UCSF

Brain derived neurotrophic factor (BDNF) and its receptor TrkB are involved in developmental maturation of cell processes, synaptogenesis, synaptic plasticity, and neuronal differentiation and survival. BDNF has been shown to play a significant role in the regulation of sensitive period plasticity in the visual cortex and maturation of inhibitory circuits. However, little is known about how BDNF/TrkB signaling may affect the maturation of synapses and function of the prefrontal cortex (PFC), especially during adolescence, a time-period of particular relevance for the onset of mental illness. In this dissertation I seek to increase understanding of how BDNF/TrkB signaling impacts the development of the prefrontal cortex, at the level of synapses and behavior. In chapter 1, I review relevant background studies on the maturation of the frontal cortex, including the role of neurotrophins (and in particular BDNF/TrkB signaling) in the developing brain as well as in sensitive period plasticity. I also review what is currently known about the role BDNF/TrkB signaling plays in common neuropsychiatric disorders including schizophrenia, mood disorders, substance abuse disorders, and autism. In Chapter 2, I use whole-cell voltage clamp recording to show that TrkB signaling plays a specific role in the development of inhibitory but not excitatory synapses in a sub-circuit of the dorsomedial prefrontal cortex during adolescence. In Chapter 3, I show that a common polymorphism in the BDNF gene alters flexibility in reversal learning in multiple paradigms. In Chapter 4, I combine approaches to shed light on the role of maturation of GABAergic inhibition on maturation of behavioral inhibition. I conclude that while BDNF and TrkB signaling play an important role in shaping both behavior and neuronal circuits in the periadolescent PFC, the relationship between the development of GABAergic inhibition and behavioral inhibition is not clear-cut. Overall I hope to provide insight into the role that BDNF/TrkB signaling has in shaping inhibitory circuits during adolescence, and ultimately how alterations in BDNF/TrkB signaling may contribute to frontal function disorders.