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Genetic analysis of the role of hippocampal inhibitory neurotransmitter receptors in learning and memory

English title Genetic analysis of the role of hippocampal inhibitory neurotransmitter receptors in learning and memory
Applicant Rudolph Uwe
Number 102113
Funding scheme Project funding
Research institution Institut für Pharmakologie und Toxikologie Universität Zürich
Institution of higher education University of Zurich - ZH
Main discipline Neurophysiology and Brain Research
Start/End 01.10.2003 - 30.09.2006
Approved amount 299'445.00
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Keywords (4)

GABAA RECEPTOR; inducible knockouts; hippocampus; learning and memory

Lay Summary (English)

Lead
Lay summary
This research project is concerned with defining the role of inhibitory neurotransmission via GABAA receptors in learning and memory as well as with defining which functions of general anesthetics (including amnesia) are mediated by which target. Memory deficits are observed in a variety of brain disorders including Alzheimer’s disease, and they currently cannot be treated satisfactorily. Understanding the mechanisms of learning and memory is expected to lead to the development of memory-enhancing agents. Previously, we and others found that 5-containing GABAA receptors inhibit memory performance, and based on these findings, the pharmaceutical industry is developing 5-inverse agonists as memory enhancers. We have developed novel tools for the study of the functions of 5-containing GABAA receptors. While the development of mice inducibly overexpressing the5 subunit is still in progress, we now have generated mice with an5 knockout specifically in the hippocampal subfields CA1 and CA3, respectively, which will allow to study the role of 5-containing GABA receptors in these brain regions. In a project aimed at identifying the targets mediating specific actions of general anesthetics, we have been able to show that the immobilizing action and the anterograde amnesic action of the general anesthetic propofol are mediated by different GABAA receptor subtypes and are pharmacologically separable.
Furthermore, we have found that barbiturates exert their immobilizing action and in part their hypnotic action via 3-containing GABAA receptors. While the respiratory depressant action of etomidate and propofol is mediated almost entirely by 3-containing GABAA receptors, the respiratory depressant action of pentobarbital is not dependent on this receptor subtype and mediated by non-GABAA receptors.Our results provide clues for the development of novel anesthetic drugs with less side effects.
Direct link to Lay Summary Last update: 21.02.2013

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Associated projects

Number Title Start Funding scheme
65355 Role of inhibitory neurotransmitter receptors in general anes- thesia: Analysis by in vivo point mutations 01.10.2001 Project funding

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