Programmatic Research on Fetal Alcohol Spectrum Disorder (FASD) Presentation to the Child Health Signature Research Program Group February 21, 2008 Daniel Savage, Ph.D. Regents’ Professor & Chair Department of Neurosciences, UNM SOM 505-272-8808 dsavage@salud.unm.edu 3

Fetal Alcohol Spectrum Disorder ( FASD ) Physical Defects FAS ~ 0.03% FAE / ARBD ~ 0.15% Alcohol-Related Neurodevelopmental Disorder (ARND) > 1% Functional Deficits

Long-Term Research Objectives Understand the neurobiologic bases of fetal ethanol-induced deficits in synaptic plasticity and learning. Identify therapeutic agents that ameliorate fetal ethanol-induced deficits in synaptic plasticity and learning. Establish combined neurobehavioral and functional neuroimaging approaches for: Diagnosis of fetal ethanol-associated brain and behavioral deficits and, Monitoring / predicting the efficacy of various behavioral and pharmacotherapeutic agents. Identify a sensitive and specific biomarker system predictive of adverse neurobehavioral outcomes in fetal ethanol-exposed offspring. 3

2. Identify therapeutic agents that ameliorate fetal ethanol- induced synaptic plasticity & learning deficits. (R21 AA16619) Concept: Use of our moderate ethanol exposure paradigm as a screen for identifying therapeutic agents for treating cognitive deficits associated with prenatal ethanol exposure. Approach: “Proof of Concept” proposal to study one cognition-enhancing agent, a selective H3 receptor antagonist ABT-239. One-trial Contextual Fear Conditioning Four-day Retention of Platform Location

Virtual Morris Water Task 3. Neurobehavioral and functional neuroimaging characterization of learning deficits in subjects with FASD (MIND C-2018) Virtual Morris Water Task Volumetrics Spectroscopy Phase II: Probe Trial MEG Control: 6 / 7 FAS: 1 / 7

4. A biomarker system for predicting adverse neurobehavioral 4. A biomarker system for predicting adverse neurobehavioral outcomes in fetal ethanol-exposed offspring. (R21 AA15420) Employ our moderate prenatal ethanol exposure paradigm to examine ethanol-induced alterations in placental protein expression using proteomic and genomic approaches. 302 genes (0.13% of all genes) were altered greater than two-fold by moderate maternal ethanol consumption Genes whose proteins associated with cytoskeletal, metabolic, endocrine, immune or neural function are altered. Follow-up Studies: 1. “Sensitivity Studies” Ethanol Dose Window of detectability 2. “Specificity Studies” Other risk factor impact Preclinical Clinical Placental Proteomics Placental Proteomics Fetal Brain Proteomics Weanling Behaviors & Neurophysiology Infant Behaviors & Neurophysiology 3

Developmental Alcohol Research Center - P20 Fetal ethanol-induced behavioral deficits: Mechanisms, diagnoses and interventions Preclinical Projects: Epigenetics of FASD Stem Cells Cognition Enhancers Predisposition to PTSD Biomarkers Diagnosis / Prognosis Preclinical Investigators: Allan, Caldwell, Cunningham, Hamilton, Perrone-Bizzozero, Savage, Valenzuela, Zhao Clinical Projects: Information Processing Infant Sensory Integration (baby MEG) Behavioral Intervention & Functional Neuroimaging Clinical investigators: Kodituwakku, Verney, Stephen, Tesche, Kiehl, May, Rayburn, Weisend Developmental Alcohol Research Center - P20 Combines basic, clinical and translational science across HSC, Main Campus and MIND