There is growing evidence that poor neuronal plasticity underlies many of the neurological deficits seen in Fetal Alcohol Spectrum Disorders (FASD). Neuronal plasticity involves making and breaking connections, which in turn are related to potentiation and depression of neuronal responses. These processes are evident in the plasticity of ocular dominance in primary visual cortex. This paradigm is based on functional and morphological cortical changes that occur after a monocular deprivation (MD) by eyelid suture is performed during a critical period of development. Accordingly, in normal animals few days of MD lead to a depression of responses of neurons driven by the deprived (closed) eye, and a potentiation of responses in neurons driven by the experienced (open) eye. Using a ferret model, we demonstrated in the past that early alcohol exposure leads to a permanent impairment in ocular dominance plasticity (ODP). Subsequently, ODP has been used by different groups to study neuronal plasticity in models of Fragile X, Neonatal-Hypoxia ischemia and Angelmann Syndrome. Our studies in ferrets used a combination of optical imaging of intrinsic signals and single unit recordings (in vivo extracellular electrophysiology). Here we will use a combination of in vivo and in vitro electrophysiology techniques to tease out the mechanisms of early alcohol exposure (EAE) on neuronal plasticity. Specifically we will test the following hypothesis: A) EAE disrupts potentiation BUT NOT depression of responses in cortical layer IV, possibly by affecting glutamatergic neurotransmission. B) EAE disrupts BOTH potentiation and depression of responses in cortical layer II/III possibly by a combined effect on glutamatergic and endocannabinoid neurotransmission. And finally C) That phosphodiesterase type 1 inhibition by vinpocetine and caffeine will restore both potentiation and depression components of neuronal plasticity in alcohol exposed mice. Testing caffeine would be of particular relevance because this drug is routinely used as a therapeutic intervention in premature babies, which could facilitate its translation to FASD subjects.

Public Health Relevance

Fetal alcohol spectrum disorder (FASD) is a leading cause of mental retardation. Here we test the hypothesis that early alcohol exposure has layer specific effects on the potentiation and depression components of neuronal plasticity in the visual cortex in vivo and in vitro. We will also test whether caffeine can restore neuronal plasticity in our model. Testing caffeine would be of particular relevance because this drug is routinely used as a therapeutic intervention in premature babies, which could facilitate its translation to FASD subjects.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
1R01AA022455-01
Application #
8563078
Study Section
Special Emphasis Panel (ZRG1-IFCN-C (02))
Program Officer
Cui, Changhai
Project Start
2014-02-05
Project End
2019-01-31
Budget Start
2014-02-05
Budget End
2015-01-31
Support Year
1
Fiscal Year
2014
Total Cost
$326,188
Indirect Cost
$113,688
Name
University of Maryland Baltimore
Department
Pediatrics
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Lantz, Crystal L; Pulimood, Nisha S; Rodrigues-Junior, Wandilson S et al. (2014) Visual defects in a mouse model of fetal alcohol spectrum disorder. Front Pediatr 2:107