LoboVault Home
 

Prenatal Alcohol Exposure Effects on NMDA Receptor Subunit Composition and Function in the Mouse Dentate Gyrus

LoboVault

Please use this identifier to cite or link to this item: http://hdl.handle.net/1928/20806

Prenatal Alcohol Exposure Effects on NMDA Receptor Subunit Composition and Function in the Mouse Dentate Gyrus

Show full item record

Title: Prenatal Alcohol Exposure Effects on NMDA Receptor Subunit Composition and Function in the Mouse Dentate Gyrus
Author: Brady, Megan
Advisor(s): Caldwell, Kevin
Committee Member(s): Allan, Andrea
Lidke, Diane
Savage, Dan
Shuttleworth, Bill
Department: University of New Mexico. Biomedical Sciences Graduate Program
Subject(s): prenatal alcohol exposure
NMDA receptor
dentate gyrus
LTP
learning and memory
Degree Level: Doctoral
Abstract: Moderate prenatal alcohol exposure (PAE) in humans leads to learning and memory impairments later in life. The range of physical, behavioral, emotional, and social dysfunctions that are associated with PAE are collectively termed fetal alcohol spectrum disorder (FASD). It is estimated that approximately 12% of women consume alcohol at some time during their pregnancy and as many as 5% of children born in the United States are impacted by PAE. Extensive research has shown that even moderate maternal drinking (1-2 drinks per day) is, in some individuals, associated with cognitive and behavioral deficits. Existing models for PAE have been useful in studying the effects of moderate exposure, including its effect on hippocampal learning and memory; however, these models often include factors, such as stress or malnutrition issues, that can confound results. To date, most studies on the behavioral consequences of PAE have focused on overall hippocampal-dependent behavioral deficits, withouth attempting to determine whether the impairment may be attributed to altered functioning of a subregion (e.g. the dentate gyrus) of the hippocampus. In contrast, biochemical and electrophysiological studies have identified dysfunctions in the hippocampal subregions. In the dentate gyrus, long term potentiation (LTP), which is considered to be a cellular mechanism of learning, is impaired in animals prenatally exposed to alcohol, as is N-methyl-D-aspartate (NMDA) receptor (NMDAR)-dependent activation of extracellular signal-regulated kinase 1/2 (ERK 1/2), which is important for LTP. This dissertation tested the hypothesis that PAE leads to impairments in dentate gyrus-dependent learning and memory, which is associated with NMDA receptor – dependent LTP deficits and NMDA receptor subunit composition alterations in the dentate gyrus. A limited access PAE model in mice was developed, producing moderate ethanol intake in dams with no evident effect on litter size, pup weight, dam food and water intake, maternal weight gain, or maternal care. In addition, although PAE mice exhibited no differences in spontaneous locomotor activity compared to controls, they did demonstrate hippocampal-dependent fear conditioned learning deficits, similar to those seen previously in the literature. They also exhibited deficits in a delayed non-match to place (DNMP) task that was dentate gyrus-dependent, indicating that PAE does produce dentate gyrus impairments. Further studies using electrophysiological techniques found that PAE mice had deficits in NMDAR-dependent LTP in the dentate gyrus, as well as a reduced contribution of GluN2B-containing receptors to NMDAR-dependent field recordings. Biochemical subcellular fractionation and immunoblotting experiments found that, compared to controls, PAE mice had increased C2´-containing GluN1 and GluN3A subunits and decreased GluN2B subunit levels in the synaptic membrane fraction isolated from the dentate gyrus. These results indicate that PAE does indeed produce a dentate gyrus-dependent deficits in learning and memory, and this deficit is likely due to alterations in synaptic plasticity that result from changes in the NMDAR subunit composition at the synaptic membrane. These studies provide the basis for several future studies that aim to explore the impact of PAE on the control of NMDAR levels, trafficking, and function.
Graduation Date: May 2012
URI: http://hdl.handle.net/1928/20806

Files in this item

Files Size Format View
Dissertation Final.pdf 2.596Mb PDF View/Open

This item appears in the following Collection(s)

Show full item record

UNM Libraries

Search LoboVault


Advanced Search

Browse

My Account