Older adults have difficulties with learning and memory acquisition. Severe impairment may be the basis for senile dementia. A vast accumulation of evidence strongly suggests that long term potentiation of synaptic function (LTP) may underlie learning and memory. Disruption of LTP in the hippocampus is well correlated to the inability to acquire some forms of temporal-spatial learning. While LTP is readily induced in young animals, it becomes increasingly difficult in older animals. This may well correlate with some learning deficits as animals age and may also reflect impairment in memory acquisition and maintenance in the elderly. Despite mild memory impairment in many elderly individuals, the ability to learn is not lost. This leaves open the possibility that other orms of plasticity are possible and may not diminish with age. Understanding the physiological basis for these forms of plasticity may result in developing different paradigms for more efficacious learning for the elderly, as well as targeting these forms of plasticity for pharmacological treatment. Although synaptic plasticity may strongly influence postsynaptic neuronal action potential firing, the ability for EPSPs of a certain strength to induce an action potential may als be modulated. This last type of modulation can be defined as E-S plasticity. We have made a novel discovery that E-S plasticity is independent of LTP, in that changes in EPSP strength are not correlated with changes in the E-S relationship generated for single postsynaptic neurons. Our preliminary evidence suggests that E-S plasticity remains robust while LTP wanes with age. Utilizing the in vitro slice preparation of the CA1 region of the hippocampus from different aged rodents, we will determine the defining characteristics of E-S plasticity and how it differs from LTP, with the overall goal of discerning different types of plasticity that still may be rapidly induced by stimulation as we age. To accomplish this we have delineated the study into three aims: 1) To determine how the relationship between LTP and E-S plasticity changes with age;2) to determine if E-S plasticity abides by Hebbian criteria of cooperativity, associativity and input specificity;and 3) to elucidate differences in the molecular signaling pathway between E-S plasticity and LTP. Although testing behavioral learning paradigms is beyond the scope of this proposal, we can eventually use pharmacological conditions determined for induction and block of E-S plasticity in the absence of LTP to see which types of learning may be specifically related to E-S plasticity. This study is ideally suited for one of the aims of the National Institute of Agng of to "study the continuum of cognitive aging across the lifespan".
As we age, we often are instantly familiar with an event, but cannot recall the details of that event unless we are cued with more information. This research postulates that the molecular mechanisms that the brain uses to identify events as familiar are different from those required for total recall of the details. We aim to characterize these mechanisms and how they change with age, in the hope that it may give us clues to different learning techniques to use when one ages, or different drugs to enhance familiarity and recall.
|Weeks, Autumn M; Harms, Jonathan E; Partin, Kathryn M et al. (2014) Functional insight into development of positive allosteric modulators of AMPA receptors. Neuropharmacology 85:57-66|
|Harms, Jonathan E; Benveniste, Morris; Kessler, Markus et al. (2014) A charge-inverting mutation in the "linker" region of ?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors alters agonist binding and gating kinetics independently of allosteric modulators. J Biol Chem 289:10702-14|
|Inagaki, Akira; Frank, C Andrew; Usachev, Yuriy M et al. (2014) Pharmacological correction of gating defects in the voltage-gated Ca(v)2.1 Ca²? channel due to a familial hemiplegic migraine mutation. Neuron 81:91-102|