Mechanisms of Kallikrein 6 in Myelin Plasticity, Motor Learning, and Fear Memory

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PROJECT ABSTRACT Mechanistic studies of learning and memory have traditionally focused on the neuron and account for early scientific advances in the field of neuroscience as well as the current therapeutic approach in neurology and psychiatry. However, this perspective leaves potential therapies untapped for stubborn cognitive diseases by neglecting the intimate relationship of glia, namely oligodendrocytes, that facilitate the memory forming actions of neurons. Recently, myelin and the myelin producing oligodendrocyte have been shown to influence motor, fear, and social learning through a process termed myelin plasticity. Aptly named, myelin plasticity refers to the sculpting of myelin networks to fine tune the neuronal networks that mediate learning. Our lab has shown that kallikrein 6 (Klk6), a secreted serine protease highly expressed by myelinating oligodendrocytes, has the power to control oligodendrocyte differentiation as well as shape myelination patterns. Further, we find global Klk6 knockout enhances fear memory and motor learning. Early preliminary data suggests it is the loss of Klk6 in oligodendrocyte precursor cells (OPC) that drives these changes. The long-term goal of this research is to determine the role(s) of Klk6 in adult CNS homeostasis and white matter pathology to develop new therapeutic targets. The objective of this grant is to understand oligodendrocyte-specific mechanisms of Klk6 in fear memory and motor learning in young adult mice. The central hypothesis to be tested is that Klk6 regulates myelin plasticity such that reduced levels promote learning and memory by unleashing myelin synthesis. We plan to test this hypothesis with two specific aims. Aim 1 seeks to understand if OPC Klk6 loss is sufficient to replicate the behavioral findings in the global Klk6 knockout animals. We will characterize myelin networks in key anatomical brain regions and study OPC dynamics with pulse labeling. Aim 2 examines the mechanistic role of Klk6 in myelin synthesis and plasticity. First, we will generate single cell RNA sequencing data in OPC- specific Klk6 knockout mice to determine Klk6 signaling pathways. Then we will measure the impact of Klk6 loss on the territory of myelinating oligodendrocytes as well as OPC differentiation. Finally, we will probe if Klk6 acts in tandem with discovered signaling pathways. This proposed research is innovative because it is the first to examine Klk6 as a molecular mediator of myelin plasticity, a new and exciting branch of neuroscience research. The proposed research is significant because we expect to expand on our fundamental knowledge of adult myelin production, elucidate new mechanisms of memory formation, and uncover a differential impact of Klk6 in males and females. Ultimately, this work will open new avenues for treatment of white matter pathology in neurology and psychiatry by improving the field’s understanding of mechanisms regulating myelin homeostasis and plasticity in the adult central nervous system.