Several lines of evidence indicate that long-term potentiation (LTP) is the substrate for commonplace forms of memory. Like memory, LTP has a consolidation phase such that it is easily disrupted for a short period after its induction but then becomes progressively more stable. Once consolidated, LTP can persist for a significant portion of the animal's lifespan. A great challenge for cellular accounts of LTP is to identify mechanisms that align with the time course of consolidation, have a logical relationship to enhanced transmission, and are still capable of producing changes of extraordinary longevity. The planned studies, which represent an extension of a previous grant, will test a specific hypothesis that appears to satisfy these constraints. The hypothesis involves integrins, a class of transmembrane proteins that connect the extracellular matrix to the intracellular cytoskeleton, and thereby generate the adhesion junctions that anchor cells. Work by the applicants and others identified several different integrins in synapses (the brain's primary adhesion junctions) and further showed that a certain number of these play a critical role in LTP consolidation. The proposed studies will test for the following sequence in hippocampus: a) the triggering events for LTP activate integrins, which then b) modify synaptic glutamate receptors and c) reorganize the actin cytoskeleton. The last of these events is known from non-neural systems to be capable of producing extremely stable changes.
Four specific aims will be used to test the integrin/LTP stabilization hypothesis.
Aim One will determine if stimulation of glutamate receptors increases integrin signaling by converting integrins from a quiescent to an active state and/or increasing their surface expression.
Aim Two will determine if up-regulation of glutamate receptors by integrins a) includes increased AMPA receptor surface expression and b) is dependent upon changes in the actin network.
Aim Three will test if actin polymerization in adult spines, an effect recently found by the applicants to accompany LTP, is initiated by integrins.
Aim Four will determine if reversal of recently induced LTP by low frequency stimulation is due to an adenosine-mediated block of actin polymerization. The results of these experiments are expected to provide a strong test of a specific hypothesis regarding how LTP, and therefore possibly memory, becomes consolidated.
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