Professor of Biochemistry & Biophysics
PHD - University of Texas, Houston
How neuronal circuitry arises in the brain during ontogeny is a central question in neuroscience. My research seeks to define the molecular mechanisms that govern development of connectivity in the mammalian brain. We have extensively probed the mechanisms of axon guidance and synaptogenesis in normal brain, and are keenly interested in defective functioning of neural genes that perturb connectivity in neuropsychiatric disorders such as autism spectrum disorders (ASDs) and schizophrenia. Our approach has been to create novel mouse genetic models designed to reveal how mutation of specific families of neural adhesion molecules (L1, NCAM) perturbs cortical connectivity and leads to abnormal behavioral responses. Notably, our studies of thalamocortical and retino-collicular development have demonstrated that neural cell adhesion molecule signaling plays a vital role in guiding specific axon populations to appropriate synaptic targets in the brain, essential for neurotransmission, sensory functions, and working memory.
Recently, polymorphisms in the NrCAM gene have been linked with ASDs, a disease associated with mis-wiring and hyperexcitability in the prefrontal cortex. Using novel mouse models for NrCAM loss of function, we showed that NrCAM is vital for normal social behavior and controls topographic connectivity in specific neural pathways. An exciting new finding is that NrCAM is a pivotal component of a receptor signaling complex for the repellent axon guidance cue Semaphorin3F. This complex appears to have dual functions regulating topographic axon guidance in amygdalar circuitry (controlling fear/anxiety and social interactions) as well as spine morphogenesis of cortical pyramidal neurons, which provide ”top-down” control of the fear response. We have generated a conditional NrCAM mutant mouse that will be a valuable new genetic tool for discerning distinct cortical and amygdalar functions underlying development of ASD-related behaviors, and for testing the pro-social neuropeptide oxytocin and its derivatives for ameliorating abnormal responses.
As a member of the Carolina Institute for Developmental Disabilities, NIMH-funded UNC Silvio Conte Center for Schizophrenia Research, and UNC Neuroscience Center, I have engaged in productive collaborations with colleagues dedicated to unraveling the neurodevelopmental mechanisms of connectivity. Our recent studies utilize optogenetic strategies to probe the detailed connectivity and function of neural circuits in mouse models, which have been facilitated by collaborations with UNC electrophysiologists Dr. Garret Stuber, Dr. Paul B. Manis, and Dr. Ben Philpot. In addition we work in coordination with with Dr. Sheryl Moy, Director of the UNC Mouse Behavioral Core Facility, on studies of sociability, working memory, and other behaviors relevant to ASD. I serve as advisor to this core for the Carolina Institute for Developmental DisabilitiesTraining Grant.
We are also members of the UNC Neuroscience Center and Neurobiology Curriculum for Graduate Research. Association with the Neuroscience Center enables us to participate in the Neuroscience Mini-Series, weekly neuroscience seminars, and the annual symposium. Students from the Neurobiology Curriculum and BBSP are invited to rotate in the lab.
- Dai J, Buhusi M, Demyanenko GP, Brennaman LH, Hruska M, Dalva MB, Maness PF. NrCAM promotes topographic retinocollicular mapping. PLOS One, in press, 2013.
- Brennaman, LH and Maness PF. EphrinA/EphA Induced ectodomain shedding of Neural Cell Adhesion Molecule regulates growth cone repulsion through ADAM10 metalloprotease. Journal of Neurochemistry, in press, 2013.
- Brennaman, LH, Zhang, X, Guan, H, Triplett, J, Brown, A, Demyanenko, GP, Manis, PM, Landmesser, L, and Maness, PF. Polysialylated NCAM and EphrinA/EphA regulate synaptic development of GABAergic interneurons in the prefrontal cortex. Cerebral Cortex, 23 (2013) 162-177.
- Dai J, Dalal JS, Thakar S, Henkemeyer M, Lemmon VP, Harunaga JS, Schlatter MC, Buhusi M, Maness PF. EphB regulates L1 phosphorylation during retinocollicular mapping. Mol Cell Neuroscience 50 (2012) 201-210.
- Enriquez-Barreto L, Palazzetti C, Brennaman LH, Maness, PF, and Fairén, A. NCAM regulates thalamocortical axon pathfinding and the organization of the cortical somatosensory representation in mouse. Frontiers in Neuroscience 5 (2012) 1-13.
- Molnár Z, Garel S, López-Bendito G, Maness PF, and Price D. Multiple mechanisms controlling the guidance of thalamocortical axons through the embryonic forebrain during development. Eur. Journal Neuroscience 35 2012, 1573-85.
- Demyanenko GP, Siesser PF, Wright AG, Brennaman LH, Bartsch U, Schachner M, Maness PF. L1 and CHL1 Cooperate in Thalamocortical Axon Targeting. Cerebral Cortex 21 (2011) 401-12.
- Demyanenko, GP, Riday, TT, Tran T.S, Dalal, JS, Darnell, EP, Brennaman, LH, Sakurai, T, Grumet, M, Philpot, BD, and Maness, PF. NrCAM Deletion Causes Topographic Mistargeting of Thalamocortical Axons to the Visual Cortex and Disrupts Visual Acuity. Journal of Neuroscience 31 (2011) 1545-1558.
- Brennaman, LH, Kochlamazashvili G, Stoenica L, Nonneman RJ, Moy SS, Schachner M, Dityatev A, Maness PF. Transgenic mice over-expressing the extracellular domain of NCAM are impaired in working memory and cortical plasticity. Neurobiology of Disease 43 (2011) 372-378.
- Brennaman, LH and Maness PF. NCAM in Neuropsychiatric and Neurodegenerative Disorders. Adv. Exp. Med. Biol. 663 (2010) 299-317.
- Demyanenko, GP, Halberstadt AI, and Maness, PF. CHL1 cooperates with PAK1-3 to regulate morphological differentiation of embryonic cortical neurons. Neuroscience 165 (2010)107-15.
- Buhusi M, Schlatter MC, Demyanenko GP, Thresher R, Maness PF. L1 interaction with ankyrin regulates mediolateral topography in the retinocollicular projection. J Neurosci. 2008 Jan 2;28(1):177-88
- Schlatter MC, Buhusi M, Wright AG, Maness PF. CHL1 promotes Sema3A-induced growth cone collapse and neurite elaboration through a motif required for recruitment of ERM proteins to the plasma membrane. J Neurochem. 2008 Feb;104(3):731-44. Epub 2007
- Wright AG, Demyanenko GP, Powell A, Schachner M, Enriquez-Barreto L, Tran TS, Polleux F, Maness PF. Close homolog of L1 and neuropilin 1 mediate guidance of thalamocortical axons at the ventral telencephalon. J Neurosci. 2007 Dec 12;27(50):13667-79
- Maness PF, Schachner M. Neural recognition molecules of the immunoglobulin superfamily: signaling transducers of axon guidance and neuronal migration.
- Nat Neurosci. 2007 Jan;10(1):19-26. Review. Erratum in: Nat Neurosci. 2007 Feb;10(2):263
- Sullivan PF, Keefe RS, Lange LA, Lange EM, Stroup TS, Lieberman J, Maness PF. NCAM1 and neurocognition in schizophrenia. Biol Psychiatry. 2007 Apr 1;61(7):902-10. Epub 2006
- Hinkle CL, Diestel S, Lieberman J, Maness PF. Metalloprotease-induced ectodomain shedding of neural cell adhesion molecule (NCAM). J Neurobiol. 2006 Oct;66(12):1378-95
3020 Genetic Medicine Bldg
Campus Box 7260
Chapel Hill, NC 27599