The long-term objective of the proposed studies is to determine whether gestational B(a)P exposure nterferes with normal behavior and neural function in C57BL mice as demonstrated by significant deficits in """"""""lippocampal synaptic plasticity and behavior. The central hypothesis to be tested is that gestational exposure to B(a)P aerosol (PM2.5mu) at levels seen in humans in certain environments result in lifelong learning and memory deficits, and that these deficits that are mediated, at least in part, through modulation of developmental NMDA/AMPA glutamate receptor subunit expression and function at a time when excitatory synapses are being formed in the hippocampus of C57BL mice.
AIM #1 will determine the disposition of B(a)P in F1 fetal brain (in C57BL mice) on gestational day (GD) 14, 16, 18, and postnatal day (PND) 0 in the hippocampus after GD14-17 inhalation exposure at doses of 0, 50, 100 and 200 mu g/m3A simultaneous determination of the effect on glutamate receptor subunit expression in utero will be conducted, using ex vivo primary neuronal cultures.
AIM #2 will test whether gestational exposure to the same inhalational doses of B(a)P results in deficits in learning, using behaviors previously shown to depend on hippocampal function.
AIM #3 will correlate gestational exposure to B(a)P with measures of hippocampal long-term potentiation (LTP), evaluated at PND 60 and 120 in F1 generation mice. The involvement of NMDA and/or, AMPA receptors in this LTP, and its changes due to B(a)P exposure, will be assessed by application of NMDA or AMPA-selective receptor antagonists prior to LTP analysis of control and B(a)P exposed F1 generation mice.
AIM #4 will test whether gestational exposure to the doses of B(a)P which lead to behavioral learning and physiological deficits also modulate the expression of various NMDA and AMPA receptor subnits, profiled for expression levels on GD18 and PND 0, 5, 10, 20, and 60 using real time PCR (for mRNA assessment) and Western blot analyses( for subunit protein assessment) in control and B(a)P exposed F1 generation C57BL mice. These studies will serve as the first step in querying the with the causality of altered glutamate receptor subunit expression subsequent to gestational exposure to B(a)P in attenuation of learning behaviors in adult animals, which will be extended in future studies by exploiting mice genetically altered to modify the expression of relevant AMPA or NMDA receptor subunits, or their downstream effector molecules. These studies are directly relevant to human consequences of B(a)P exposure, and we anticipate that our studies will lead to the rigorous characterization of an important animal model both to understand the etiology of environmental toxin-induced neurological dysfunction and to test hypotheses regarding effective therapeutic or other interventions .
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