The Role of KIBRA in Synaptic Plasticity Across Age




Mendoza, Matthew Lee

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Over the last four decades, neurobiology has gained valuable insight into the cellular and molecular mechanisms of learning and memory. However, a complete understanding of how we learn and remember information remains at the frontier of neuroscience research. In particular, the molecular bases for age-dependent changes in our capacity to learn and remember are poorly understood. Identifying the neural basis of age-dependent changes in learning and memory will not only provide crucial insights into the pathological mechanisms underlying progressive neurological disorders but also guide neurodevelopmentally informed educational strategies and legal policies. Synaptic plasticity, expressed as persistent increases (long-term potentiation, LTP) or decreases (long-term depression, LTD) in synaptic strength is thought to be a key cellular mechanism underlying cognitive functions such as learning and memory. AMPA-type glutamate receptors mediate the vast majority of fast-excitatory synaptic transmission in the central nervous system, and dynamic AMPA receptor trafficking is critical for many forms of synaptic plasticity. The coordinated movement of AMPA receptors into and out of a synapse is regulated by interactions with multiple proteins including the synaptic scaffold KIBRA (Kidney and Brain Protein). Previous evidence indicates that KIBRA and it's respective binding partners are associated with age-emergent neurological diseases such as Tourette, Schizophrenia, Alzheimer's, and Autism Spectrum Disorders. While there is a growing body of human literature implicating KIBRA in learning and memory, KIBRA's molecular function and contribution to cognitive maturation remains poorly understood. Therefore, this dissertation was designed to focus on the role of KIBRA in synaptic plasticity and AMPA receptor trafficking across the juvenile and adult brain. In Chapter 1, I review the pertinent literature to frame the overall trajectory of this dissertation. Next, in Chapter 2, using novel inducible and conditional KIBRA knock mice, I show that KIBRA acutely influences hippocampal LTP selectively in the adult brain, but not the juvenile brain. These adult-specific deficits in LTP were associated with a reduction in the basal and activity-dependent expression of AMPA receptors and AMPA receptor complex interactors. In Chapter 3, I examine KIBRA's role in LTD. Contrary to published results in conventional KIBRA KO mice on a hybrid C57Bl6N/FVB background, we show that acute manipulation of KIBRA on a C57Bl6N background does not influence hippocampal LTD. Lastly, I show that acute reduction of KIBRA influences GluA2 phosphorylation at S880, which might restrict the recycling of internalized AMPA receptors. Taken together, my data suggest that KIBRA preferentially influences LTP as opposed to LTD. KIBRA's role in LTP is selective to the adult hippocampus and loss of KIBRA reduces the expression and trafficking of AMPA receptors. In Chapter 4, I discuss the implication of this work and layout future directions.

General Notes

Pages 44-164 are misnumbered as pages 32-152.

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