The PLs lab and others have previously shown that aged, learning-impaired animals have deficits in both the early and late phases of LTP. The focus of the current proposal will be on attempts to identify the cellular and molecular bases of these deficits. In addition, in collaborations with other members of this program project, the PL will also examine nutritional and growth-factor-based interventions for their ability to ameliorate age-related molecular, cellular and behavioral deficits.
Aims 1 and 2 will focus on early phase LTP that is usually defined as the first 30-120 minutes following LTP induction. In the previous funding period, the PL demonstrated that age-related deficits in NMDAR function might play a role in deficits in the early phase of LTP and behavior.
In aim 1, he will use correlational analyses to test this hypothesis.
In aim 2, he will attempt to identify the mechanism of these age-related deficits in NMDAR function. This will include analyses of NMDAR gene transcription, mRNA and subunit protein turnover. In the previous funding period, the PL also demonstrated that there was a relatively selective, PKA-dependent increase in the transcription and synthesis of the k/AMPAR that may underlie the potentiation seen in the late phase of LTP.
In Aims 3 and 4, he will attempt to determine whether deficits in either the PKA-regulated k/AMPA gene expression or the synaptic targeting of the newly synthesized k/AMPAR underlie age-related deficits in late phase LTP. Lastly, in Aim 5 he will examine the ability of nutritional and growth-factor- based interventions to prevent or ameliorate the age-related deficits.
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