Prenatal Nicotine Exposure and Glutamatergic-Cholinergic Interplay
Type of Degreedissertation
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Smoking in pregnant women is reported as a risk factor in neurobehavioral alterations such as learning and memory deficits. Prenatal exposure of nicotine (6mg/kg /day) in animal models induces memory impairment associated with cholinergic/glutamatergic dysfunction. Rodent model of prenatal nicotine exposure (PREN), receiving nicotine infusions in pregnant dams, developed memory deficits. Here, we demonstrate that basal synaptic transmission (BST), forms of synaptic plasticity, including long-term potentiation (LTP) are impaired at Schaffer collateral (SC) synapses in PREN rodents. Mean amplitudes and frequency of AMPAR (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor) and NMDAR (N-Methyl-D-Aspartate) mediated sEPSCs (spontaneous Excitatory Post Synaptic Currents) were reduced. Concentrations of NMDAR subunits NR1/2A, postsynaptic density protein-95 (PSD-95) and CaMKII (Calmodulin Kinase II) decreased in PREN hippocampus. Moreover, deficits in LTP and BST were accompanied by altered synaptic α7/β2 nicotinic acetylcholine receptors (nAChRs) activity. Co-immunoprecipitation studies revealed α7/β2-nAChRs complexes with NR1, vesicular glutamate transporter (VGLUT), PSD-95 and synapse-associated protein (SAP102), disrupted in PREN rodents. Additionally, the nicotinic signaling pathway was impaired in them. α7/β2-nAChRs facilitate release of other neurotransmitters including glutamate. Here, we tried to address whether nAChR subunits are responsible for deficits in synaptic plasticity in PREN rodents. First, we found that, expressions of α7and β2-nAChRs are decreased. Moreover, blockade of α7-nAChRs with Methyllycaconitine (MLA) in control animals impaired LTP. Western blots analysis of hippocampal lysates revealed decreased expression of PSD 95/SAP102. These proteins are involved in regulating organization of postsynaptic components at nicotinic synapses. These results suggest that PREN-impaired LTP/PPF arise as consequence of dysfunctional α7/ β2 nAChRs. Hence it is logical to opine that nAChRs may be an important target to help ameliorate cognitive deficits. Studies indicate cognitive deficits are enduring. This study was performed to investigate the effects of prenatal nicotine exposure on excitatory synaptic physiology and cellular signaling in hippocampus. Reduced nAChR expression and modified MAPK signaling, consequences of PREN are thought to be potential mechanisms for disrupted excitatory synaptic physiology in hippocampus of PREN rats. In addition, we identify alterations in synaptic plasticity, BST, decreased AMPAR synaptic currents and reduced nAChR levels and their signaling in the hippocampus of PREN rodents as mechanisms underlying long lasting cognitive impairments.