Cholinergic innervation of hippocampus is required for some forms of learning and memory. The degeneration of cholinergic septohippocampal afferents is one hallmark of Alzheimer's Disease (AD) and the severity of cognitive decline is correlated with cholinergic impairment. The overlap between acetylcholine (ACh), hippocampal synaptic plasticity, learning and memory, and AD stimulates investigations into mechanisms by which ACh modulates hippocampal function, since alterations in these mechanisms may underlie some cognitive deficiencies in AD. Our understanding of cholinergic modulation of synaptic function and plasticity is not clear, hence our ability to treat or prevent cholinergic dependent cognitive decline will remain sub-optimal unless these mechanisms are unraveled. We have characterized a form of long-term depression (mLTD) in the CA1 region of rat hippocampus in vitro that is induced via activation of M1 muscarinic receptors (M1 AChRs). mLTD is activity and NMDA receptor dependent and is occluded by LTD induced by low frequency stimulation. The pre vs. postsynaptic location of the MI AChRs is unknown and the downstream events have not been identified. We have found that cholinergic denervation (CD) of hippocampus, a model of cholinergic hypofunction that occurs in AD, prevents the induction of mLTD. Interestingly, CD stimulates ingrowth of sympathetic axons into hippocampus and restores mLTD to control levels through an unknown mechanism. Herein we will test the hypothesis that mLTD requires activation of the signaling cascade linked to M1 AChRs and that cholinergic denervation of hippocampus alters the induction of mLTD by altering the coupling of M1 AChRs to their signal transduction pathway. We will use a combination of electrophysiology in brain slices together with pharmacological tools, biochemistry and immunohistochemistry to carry out the proposed aims: 1) examine the cellular mechanisms underlying mLTD; 2) will examine how CD and sympathetic ingrowth alters mLTD induction/expression; 3) examine norepinephrine-induced changes in synaptic transmission interact with mLTD. It is expected that results from this study will provide insight into designing novel therapeutic strategies for symptoms of cholinergic impairment.
