Fetal alcohol syndrome (FAS) continues to be one of the leading causes of birth defects. Although it is preventable by abstaining from alcohol consumption while pregnant, the estimated incidence for FAS in the United States is 0.2 to 1.0 per 1000 live births. Currently there are no preventable treatments for FAS. It is well characterized that ethanol exposure during development affects the central nervous system ranging from subtle structural and functional alterations to widespread neuronal death. Following ethanol (EtOH) exposure, the mechanism as to how it causes widespread neuronal degeneration is not well characterized. It has been postulated that EtOH-induced cell death results from excessive inhibition of neuronal activity in the developing neocortex. EtOH has been thought to act like a benzodiazepine by enhancing GABAARs postsynaptically. However, previous work from our laboratory suggests that EtOH increases neuronal excitability, by increasing GABA release. I hypothesize that EtOH increases GABA release leading to excitation of neurons in cortical layers that undergo apoptotic cell death in response to EtOH exposure (layers II and IV) but not in layers that do not (i.e. layer III).
In specific aim #1, I will use a combination of whole-cell and perforated patch-electrophysiological techniques to determine if EtOH is differentially affecting GABAergic transmission in layers INV of the neonatal somatosensory cortex.
In specific aim #2, I will determine if activation of the GABAAR results in excitation in the same neuronal layers by using a combination of loose cell-attached electrophysiological and Ca2+ imaging techniques. If I determine that there is an increase in excitability of the target cell, I will then determine if EtOH increases excitability by increasing action potential-dependent GABA release. In the long-term, these studies might form the basis for the development of novel therapeutic interventions against FAS that target the excitatory actions of GABAARs in immature neurons. ? Lay summary: Fetal alcohol exposure is a common cause of mental disabilities in the U.S. The mechanism by which alcohol damages the developing brain are poorly characterized. The studies proposed here will increase our understanding of how alcohol affects the actions of the neurotransmitter GABA and in the long term might form the basis for the developmental treatments against this problem. ? ? ?
| Bragin, Denis E; Sanderson, Jennifer L; Peterson, Steven et al. (2009) Development of epileptiform excitability in the deep entorhinal cortex after status epilepticus. Eur J Neurosci 30:611-24 |
| Sanderson, Jennifer L; Donald Partridge, L; Valenzuela, C Fernando (2009) Modulation of GABAergic and glutamatergic transmission by ethanol in the developing neocortex: an in vitro test of the excessive inhibition hypothesis of fetal alcohol spectrum disorder. Neuropharmacology 56:541-55 |
