Control of Junctional Conductance at Auditory Afferents

Project: Research project

Project Details

Description

DESCRIPTION (provided by applicant): The long-term objective of the proposed
research is to study the role and properties of electrical synaptic
transmission via gap junctions in the CNS, in particular in the auditory
system. The experimental model involves identified mixed electrical and
chemical, (glutamatergic) synapses between eighth nerve auditory primary
afferents and the goldfish Mauthner (M-) cell. While most studies of gap
junction function utilize exogenous expression systems, this preparation
uniquely allows continuous monitoring and quantification of changes in
junctional conductance in vivo. Both components of the synaptic response
exhibit activity-dependent modifications on their strength that is mediated via
activation of NMDA receptors. Paired intradendritic and single afferent
recordings, molecular biology techniques, and immunocytochemistry, will be used
to test specific hypotheses and mechanisms underlying modifications of
electrical transmission induced by eighth nerve tetani, determinants of
bi-directional communication and the identity of specific gap junction
proteins. Aim 1 explores the cellular and molecular mechanisms underlying
activity-dependent modification (potentiation and depression) of gap junctional
conductance. It is based on data suggesting that changes in electrical coupling
at single terminals following brief tetani can be in the form of both
depressions and potentiations. I will explore the roles of elevated levels of
postsynaptic calcium/calmodulin-dependent kinase II (CamKIl), protein
phosphatases and agents interfering with postsynaptic exofendocytosis on
unitary and population synaptic responses. Aim 2 is to investigate the possibIe
role of somatostatin in activity-dependent plasticity of these junctions. This
peptide is co-localized with glutamate at presynaptic terminals and preliminary
data shows that its application enhances both components of the synaptic
response. Since both somatostatin and glutamate are likely to be co-released
during tetani, I propose to explore their possible functional interactions and
underlying intracellular mechanisms. Aim 3 concerns identification of the
neuron-specific gap junction proteins at these connections. Sub-cellular
distributions of antibodies specific to various connexins will be analyzed with
immunocytochemistry, using confocal and freeze-fracture electron microscopy,
and single cell RT-PCR of the coupled cells.

The proposed research addresses the concept that intercellular coupling through
gap junction channels is dynamic, based on its functional interaction with
neighboring glutamatergic synapses and peptidergic transmission. These
modulatory phenomena could constitute a widespread property of electrical
synapses in general, relevant not only to normal brain function in structures
such as the retina, inferior olive, and neocortex where both forms of
transmission co-exist, but also to numerous health-related issues such as
epilepsy.
StatusFinished
Effective start/end date2/28/021/31/08

ASJC

  • Speech and Hearing

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