Establishment of proper neural circuits: A molecular and ultrastructural study

The establishment of proper neural circuits in the central nervous system is paramount to producing a functional nervous system. The formation of such circuitry in the developing animal, or later in the adult brain, requires several important regulated steps. Disruptions in any of these processes can have deleterious effects on the organism. The goal of my dissertation research was to conduct molecular and ultrastructural studies to elucidate mechanisms by which neural circuits are established.;First, I will discuss the formation of a hippocampal circuit following adult neurogenesis. It has been well established that neurogenesis is ongoing into adulthood in the hippocampi of many mammals, including humans. While it is accepted that these new neurons receive functional inputs, it has yet to be shown that they form synaptic outputs with target neurons. Thus, if and when these new neurons are capable of contributing to hippocampal function remains an open question. By performing ultrastructural analysis of their axons, I will show that adult-born neurons form structurally normal synaptic contacts with their targets through a developmental process that is very similar to, albeit slower than, that of the neonate. The molecules that regulate the synaptic integration of new neurons in the adult brain have not yet been elucidated. I therefore investigated the role of Disrupted-in-Schizophrenia 1, a gene which is expressed highly in the adult hippocampus and has known ties to major mental illness, on the development of these new neurons and their synaptic contacts. I will show that a partial loss of this gene in adult-born cells results in altered cell morphology, an increased rate of synaptic integration, and apparent changes in synaptic stability.;Next, I will discuss circuit formation in the developing animal. My studies focus on the guidance and pruning of the corticospinal tract. During development, axons arising from cortical neurons undergo a complex set of guidance decisions as they target the spinal cord. The guidance of corticospinal axons has been extensively studied; however, analysis of mutant mice makes it clear that other unidentified molecular cues are involved in this guidance. Later, corticospinal axons arising from different cortical regions exhibit stereotyped pruning of axons from distinct target areas. This pruning event has long been studied, however, very little is known about the mechanism by which this pruning occurs. I will show that plexin signaling is required for both the guidance and pruning of corticospinal axons. Importantly, plexins regulate the guidance and pruning of specific subsets of corticospinal axons, and this specificity is dependent upon the location of the parent cells in the neocortex.;In summary, my research has advanced our understanding of molecular and cellular mechanisms that govern the development of neural circuits in the developing and adult brain.