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.

TMEM16A is a novel calcium-activated chloride channel first cloned in 2008. It is responsible for regulating secretions from the epithelium, excitability of smooth muscle, membrane potential of neurons, and cellular proliferation. This work describes two studies investigating the structure and function of TMEM16A ion channels. In the first, I report a series of experiments that show that TMEM16A channels have a homodimeric architecture facilitated by its cytoplasmic N-terminus. This dimerization domain is important for channel assembly in eukaryotic cells, and the in vitro association of peptides containing the dimerization domain is consistent with a homotypic protein-protein interaction. Amino acid substitutions in the dimerization domain affect functional TMEM16A-CaCC channel expression as expected from its critical role in channel subunit assembly. In the second, I describe the identification of four acidic amino acid residues as putative calcium-binding sites. Alterations of the charge, polarity, and size of amino acid side chains at these sites alter the ability of different divalent cations to activate the channel. Furthermore, gating of TMEM16A mutants containing double cysteine substitutions at these residues are sensitive to the redox potential of the internal solution, providing evidence for their physical proximity and solvent accessibility.