The long term goal of this project is to have a better understanding of precisely how the release of the neurotransmitter acetylcholine affects function in a prototypic cortical area of the brain crucially involved in the formation of long term memories. More specifically, we are interested in how the inputs from an area of the brain called the medial septum/diagonal band of Broca, (which releases acetylcholine), affects processing of neural information in an output structure of a cortical area of the brain, (hippocampal CA1), crucial to the formation of long term memories. These studies will have important implications for developing treatments for Alzheimer's disease and possibly schizophrenia. The loss of cholinergic neurons that project to cortical structures in the brain is a hallmark of Alzheimer's disease. Furthermore, drugs that prolong the presence of acetylcholine in the extracellular space are one of the treatments used to alleviate symptoms in Alzheimer's patients. Moreover, dysfunction of neuronal nicotinic receptors has been correlated to some familial forms of schizophrenia.
The specific aims for this five year project are to understand how acetylcholine release affects inhibitory interneuron function and ultimately the processing of information in hippocampal CA1. To do this we will express a protein called ChIEF in cholinergic neurons that can excite neurons and its processes when exposed to blue light. This will allow us to elicit the release of acetylcholine in live intact slices of hippocampal CA1 by merely flashing blue light upon them. We will then examine how acetylcholine release through the activation of both nicotinic and muscarinic receptors affects interneuron function and ultimately hippocampal CA1 network function. We will do this by recording electrical responses in interneurons and pyramidal neurons of hippocampal CA1 via whole cell patch clamp methods, and by recording activity in the entire network by using voltage-sensitive dye imaging. The results from these studies will have important implications for the treatment of Alzheimer's disease and some familial forms of schizophrenia.

Public Health Relevance

The loss of neurons that release a neurotransmitter called acetylcholine in the brain is a hallmark of Alzheimer's disease. Furthermore, dysfunction of molecules that bind acetylcholine have been correlated to some familial forms of schizophrenia. These studies will investigate how acetylcholine affects an area of the brain involved in the formation of long term memories and will have important implications for the treatment of Alzheimer's disease and some familial forms of schizophrenia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH094626-02
Application #
8264401
Study Section
Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
Program Officer
Nadler, Laurie S
Project Start
2011-05-13
Project End
2016-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
2
Fiscal Year
2012
Total Cost
$373,750
Indirect Cost
$123,750
Name
Virginia Commonwealth University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
105300446
City
Richmond
State
VA
Country
United States
Zip Code
23298
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Bell, L Andrew; Bell, Karen A; McQuiston, A Rory (2015) Activation of muscarinic receptors by ACh release in hippocampal CA1 depolarizes VIP but has varying effects on parvalbumin-expressing basket cells. J Physiol 593:197-215
McQuiston, A Rory (2014) Acetylcholine release and inhibitory interneuron activity in hippocampal CA1. Front Synaptic Neurosci 6:20
Bell, L Andrew; Bell, Karen A; McQuiston, A Rory (2014) Activation of muscarinic receptors by ACh release in hippocampal CA1 depolarizes VIP but has varying effects on parvalbumin-expressing basket cells. J Physiol :
Bell, L Andrew; Bell, Karen A; McQuiston, A Rory (2013) Synaptic muscarinic response types in hippocampal CA1 interneurons depend on different levels of presynaptic activity and different muscarinic receptor subtypes. Neuropharmacology 73:160-73
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