Molecular mechanisms underlying sensory-driven structural and functional plasticity in the awake developing brain

• Main Author: Chen, Simon
• Language: English
• Published: University of British Columbia 2012
• Online Access: http://hdl.handle.net/2429/42763

During early brain development, formation of functional neural circuits requires correct neuronal morphological growth and formation of appropriate synaptic connections. In addition, sensory experience and neural activity impart lasting effects on morphological and functional complexity by directing synapse formation and synaptic plasticity. Errors in these events may result in the creation of dysfunctional circuits underlying common neurodevelopmental disorders, including Autism Spectrum Disorder (ASDs), schizophrenia, and epilepsy. Therefore, to understand the normal development and the pathophysiology of these disorders, we must decipher the molecular mechanisms regulating developmental neural circuit structural and functional plasticity. This dissertation discusses work on the molecular mechanisms underlying structural and functional plasticity in the developing brain, ranging from cell adhesion molecules involved with initial synapse formation to transcription factors regulating sensory experience-driven functional plasticity. In the first half of the dissertation, using two-photon time-lapse imaging of individual growing neurons within intact and awake embryonic Xenopus brains, I found that the cell adhesion molecules, neurexin (NRX) and neuroligin-1 (NLG1), confer stabilization to labile dendritic filopodia, supporting their transition into longer and persistent branches through an activity-dependent multistep process. Disrupting NRX-NLG1 function destabilizes filopodia and culminates in reduced dendritic arbor complexity as neurons mature over days. These findings suggest that abnormalities in brain neuron structural development may contribute to ASDs. In the second half of the dissertation, I used in vivo two-photon calcium imaging of visual network activity and rapid time-lapse imaging of individual growing brain neurons to identify morphological correlates of experience-driven functional potentiation and depression during critical periods of neural circuit formation. Further, I identified the transcription factor MEF2A/2D as a major regulator of neuronal response to plasticity-inducing stimuli directing both structural and functional changes. Unpatterned sensory stimuli that change plasticity thresholds induce rapid degradation of MEF2A/2D through a classical apoptotic pathway requiring NMDA receptors and caspases-9, 3 and 7, demonstrating natural sensory experience fine-tunes the plasticity thresholds of neurons during neural circuit formation. Together, work in this dissertation provides new insights into the molecular and cellular mechanisms of how sensory experience and synapse formation direct structural and functional plasticity in the embryonic developing brain. === Medicine, Faculty of === Graduate