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A holy grail in neuroscience is being able to control plasticity to facilitate recovery from insult in the adult brain. Despite success in animal models, few therapies have translated from bench to bedside. This thesis is aimed at addressing 2 major stumbling blocks in translation. The first gap is in our understanding of the mechanisms of plasticity-enhancing therapies, and the second is in our understanding the relevance of those mechanisms for human development. In chapters 2 and 3, I address the first gap by asking whether fluoxetine, a selective serotonin reuptake inhibitor, which reinstates juvenile-like plasticity in adult animals, reinstates a juvenile-like synaptic environment. We found evidence to suggest that fluoxetine is neuroprotective, as it rescued all of the MD-driven changes, but surprisingly we found no evidence that fluoxetine recreated a juvenile-like synaptic environment, with the exception of Ube3A. Ube3A is necessary for critical period plasticity, indicating that Ube3A may play a crucial in enhancing plasticity in the adult cortex. In chapter 4, I address whether D-serine, an amino acid that has similar effects to fluoxetine in terms of both plasticity and anti-depression, shares a common neurobiological signature with fluoxetine. I found that D-serine’s effects were strikingly similar to fluoxetine, with respect to markers of the E/I balance, indicating that it may be an effective alternative to fluoxetine. In chapter 5, I address the second gap by studying the development of 5 glutamatergic proteins in human V1. Some changes occurred early, as would be predicted from animals studies, while other changes were protracted, lasting into the 4th decade. These results will help guide the use of treatments, like fluoxetine, which effect glutamatergic proteins. iv Together the findings in this thesis significantly advances our understanding of the mechanisms involved in restating plasticity in the adult cortex, and their relevance to humans. / Dissertation / Doctor of Philosophy (PhD) / Neurons change to rewire, adapt, and recover. This plasticity is greatest early in development, so much research has focused on bringing it back in adults. There has been amazing progress in animal models, but this has not translated to humans. Two reasons for this are that we do not fully understand the mechanisms of these treatments in animals or whether those mechanisms are relevant for humans. My thesis addresses this by studying how 2 treatments, fluoxetine and D-serine, affect proteins that are important for plasticity, and how those proteins develop in the humans. I found that these treatments are neuroprotective, but do not recreate a younger state. One interesting standout is an increase in Ube3A, which is essential for juvenile plasticity. I also found that much of human development is similar to animals, but the time course for some proteins is uniquely prolonged in humans. These findings have implications for the use of plasticity-enhancing treatments at different ages.

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