The objective of this research project is to study the regulation of inhibition by alcohol in the mouse thalamus. The thalamus is well known to act as a relay of sensory information to the cortex and to play an important role in the regulation of sleep. Thalamocortical relay neurons in the ventrobasal (VB) complex exhibit a bi-stable pattern of excitability. In the """"""""tonic firing"""""""" mode (when the neuron is depolarized), the neurons fire continuously, while in the """"""""burst firing"""""""" mode (when the neuron is hyperpolarized), VB neurons fire brief rapid bursts of action potentials superimposed on a slow (delta) rhythm of about 3-5Hz that is a feature of slow wave sleep and absence epilepsy. VB neurons receive inhibitory inputs from GABAergic neurons in the peripheral reticular nucleus (RTN), which results in the activation of synaptic GABAA receptors (GABAA-R) and the generation of fast IPSPs in VB neurons. In addition to these 'phasic'inhibitory events, VB neurons also show 'tonic'inhibition, due to the persistent activation of extra-synaptic GABAA-R. This tonic inhibition generates a constant hyperpolarizing influence on the VB neurons. It has been hypothesized that both synaptic and tonic inhibition can have a strong influence on the timing and synchronization of """"""""burst firing"""""""" in the relay neurons. We propose to carry out a comprehensive study of the interactions of alcohol with GABA in the thalamus. Although a variety of GABAAsubtypes exist in the thalamus, synaptic inhibition involves a, and y2 subunits in VB and cc3, f33 and Y2 subunits in RTN. Tonic inhibition in VB is generated by receptors containing ct4 and 5 subunits, a population of GABAA-Rs that is suggested to be highly sensitive to modulation by alcohol.
The specific aims of this revised proposal are: 1) To study the effects of alcohol on GABA-mediated inhibition in VB and RTN neurons. 2) To study the effects of alcohol and GABAA-R antagonists on signal processing by VB neurons. 3) To investigate the mechanisms of the effects of alcohol on inhibition in VB and RTN neurons. Acute and chronic use of alcohol is known to disrupt sleep, so the detailed investigation of alcohol effects in the thalamus should provide insights that could direct future studies into sleep disorders in alcoholics and assist in the development of useful therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA016393-05
Application #
7806436
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Liu, Qi-Ying
Project Start
2007-04-01
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
5
Fiscal Year
2010
Total Cost
$214,942
Indirect Cost
Name
Columbia University (N.Y.)
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Keramidas, Angelo; Harrison, Neil L (2010) The activation mechanism of alpha1beta2gamma2S and alpha3beta3gamma2S GABAA receptors. J Gen Physiol 135:59-75
Ying, Shui-Wang; Werner, David F; Homanics, Gregg E et al. (2009) Isoflurane modulates excitability in the mouse thalamus via GABA-dependent and GABA-independent mechanisms. Neuropharmacology 56:438-47
Belelli, Delia; Harrison, Neil L; Maguire, Jamie et al. (2009) Extrasynaptic GABAA receptors: form, pharmacology, and function. J Neurosci 29:12757-63
Trudell, James R; Yue, Minerva E; Bertaccini, Edward J et al. (2008) Molecular modeling and mutagenesis reveals a tetradentate binding site for Zn2+ in GABA(A) alphabeta receptors and provides a structural basis for the modulating effect of the gamma subunit. J Chem Inf Model 48:344-9
Jia, Fan; Yue, Minerva; Chandra, Dev et al. (2008) Taurine is a potent activator of extrasynaptic GABA(A) receptors in the thalamus. J Neurosci 28:106-15
Jia, Fan; Yue, Minerva; Chandra, Dev et al. (2008) Isoflurane is a potent modulator of extrasynaptic GABA(A) receptors in the thalamus. J Pharmacol Exp Ther 324:1127-35
Jia, Fan; Chandra, Dev; Homanics, Gregg E et al. (2008) Ethanol modulates synaptic and extrasynaptic GABAA receptors in the thalamus. J Pharmacol Exp Ther 326:475-82