Impaired Memory Retention and Decreased Long-Term Potentiation in Integrin-Associated Protein-Deficient Mice

Autor: Hai L. Wang, A-Min Huang, Frederik P. Lindberg, Eminy H.Y. Lee, Hui P. Chang
Rok vydání: 1999
Předmět:
Zdroj: Learning & Memory. 6:448-457
ISSN: 1549-5485
1072-0502
DOI: 10.1101/lm.6.5.448
Popis: Vertebrate memory formation requires de novo gene expression and protein synthesis as mRNA and protein synthesis inhibitors are known to impair long-term memory formation (Davis and Squire 1984). Long-term memories are also believed to be stored by modification of pre-existing synapses or formation of new synaptic contacts (Weiler et al. 1995). Using a PCR differential display method, previously we have found that hippocampal integrin-associated protein (IAP) mRNA levels are fourfold higher in rats showing good retention performance than in poor memory controls or untrained animals in a one-way inhibitory avoidance learning task (Huang et al. 1998). Furthermore, IAP antisense oligonucleotide treatment significantly impaired retention performance and inhibited long-term potentiation (LTP), a synaptic model for long-term memory (Bliss and Collingridge 1993) in rats (Huang et al. 1998). These results suggest that IAP mRNA expression is necessary for memory formation and synaptic plasticity in rats. Integrins are heterodimeric cell surface receptors that mediate regulated cell–cell interactions and adhesive interactions between cells and the extracellular matrix (ECM) proteins (Juliano and Haskill 1993; Clark and Brugge 1995). Recent evidence has shown that integrins are also involved in various central nervous system functions (for review, see Jones 1996). For example, integrins are known to be involved in anatomical organization and neurite growth during development (Reichardt and Tomaselli 1991; Defreitas et al. 1995). More related to the present study, integrin and integrinlike proteins are involved in neuroplasticity because the integrin antagonist GRGDSP and the GRGDSP analog peptides have been shown to inhibit LTP in rats (Staubli et al. 1990, 1998). The IAP is a 50-kD ubiquitously expressed membrane glycoprotein that is associated with integrin (Brown et al. 1990) and regulates the function of αvβ3 class of integrins in placenta and platelets (Lindberg et al. 1993, 1996b). It also acts as a receptor for the cell-binding domain of the thrombospondin (TSP) family of ECM proteins (Schwartz et al. 1993; Gao et al. 1996a,b). In a very recent study, IAP has been demonstrated to have its selective binding partner on the cell membrane of cerebellar neurons (Jiang et al. 1999). Immunological studies have shown that IAP can also act independent of β3 integrins in T-cell costimulation (Reinhold et al. 1997). These results suggest that IAP may have independent physiological functions. In the present study, we aimed to further investigate the role of IAP involved in memory processing and LTP. If IAP does play an important role in memory formation and synaptic plasticity, it is expected that both retention performance and LTP are impaired in animals deficient in IAP. To test this hypothesis, we have used IAP-deficient mice and have adopted both the in vivo LTP model and the inhibitory avoidance learning paradigm, the paradigm originally used to demonstrate the IAP gene (Huang et al. 1998). Flow cytometry of red blood cells was used to verify the genotype of all animals and Western blot analysis was used to verify the lack of the IAP protein in IAP knockout mice. Our results demonstrate that IAP plays an essential role in the process of memory formation and synaptic plasticity in rats and mice.
Databáze: OpenAIRE
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