Bryan W. Luikart, PhD
Associate Professor of Molecular and Systems Biology
Frank and Myra Weiser Scholar in the Neurosciences
Molecular and Systems Biology
1999 B.S., Molecular and Cell Biology (Summa Cum Laude), Texas A&M University, College Station, Texas
2004 Ph.D., Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas (Luis F. Parada, mentor)
Neuroscience Center at Dartmouth
Program in Experimental and Molecular Medicine
Bryan W. Luikart
1 Medical Center Drive
Lebanon NH 03756
The Impact of Pten Dysfunction on Neuronal Physiology - a Model for Autism
Autism Spectrum Disorder (ASD) is a developmental disorder characterized by symptoms such as altered social interaction, restricted communication, and stereotyped behavior. ASD represents a broad class of disorders that have common features, but no single genetic defect is responsible for all forms of ASD. An example of a genetic defect that may cause some forms of ASD is mutations in the gene Pten. Mutations in Pten have been in 5 to 17% of patients with ASD and an enlarged head (macrocephaly). Deletion of Pten in the mouse brain also causes macrocephaly and deficits in social behavior, suggesting that abnormal Pten signaling in neurons may cause this type of ASD. We are currently investigating the functional impact of specific autism-related mutations of Pten on neuronal form and function. We are also examining other genes that may interact with Pten to alter neuronal physiology and synapse formation. We use both in vitro models and in vivo molecular manipulation with viral vectors, whole-cell electrophysiology, and advanced microscopy to test directed hypotheses. Understanding the primary effects of Pten mutations on the function of individual neurons will improve our understanding of the dysfunctional autistic brain. Further, establishing that manipulation of Pten in the mouse can mimic the symptoms of human ASD patients will allow scientists to test treatments that could cure certain forms of ASD.
The Role of microRNAs During Adult Hippocampal Neurogenesis
New neurons are born and functionally integrate into the synaptic circuitry of the adult hippocampal dentate gyrus. Hippocampal neurogenesis is necessary for a normal behavioral response to antidepressant treatments. Thus the molecular mechanisms governing the successful birth and integration of newborn neurons could be exploited to improve treatments for affective disorders. In this project we will explore the impact of microRNAs on adult neurogenesis. MicroRNAs influence the expression of hundreds of genes potentially regulating gene assemblies important for the birth, differentiation, and integration of newborn neurons. Neuronal activity enhances neurogenesis. Thus, microRNAs that are regulated by activity are potential candidates regulating neurogenesis. We have identified an array of activity dependent microRNAs in a screen of the epileptic mouse dentate gyrus. This project will focus on examining the expression and function of these candidate activity dependent microRNAs. Using lentiviral and retroviral reporters via in vivo stereotaxic surgery we will determine whether a microRNA is expressed at the right place and right time to influence the integration of newborn neurons. Further, we will employ retroviral knockdown of candidate microRNAs to determine whether this has a functional impact on adult neurogenesis.
Rotations and Thesis Projects:
Rotations can be tailored to the interest of specific students. We commonly use whole-cell electrophysiology, molecular cloning to produce novel viral vectors, in vivo viral injections, histology and advanced microscopy to study the topics described above.
NIMH R01 “The Impact of Pten Signaling on Neuronal Form and Function” (R01MH097949-01)
Neurogenetics, Neural Circuits and Plasticity; Course in Experimental Molecular Medicine (PEMM101)
Autism Spectrum Disorder; Neurobiology of Disease (PEMM 211)
Endocrinology Lecturer and Small Group Leader; Medical Physiology (PHSL120)
Molecular Neuroscience; Neuroscience II (PEMM 212)
Neurotrophins and Neuronal Morphology; Advanced Biomedical Physiology (PEMM 271)
Nuclear Excluded Autism-Associated Phosphatase and Tensin Homolog Mutations Dysregulate Neuronal Growth.
A recombinant lentiviral PDGF-driven mouse model of proneural glioblastoma.
MiR-338-3p regulates neuronal maturation and suppresses glioblastoma proliferation.
A synthetic small-molecule Isoxazole-9 protects against methamphetamine relapse.
Can fearlessness come in a tiny package?
Designing, Packaging, and Delivery of High Titer CRISPR Retro and Lentiviruses via Stereotaxic Injection.
A Retroviral CRISPR-Cas9 System for Cellular Autism-Associated Phenotype Discovery in Developing Neurons.
Rapamycin prevents, but does not reverse, aberrant migration in Pten knockout neurons.
Cognitive Deficits Associated with Nav1.1 Alterations: Involvement of Neuronal Firing Dynamics and Oscillations.
DREADDS: Use and application in behavioral neuroscience.