DOI
https://doi.org/10.25772/2YQZ-KD38
Defense Date
2012
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Neuroscience
First Advisor
Alexandre E. Medina
Abstract
Neuronal plasticity deficits underlie many of the neurobehavioral problems seen in Fetal Alcohol Spectrum Disorders (FASD). Recently, we showed that third trimester alcohol exposure lead to a persistent disruption in ocular dominance (OD) plasticity. For instance, few days of monocular deprivation results in a robust reduction of cortical regions responsive to the deprived eye in normal animals, but not in ferrets exposed early to alcohol. This plasticity deficit can be reversed if alcohol-exposed animals are treated with a phosphodiesterase type 1 (PDE1) inhibitor during the period of monocular deprivation. PDE1 inhibition can increase cAMP and cGMP levels, activating transcription factors such as the cAMP response element binding protein (CREB) and the Serum response factor (SRF). SRF is important for many plasticity processes such as LTP, LTD, spine motility and axonal pathfinding. Here we attempt to rescue OD plasticity in alcohol-treated ferrets using a Sindbis viral vector to express a constitutively active form of SRF during the period of monocular deprivation. Using optical imaging of intrinsic signals and single unit recordings we observed that overexpression of a constitutively active form of SRF (Sindbis SRF+), but neither its dominant negative (SRF-) nor GFP, restored OD plasticity in alcohol-treated animals. Surprisingly, this restoration was observed throughout the extent of the primary visual cortex and most cells infected by the virus were positive for GFAP rather than NeuN. Hence, we further tested whether overexpression of SRF exclusively in astrocytes is sufficient to restore OD plasticity in alcohol-exposed ferrets. To accomplish that, first we exposed cultured astrocytes to the SRF+, SRF- or control GFP viruses. After 24h, these astrocytes were implanted in the visual cortex of alcohol-exposed animals or saline controls one day before MD. Optical imaging of intrinsic signals showed that alcohol-exposed animals that were implanted with astrocytes expressing SRF, but not SRF- or GFP, showed robust restoration of OD plasticity in all visual cortex. These findings suggest that overexpression of SRF exclusively in astrocytes can improve neuronal plasticity in FASD.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
April 2012