In both humans and laboratory animal models, exposure to alcohol during development has been shown to cause a multitude of dose-dependent effects on the structure and function of the central nervous system, resulting in a range of physical, behavioral, cognitive and social dysfunctions that are collectively termed fetal alcohol spectrum disorders (FASD). The N-methyl-D-aspartate (NMDA) receptor (NMDAR) has been shown to play a critical role in learning and memory, and consequently has been a focus of studies aiming to identify mechanisms that underlie the detrimental effects of prenatal alcohol exposure (PAE) on cognition. The proposed studies aim to test the hypothesis that PAE alters the distribution of NMDAR subunits between synaptic and extrasynaptic compartments (Aim 1) and/or the properties of the NMDAR-channel complex (Aim 2) leading to impaired NMDAR function in the mouse dentate gyrus.
Two specific aims have been developed to test this hypothesis:
Aim 1 : PAE alters the distribution of NMDAR between synaptic and extrasynaptic compartments in the dentate gyrus Aim 1a: Determine the levels of synaptic and extrasynaptic NMDAR subunits in control and FASD mice under basal and activated states.
Aim 1 b: Assess the impact of PAE on mechanisms controlling the localization of NMDAR subunits under basal and activated conditions.
Aim 1 b1: Determine the associations of NMDA receptor subunits with synaptic scaffolding proteins (PSD-95, PSD-93, and SAP-102) in control and FASD mice.
Aim 1 b2: Assess the impact of PAE on the levels of phosphorylated and total (phosphorylated + non- phosphorylated) forms of NMDAR subunits in control and FASD mice.
Aim 2 : NMDAR function is impaired in the dentate gyrus granule cells Aim 2a: Measure whole-cell synaptic NMDAR-dependent currents in hippocampal slices prepared from control and FASD mice following perforant pathway stimulation.
Aim 2 b: Measure whole-cell NMDA-dependent synaptic and extrasynaptic currents in hippocampal slices prepared from control and FASD mice.

Public Health Relevance

Exposure to alcohol during development has been shown to cause a multitude of dose-dependent effects on the structure and function of the central nervous system. These effects are manifested as a range of physical, behavioral, cognitive and social dysfunctions. The studies proposed in this grant aim to identify neurochemical mechanisms that underlie the damaging effects of prenatal alcohol exposure on cognition, and thus identify novel targets for therapeutic intervention in the treatment of fetal alcohol spectrum disorders (FASD).

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Small Research Grants (R03)
Project #
5R03AA020101-02
Application #
8150472
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Cui, Changhai
Project Start
2010-09-30
Project End
2013-08-31
Budget Start
2011-09-01
Budget End
2013-08-31
Support Year
2
Fiscal Year
2011
Total Cost
$72,571
Indirect Cost
Name
University of New Mexico Health Sciences Center
Department
Neurosciences
Type
Schools of Medicine
DUNS #
829868723
City
Albuquerque
State
NM
Country
United States
Zip Code
87131
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