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Bryan W. Luikart, PhD

Title(s):
Associate Professor of Molecular and Systems Biology

Additional Titles/Positions/Affiliations:
Frank and Myra Weiser Scholar in the Neurosciences

Department(s):
Molecular and Systems Biology

Education:
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)

Programs:
Neuroscience Center at Dartmouth
Program in Experimental and Molecular Medicine

Websites:
http://www.synapticplasticity.com

Contact Information:

Bryan W. Luikart
Vail 604
74 College Street
Hanover NH 03755

Office: 603-650-1633
Phone: 603-650-1643


Professional Interests:

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.

Cytoskeletal regulation in neuronal development
Autism is clearly a spectrum of disorders in which around half of the cases are associated with a specific genetic mutation. However, no more than 2% of all cases are caused by any one mutation. Autism-associated mutations modeled in the mouse brain cause defects in morphological development and synaptic connectivity of neurons. Thus, regulation of neuronal growth and sculpting of synaptic connectivity may underly the development of cognitive and affective behaviors that are altered in autism. We know that growth factors and related signaling pathways modulate neuronal growth through the regulation of translation and cytoskeletal remodeling. While we have learned a great deal about these pathways and the regulation of translation through the context of autism research, the dysregulation of cytoskeletal dynamics in the context of autism is largely unexplored. In this project we have used a bioinformatic approach to predict whether gene mutations found in patients with autism will directly regulate cytoskeletal proteins. We are now using our retroviral CRISPR system to examine the morphological impact of the genes that likely impact the cytoskeleton. For genes having an impact in this somatic cell screen, we are implementing CRISPR in mouse zygotes to generate novel whole-animal models for autism.

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.

Grant Information:

NIMH R01 “The Impact of Pten Signaling on Neuronal Form and Function” (R01MH097949-01)

Courses Taught:

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)
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Selected Publications:

 

Nuclear Excluded Autism-Associated Phosphatase and Tensin Homolog Mutations Dysregulate Neuronal Growth.
Fricano-Kugler CJ, Getz SA, Williams MR, Zurawel AA, DeSpenza T Jr, Frazel PW, Li M, O'Malley AJ, Moen EL, Luikart BW
Biol Psychiatry. 2018 Aug 15;84(4):265-277. doi: 10.1016/j.biopsych.2017.11.025. Epub 2017 Dec 2.
PMID: 29373119

A recombinant lentiviral PDGF-driven mouse model of proneural glioblastoma.
Rahme GJ, Luikart BW, Cheng C, Israel MA
Neuro Oncol. 2018 Feb 19;20(3):332-342. doi: 10.1093/neuonc/nox129.
PMID: 29016807

MiR-338-3p regulates neuronal maturation and suppresses glioblastoma proliferation.
Howe JR 6th, Li ES, Streeter SE, Rahme GJ, Chipumuro E, Russo GB, Litzky JF, Hills LB, Rodgers KR, Skelton PD, Luikart BW
PLoS One. 2017;12(5):e0177661. doi: 10.1371/journal.pone.0177661. Epub 2017 May 11.
PMID: 28493990

A synthetic small-molecule Isoxazole-9 protects against methamphetamine relapse.
Galinato MH, Lockner JW, Fannon-Pavlich MJ, Sobieraj JC, Staples MC, Somkuwar SS, Ghofranian A, Chaing S, Navarro AI, Joea A, Luikart BW, Janda KD, Heyser C, Koob GF, Mandyam CD
Mol Psychiatry. 2018 Mar;23(3):629-638. doi: 10.1038/mp.2017.46. Epub 2017 Mar 28.
PMID: 28348387

Can fearlessness come in a tiny package?
Luikart BW
Elife. 2017 Feb 6;6 pii: e24575. doi: 10.7554/eLife.24575. Epub 2017 Feb 6.
PMID: 28165326

Designing, Packaging, and Delivery of High Titer CRISPR Retro and Lentiviruses via Stereotaxic Injection.
Fricano-Kugler CJ, Williams MR, Salinaro JR, Li M, Luikart B
J Vis Exp. 2016 May 23;(111) doi: 10.3791/53783. Epub 2016 May 23.
PMID: 27285851

A Retroviral CRISPR-Cas9 System for Cellular Autism-Associated Phenotype Discovery in Developing Neurons.
Williams MR, Fricano-Kugler CJ, Getz SA, Skelton PD, Lee J, Rizzuto CP, Geller JS, Li M, Luikart BW
Sci Rep. 2016 May 10;6:25611. doi: 10.1038/srep25611. Epub 2016 May 10.
PMID: 27161796

Rapamycin prevents, but does not reverse, aberrant migration in Pten knockout neurons.
Getz SA, DeSpenza T Jr, Li M, Luikart BW
Neurobiol Dis. 2016 Sep;93:12-20. doi: 10.1016/j.nbd.2016.03.010. Epub 2016 Mar 15.
PMID: 26992888

Cognitive Deficits Associated with Nav1.1 Alterations: Involvement of Neuronal Firing Dynamics and Oscillations.
Bender AC, Luikart BW, Lenck-Santini PP
PLoS One. 2016;11(3):e0151538. doi: 10.1371/journal.pone.0151538. Epub 2016 Mar 15.
PMID: 26978272

DREADDS: Use and application in behavioral neuroscience.
Smith KS, Bucci DJ, Luikart BW, Mahler SV
Behav Neurosci. 2016 Apr;130(2):137-55. doi: 10.1037/bne0000135. Epub 2016 Feb 25.
PMID: 26913540