations within the genome and proteome that are associated with the aging process separately from the genetic/proteomic program(s) associated with MCI and AD. Finally, the demonstration that an FGF peptide may enhance memory is relevant towards pharmacotherapeutic interventions in AD, as many neurotrophic factors, including FGF, have been proposed as possible targets to halt the neurodegenerative process (see Mufson et al. for a review). In summary, the report by Cavallaro et al. provides a myriad of gene expression level changes for a well-established water maze task. These data comprise an initial report of genome-wide changes during learning and memory that are relevant toward understanding molecular substrates for memory loss in neurodegenerative disorders.—Stephen Ginsberg, Center for Dementia Research, Nathan Kline Institute, New York University School of Medicine, Orangeburg, New York.
Cavallaro S, Dagata V, Alkon DL.
Programs of gene expression during the laying down of memory formation as revealed by DNA microarrays.
Neurochem Res. 2002 Oct;27(10):1201-7.
Cavallaro S, Meiri N, Yi CL, Musco S, Ma W, Goldberg J, Alkon DL.
Late memory-related genes in the hippocampus revealed by RNA fingerprinting.
Proc Natl Acad Sci U S A. 1997 Sep 2;94(18):9669-73.
Cavallaro S, Schreurs BG, Zhao W, D'Agata V, Alkon DL.
Gene expression profiles during long-term memory consolidation.
Eur J Neurosci. 2001 May;13(9):1809-15.
Mufson EJ, Kroin JS, Sendera TJ, Sobreviela T.
Distribution and retrograde transport of trophic factors in the central nervous system: functional implications for the treatment of neurodegenerative diseases.
Prog Neurobiol. 1999 Feb;57(4):451-84.
Ohbayashi N, Hoshikawa M, Kimura S, Yamasaki M, Fukui S, Itoh N.
Structure and expression of the mRNA encoding a novel fibroblast growth factor, FGF-18.
J Biol Chem. 1998 Jul 17;273(29):18161-4.