Connexin32-mediated control of progenitor cell fate in injured and uninjured adult mouse brain

Gap junction protein expression has been implicated in progenitor cell proliferation, survival, and specification during development. The present study was undertaken to establish the role of the gap junction protein connexin32 in dictating progenitor cell fate in adult mouse brain. In the dentate gyrus of the hippocampus, I localized the connexin32 protein to a subset of NG2 + early oligodendrocyte progenitors. In connexin32-null mutant mice, I found an increase in the total number of proliferating early oligodendrocyte progenitors and demonstrated that the turnover of these cells is constitutively enhanced (Chapter 2). Furthermore, behavioural testing in a learning and memory task revealed that connexin32-deficient mice exhibit impaired reference memory, indicating that progenitor cells may play a role in hippocampal associated cognitive function (Chapter 3). In vitro analysis further demonstrated that these progenitors are able to differentiate into neurons upon a neurogenic stimulus. In Chapter 4, I assessed the ability of hippocampal progenitors to activate and regenerate brain tissue in vivo, following kainic acid-induced epileptiform seizures, in the presence or absence of connexin32. I show that connexin32-null mutation promotes more effective neurogenesis from NG2+ progenitor cells activated in the CA3a/b pyramidal zone, following excitotoxic injury. To confirm the role of connexin32 in determining progenitor cell fate, I performed a series of gain of function studies by inducing ectopic connexin32 expression in neurosphere progenitor cultures (Chapter 5). I show that connexin32 promotes oligodendrogenesis in vitro, at the expense of neurogenesis. These experiments provide insight into connexin-mediated control of neural progenitor specification and begin to identify connexins as possible therapeutic targets following brain injury