The brain receives time encoded signals whose information content is meaningful only if temporal sequences can be processed as a whole. This temporal binding process requires memory buffers, the nature and identity of which remain a mystery. Unraveling this mystery may provide insights for the pathogenesis and management of epilepsy, schizophrenia, and other neuro-psychiatric disorders. We postulate that the cellular substrates for these memory buffers are feedforward networks and that the molecular substrate for information storage is the bound- but-blocked state of the NMDA receptors. In preliminary studies we have demonstrated a phenomenon we called Dendritic Hold and Read (DHR). It is based on the idea that the glutamate-bound but Mg2+-blocked state of the NMDA receptor is a quasi-stable state that holds information on the history of synaptic excitation. This information can be held for hundreds of milliseconds and then be conditionally retrieved with a second independent 'gating' depolarization to produce a local regenerative dendritic spike. In this proposal we will combine electrophysiology, optogenetics, and state-of- the-art optical technologies to show that DHR enables the operation of feedforward memory in the hippocampus. More specifically, we will test pharmacologic means to manipulate the duration of the elementary unit of short term memory (Specific Aim 1). We will show that theta rhythm serves as the endogenous clock that drives feedforward memory (Specific Aim 2). And we will attempt to demonstrate the time-to-space transform that is the fundamental principle of feedforward memory (Specific Aim 3). This is a high risk, high reward proposal. The risk comes from proposing a totally novel theory of short term memory. This risk is counter balanced by compelling biophysical reasoning and abundance of preliminary data. The reward is in providing novel insights and treatment strategies for schizophrenia and Alzheimer's disease. It also provides insights into why distal dendrites are so excitable and epileptogenic.
Neuro-psychiatric disorders present a significant problem in the VA population. NMDA receptor dysfunction is linked to multiple neuro-psychiatric disorders. NMDA-mediated hyperexcitability contributes to epilepsy. Conditions that result in a hypo-NMDA state such as after ingestion of the NMDA receptor antagonist, PCP, will produce a state that almost completely mirrors the abnormal behavior in schizophrenia. The prevalence of epilepsy and schizophrenia is 1% of the general population for each, similar to that in the VA population. Furthermore, NMDA receptors are the targets of some of the latest medications to treat Alzheimer's disease and schizophrenia. For these reasons it is imperative to better understand the function of NMDA receptors in normal brain and to understand why they are expressed in such surprisingly high densities.
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