The loss or dysfunction of GABAergic inhibitory interneurons, particularly parvalbumin (PV) expressing interneurons, is implicated in severe psychiatric disorders including schizophrenia, bipolar depression, and Tourette syndrome. PV+ interneurons regulate excitatory neuron output and are important for coordinating brain rhythms so that excitatory neurons can fire in synchrony- properties deemed to be critical for their function in cognition and behavioral control. This proposal describes the career development plan and research aims that Karen M|ller Smith, Ph.D. will achieve during her mentored career development training. The immediate goal of this proposal is to prepare Dr. Smith for an independent research career by providing her with theoretical and knowledge-based training in the neurobiology of psychiatric disorders through formal course work in neuroscience, neurodevelopmental disorders and statistics, and through mentored research training in primary tissue culture, cell transplantation, behavioral analysis of transgenic mice, gene expression microarray experiments using the translating ribosome affinity purification (TRAP) method, and target validation experiments using in vivo electroporation of silencing RNA (siRNA) constructs. The long-term goal is to gain an understanding of the developmental events contributing to the maturation and survival of cortical interneurons during the critical period of their synaptic integration and cell maturation in the postnatal brain. Dr. Smith obtained her Ph.D. in genetics by performing candidate gene analysis of dopaminergic system genes in Attention Deficit Hyperactivity Disorder (ADHD). During her postdoctoral training at the Yale Child Study Center (YCSC), Dr. Smith participated in the T32 Neurobiology of Childhood Neuropsychiatric Disorders training program and has gained expertise in developmental neurobiology, anatomical analysis and behavioral characterization of transgenic mice while performing several studies to elucidate the role of fibroblast growth factor (Fgf) signaling in cortical development and behavior. Dr. Smith will continue her studies at YCSC, under the primary mentorship of Dr. Flora Vaccarino, with the assistance of a distinguished group of scientific advisors consisting of experts in psychiatry, neurobiology, and molecular genetics, who will provide guidance with her research design, performance of experiments, and data analysis. The diverse research environment at Yale offers numerous opportunities to learn from internationally recognized experts in the fields of psychiatry, neurobiology, and developmental biology and to attend seminars hosted by the various departments in neurobiology and psychiatric research. Dr. Smith will take advantage of these resources in order to attend courses, seminar series, journal clubs, and hands on training at core facilities. Dr. Smith will enhance these activities by attending scientific conferences and an intense workshop course in neuroscience methodologies. In the research proposal, Dr. Smith will utilize mice lacking the fibroblast growth factor receptor 1 (Fgfr1) gene, which exhibit a decrease in PV+ cortical inhibitory interneurons that is correlated with hyperactive behavior, in order to gain a better understanding of how the neuronal circuitry involved in behavioral inhibition is established. The loss of interneurons in Fgfr1 mutants occurs postnatally, when Fgfr1 is expressed in glial cells of the cortex, particularly astrocytes. Dr. Smith will investigate whether the astrocytes of Fgfr1 mutants are less capable of supporting the survival and maturation of cortical interneurons by in vitro co-culture, and by cell transplantation of interneurons into control and Fgfr1 mutant cerebral cortices. She will generate astrocyte specific mutations of Fgfr1 to test the hypothesis that Fgfr1 signaling in astrocytes is essential for proper maturation of inhibitory interneurons. Dr. Smith will utilize TRAP and microarray analysis to identify pathways that are disrupted by Fgfr1 mutations in astrocytes, and will test the effects of candidate genes upon interneuron maturation by in vivo electroporation of silencing RNAs. These studies will allow Dr. Smith to determine the role of Fgfr1 in establishing the proper proportion of PV+ interneurons in the cortex, and will shed light into the postnatal development of PV+ interneurons, a problem with direct relevance to schizophrenia and bipolar depression. Results from this research will inform future studies aimed at promoting the health and maturation cortical interneurons.
This project will address the postnatal development of an important subtype of neurons, cortical inhibitory interneurons, which are diminished in schizophrenia and bipolar depression, and in mice lacking the Fgfr1 gene. The research will focus on the role of glia, supportive cells of the brain that express Fgfr1, in maintaining the health and maturation of inhibitory interneurons at a time when interneurons are integrating into the brain circuitry. The ultimate goal of this research is to identify mechanisms that contribute to interneuron maturation and survival, possibly leading to novel therapies aimed at preventing or reversing interneuron disruption in psychiatric illnesses.
|Smith, Karen Müller (2018) Hyperactivity in mice lacking one allele of the glutamic acid decarboxylase 67 gene. Atten Defic Hyperact Disord 10:267-271|
|Choubey, Lisha; Collette, Jantzen C; Smith, Karen Müller (2017) Quantitative assessment of fibroblast growth factor receptor 1 expression in neurons and glia. PeerJ 5:e3173|
|Collette, Jantzen C; Choubey, Lisha; Smith, Karen Müller (2017) -Glial and stem cell expression of murine Fibroblast Growth Factor Receptor 1 in the embryonic and perinatal nervous system. PeerJ 5:e3519|
|Smith, Karen Müller; Maragnoli, Maria Elisabetta; Phull, Pooja M et al. (2014) Fgfr1 inactivation in the mouse telencephalon results in impaired maturation of interneurons expressing parvalbumin. PLoS One 9:e103696|
|Muller Smith, Karen; Williamson, Theresa L; Schwartz, Michael L et al. (2012) Impaired motor coordination and disrupted cerebellar architecture in Fgfr1 and Fgfr2 double knockout mice. Brain Res 1460:12-24|