Adolescents who use alcohol have a greater risk for developing memory and cognitive deficits compared to adults. Such cognitive and memory disturbances elicited by adolescent alcohol abuse significantly impact psychosocial functioning and can persist long into adulthood. The molecular mechanisms responsible for the persistence of memory deficits are unknown, but likely involve ethanol-induced changes at synapses involved in memory formation. Our findings show a novel enhancement of long-term potentiation (LTP) of synaptic responses in CA1 hippocampal synapses in animals that have been chronically exposed to ethanol as early adolescents. Similar ethanol exposure in older animals does not produce the same effects on hippocampal LTP. Hippocampal LTP is a form of synaptic plasticity that results in the persistent enhancement of excitatory synaptic transmission and is considered a substrate for memory. Importantly, LTP is triggered by an influx of intracellular Ca2+ and initiates downstream actions on signaling cascades and gene expression. Under control conditions LTP at CA1 synapses is initiated by Ca2+ influx via postsynaptic NMDA- subtype of glutamate receptors; whereas our findings show that NMDA-receptors are not involved in the enhanced LTP response in slices from rats exposed to ethanol as early-adolescents. The proposal will focus on identifying the Ca2+ signaling cascades that contribute to the unique LTP response produced by adolescent ethanol exposure. The experiments will incorporate cellular (extracellular electrophysiology and intracellular current-clamp recordings) and biochemical tools (Western blot protein analysis) in hippocampal CA1 slices from adolescent rats exposed to chronic intermittent ethanol and age-matched ethanol-na?ve controls. We will test the hypotheses that ethanol exposure in adolescents (1) upregulates the expression and/or function of sigma-1-receptors in hippocampus, which are endogenous targets of neuroactive steroids and regulators of intracellular Ca2+ dynamics; (2) facilitates the activation of postsynaptic L-type voltagegated calcium channels; (3) activates critical signaling proteins, including the MAPK/ERK1/2, CREB, BDNF and TrKB-receptors that are linked to L-type Ca2+ channel activation. These experiments will provide critical insights into the molecular mechanisms responsible for the age-dependent switch in the LTP-activated pathways elicited by ethanol exposure during the adolescent period of development. ? ? ?
| Sabeti, Jilla (2011) Ethanol exposure in early adolescence inhibits intrinsic neuronal plasticity via sigma-1 receptor activation in hippocampal CA1 neurons. Alcohol Clin Exp Res 35:885-904 |
