Molecular Regulation of the Corticostriatal Circuits by the Forkhead P Genes

Grant Type
Grant Year
Institution Location
Institution Organization Name
Yale University
Investigators Name
Sestan, Nenad, MD, PhD

Gilles de la Tourette Syndrome (TS) is a developmental disorder characterized by a wide range of motor and behavioral symptoms, with motor and vocal tics being the prominent features. Etiology of the vocal tics is still largely unknown, although it is thought to involve alterations in the development and function of neural connections between the cerebral cortex and basal ganglia. To identify genes that are differentially expressed in distinct components of the cortico-basal ganglia neural pathways, we used Affymetrix Gene Chips to compare the expression of thousands of genes in different regions of the developing mouse brain. We identified several genes whose expression levels were dramatically different between distinct components of the corticostriatal system. Two of the genes whose differential expressions were validated using different techniques were Forkhead P (Foxp) 1 and 2 genes. Of these two genes, the Foxp2 is of particular interest since it is mutated in humans suffering from a verbal and orofacial dyspraxia (continuous impairment of articulation unrelated to impairment of muscle function). The deficits in affected humans appear early in childhood in the control of fine coordinated face and mouth movements that are required for speech production. Interestingly, several abnormalities with speech and language have been found in the TS population, suggesting that corticostriatal circuits involved in vocalization may also be affected in TS. Our preliminary results have shown that Foxp1 and 2 are expressed exclusively by projection neurons in the motor related regions of the mouse and human brain. To determine whether Foxp1 and 2 activities are required for the normal development of cortico-basal ganglia connections in the brain, we will determine whether their differentiation and patterning are impaired in the absence of Foxp2 activity, using the lentiviral delivery of small interfering RNAs that inhibit gene expression. Next, using the same delivery system, we will try to alter the differentiation and patterning of corticostriatal circuits by misexpressing Foxp1 and 2 genes. Finally, we will search for genes that are selectively modulated by Foxp2 in the corticostriatal neurons using microarray technology. The elucidation of how Foxp1 and 2 may regulate development of the corticostriatal circuitry as outlined in this proposal will help in understanding normal brain development and the neurobiological underpinnings of TS. Hopefully, using this information, it may become possible to identify candidate genes for TS and develop new strategies for the treatment of speech and motor related disorders. Nenad Sestan M.D., Ph.D. Yale University School of Medicine, New Haven, CT Award: $68,181 This award is in memory of Rece Ochsman in gratitude for over two decades of generous support of the TSA Research program Tourette Association of America Inc. – Research Grant Award 2004-2005