: Glutamate and gamma-aminobutryic acid (GABA) are major central nervous system (CNS) excitatory and inhibitory neurotransmitters respectively. Selective glutamate release inhibitors (GRIs) appear to be effective treatments for disorders including seizures, amyotrophic lateral sclerosis, and bipolar disorder. Understanding the cellular underpinnings of the acute actions of GRIs on glutamate release is the goal of this proposal. While several glutamate release inhibitors (GRIs) have been described, the evidence for a selective anti-glutamate effect is indirect and has been disputed. Our recent results suggest that the selective anti-glutamate effect of these drugs can be explained by partial block of the presynaptic sodium channels (NaChs) that underlie the action potential. Elucidation of the mechanisms by which partial NaCh block depresses glutamate release should yield insight into the details of action potential coupling to transmitter release and permit more rational and effective drug design.
The first aims of the proposal are to understand the acute effects of weak NaCh blockade on glutamate release. NaCh block may disturb action potential coupling to glutamate release either by promoting failure of action potential propagation through branches of the axon or by altering the amplitude of the action potential. Using two in vitro systems for analyzing glutamate neurotransmission, we will distinguish between these two potential mechanisms. Because of the exquisite sensitivity of glutamate release to partial NaCh block, a second hypothesis to be tested is that NaCh inactivation during high-frequency presynaptic activity yields depression of glutamate release, even in the absence of exogenous NaCh blockers.
A final aim i s to understand the effect of these drugs on recently described postsynaptic amplification of synaptic potentials through atypical non-inactivating sodium channels. Our studies should lend insight into the cellular mechanisms of a class of clinically important anticonvulsants and neuroprotectants. In addition, we expect our results to elucidate details of the mechanisms of action potential coupling to chemical neurotransmission and a possible mechanism of synaptic plasticity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS040488-04
Application #
6753557
Study Section
Special Emphasis Panel (ZRG1-MDCN-4 (01))
Program Officer
Talley, Edmund M
Project Start
2001-06-01
Project End
2006-05-31
Budget Start
2004-06-01
Budget End
2006-05-31
Support Year
4
Fiscal Year
2004
Total Cost
$231,000
Indirect Cost
Name
Washington University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Moulder, Krista L; Mennerick, Steven (2006) Synaptic vesicles: turning reluctance into action. Neuroscientist 12:11-5
Moulder, Krista L; Jiang, Xiaoping; Taylor, Amanda A et al. (2006) Physiological activity depresses synaptic function through an effect on vesicle priming. J Neurosci 26:6618-26
Eisenman, Lawrence N; Kress, Geraldine; Zorumski, Charles F et al. (2006) A spontaneous tonic chloride conductance in solitary glutamatergic hippocampal neurons. Brain Res 1118:66-74
Meeks, Julian P; Jiang, Xiaoping; Mennerick, Steven (2005) Action potential fidelity during normal and epileptiform activity in paired soma-axon recordings from rat hippocampus. J Physiol 566:425-41
Pathirathna, Sriyani; Brimelow, Barbara C; Jagodic, Miljen M et al. (2005) New evidence that both T-type calcium channels and GABAA channels are responsible for the potent peripheral analgesic effects of 5alpha-reduced neuroactive steroids. Pain 114:429-43
Moulder, Krista L; Mennerick, Steven (2005) Reluctant vesicles contribute to the total readily releasable pool in glutamatergic hippocampal neurons. J Neurosci 25:3842-50
Mennerick, Steven; He, Yejun; Jiang, Xin et al. (2004) Selective antagonism of 5alpha-reduced neurosteroid effects at GABA(A) receptors. Mol Pharmacol 65:1191-7
Meeks, Julian P; Mennerick, Steven (2004) Selective effects of potassium elevations on glutamate signaling and action potential conduction in hippocampus. J Neurosci 24:197-206
Shu, Hong-Jin; Eisenman, Lawrence N; Jinadasa, Deepani et al. (2004) Slow actions of neuroactive steroids at GABAA receptors. J Neurosci 24:6667-75
Moulder, Krista L; Meeks, Julian P; Shute, Amanda A et al. (2004) Plastic elimination of functional glutamate release sites by depolarization. Neuron 42:423-35

Showing the most recent 10 out of 17 publications