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Abstract
The Eph receptor tyrosine kinases and their ligands, the ephrins, make up two large protein families that are involved in a wide array of biological processes during development and adulthood. In the central nervous system, for example, these molecules are involved in axon guidance, cell migration, boundary formation, and dendritic spine morphogenesis. The basal ganglia system is a group of brain nuclei that express some of these proteins during development but their role in the development and function of this part of the brain is unknown. The basal ganglia system is a critical component of many brain functions such as motor control, emotion, and implicit learning, and its dysfunction is associated with several neurological disorders such as Parkinson's Disease. However, the molecular mechanisms that control the development of this brain region are not currently understood.
The purpose of the research described in this dissertation was to determine if Eph receptors and ephrins are involved in basal ganglia development. Anatomical and behavioral abnormalities in knock-out mice deficient for receptors EphA4 or EphB1 were examined. EphB1 mutant mice exhibited a 40% loss of neurons in the substantia nigra pars reticulata (the major output nucleus of the basal ganglia), as well as a significant increase in spontaneous locomotor behavior. In response to cocaine or amphetamine, these mice exhibited a relatively small increase in locomotion compared to normal mice. EphB1 mutants also exhibited an abnormal response to apomorphine, a dopamine receptor agonist, which was a noticeable decrease in locomotion. Neither EphA4 nor EphB1 deletion led to anatomical changes in the striatum, the major input nucleus of the basal ganglia. However, deletion of EphA4 led to a larger increase in spontaneous locomotor behavior than deletion of EphB1. The anatomical changes observed in EphB1 mutants may be linked to their behavioral phenotype. Loss of output from the basal ganglia would lead to a loss of inhibition over the motor control centers of the brain, which would lead, to hyperactivity. More studies are needed to determine the role of EphA4 in this system. These results suggest that Eph receptors are involved in development and function of the basal ganglia.
