Role of Tyrosine Receptor Kinase B in the Development and Function of the Central Nervous System
Tyrosine Receptor Kinase B (TrkB) was initially identified as the high-affinity receptor for Brain-Derived Neurotrophic Factor (BDNF) in regulating the survival of sympathetic and sensory neurons. In the CNS, however, BDNF-TrkB interaction has been shown to regulate diverse aspects of development, physiology and pathology. In the current studies we focus on the roles of TrkB and its downstream signaling pathways in the progression and amelioration of CNS diseases. Though the nature of the diseases diverges, they share a common molecular regulatory mechanism. First we report that TrkB is required cell-autonomously to regulate the generation of new neurons. Mice lacking TrkB in hippocampal neural progenitor cells had impaired proliferation and neurogenesis, and are behaviorally insensitive to antidepressive treatments. Specific deletion of NF1, an antagonist of Ras, in adult neural progenitor cells enabled rapid proliferative and behavioral responses to sub-chronic antidepressants, and led to spontaneous antidepressive-like behaviors in the long run. Thus, our findings demonstrate impairment of the neural precursor niche as an etiological factor for refractory responses to antidepressive regimen, and the activation of adult neurogenesis as an approach to modulate depression and anxiety-like behaviors. In the second half, we report that ablation of Bdnf from the cortex and the substantia nigra leads to depletion of BDNF protein in the striatum. Mice lacking BDNF-TrkB signaling in the corticostriatal and nigrostriatal circuits displayed severe motor deficits and striatal degeneration reminiscent of the Huntington?disease. In contrast, specific ablation of TrkB from the striatal medium spiny neurons resulted in late-onset neuronal loss and spine degeneration, without causing obvious movement abnormalities. Thus, our results establish an essential role for TrkB in regulating the normal maturation and maintenance of striatal medium spiny neurons.