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Interplay betwen presynaptic terminals and GABAA receptors for the formation and plasticity of GABAergic synapses: a combined morphological and functional analysis

English title Interplay betwen presynaptic terminals and GABAA receptors for the fomation and plasticity of GABAergic synapses: a combined morphological and functional analysis
Applicant Fritschy Jean-Marc
Number 108260
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 01.04.2005 - 31.03.2010
Approved amount 819'000.00
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All Disciplines (3)

Discipline
Neurophysiology and Brain Research
Cellular Biology, Cytology
Pharmacology, Pharmacy

Keywords (5)

synaptogenesis; gephyrin; neurogenesis; immuno-electron microscopy; gene targeting

Lay Summary (English)

Lead
Lay summary
Synapses are highly specialized sites of contacts between neurons, mediating the transfer of information along neuronal circuits. Formation and elimination of synapses contribute to learning and memory throughout life. The majority of neurological and psychiatric disorders are due to defects in synaptic function, and most drugs acting in the brain influence synaptic transmission. Complex molecular mechanisms, involving hundreds of proteins, are involved in the formation, long-term maintenance, and plasticity of synapses. The aim of this proposal is to investigate the formation and plasticity of synapses using the neurotransmitter GABA, which act as a “brake” in neuronal circuits by limiting the excitability of neurons. Drugs that increase GABAergic transmission are anti-epileptic, sleep promoting, anxiolytic, and muscle relaxant. In a first project, we will focus on the organization of the postsynaptic element, which is orchestrated by a multifunctional protein, gephyrin. This protein contributes to the aggregation of receptors in the postsynaptic membrane, a key element for successful neurotransmission. We will therefore investigate how signals mediated by GABAA receptors influence the function of gephyrin for formation and maintenance of synapses, both in adult and developing brain.A second project will be devoted to elucidating how new neurons born in the adult brain differentiate and become integrated in existing synaptic circuits. Since neuronal replacement strategies are attractive future therapies for neurodegenerative disorders and stroke, it is essential to understand how neuronal integration takes place in the brain under physiological conditions. We will address this issue by labeling newborn neurons of the olfactory bulb with lentiviruses and monitoring their development and synaptic integration. Finally, to further our understanding of the mechanisms regulating neurogenesis and regeneration in adult brain, we will study these phenomena in the olfactory epithelium, in which neurons are replaced throughout life, by focusing on signaling mechanisms that regulate apoptosis and regeneration in this tissue. Altogether, these studies will provide new insights into fundamental molecular and cellular mechanisms contributing to the long-term maintenance and plasticity of neuronal circuits in adult brain.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

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Associated projects

Number Title Start Funding scheme
63901 Plasticity of GABAergic synapses: cellular mechanisms in vitro and significance for temporal lobe epilepsy 01.01.2002 Project funding

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