Michael R. Akins, PhD - US grants

DESCRIPTION (provided by applicant): The nervous system relies on precise wiring to accurately and consistently process information. This precision relies on accurate long distance navigation by axons and dendrites, as well as recognition of these neurites by each other to form appropriate synapses. In particular, axons of a similar function share a similar path and may selectively fasciculate as they travel that path. Upon reaching their targets, the axons defasciculate to appropriately form synapses with their specific target. Selective axon fasciculation and synapse formation both rely on intercellular adhesion. One family of adhesion molecules that could mediate both types of adhesion is the cadherin family. Cadherins are cell-cell adhesion molecules expressed along extending neurites and at developing and stable synapses. I propose to test the hypothesis that cadherins are mediating developmental events in the olfactory system, specifically in axon extension and synapse formation. I will begin my study by examining where and when cadherins are expressed in the olfactory system in vivo, to determine what potential roles they could be playing based upon their location of expression. To test specific hypotheses regarding the functions of cadherins, I will develop a series of in vitro assays. These assays will allow perturbation of cadherin and catenin function in a more easily manipulable system. I will thus examine the olfactory system, both in vivo and in vitro, to determine the role that molecular cues may be playing in guiding axonal and synaptic specificity.

[unreadable] DESCRIPTION (provided by applicant): Neurons communicate through synapses, specialized junctions between presynaptic and postsynaptic neurons. Changes in synapse formation lead to altered synaptic plasticity and circuit formation, which can lead to changes in mood, behavior, and learning & memory. Additionally, some altered states, including disease and drug addiction, arise from alterations in synaptic efficacy. Recent work has identified cell adhesion molecules capable of inducing synapse formation. One of these is SynCAMI, the seminal member of the SynCAM family, which contains four related proteins. The objective of this proposal is to determine whether the individual SynCAMs have different synaptic induction properties and may thus contribute to a molecular code for synapse formation. The proposed studies are thus fundamental to understanding both the normal and diseased brain. Three specific aims will be pursued to achieve this objective. In the first, the ability of the SynCAMs to induce presynaptic and postsynaptic terminals will be uncovered. In the second, the interactions between the SynCAMs that lead to this synapse induction will be determined in vitro. Here, the key question is to what extent each SynCAM preferentially interacts with itself or with others to induce a cellular response. In the third, these relationships between the SynCAMs will be tested in vivo. To address this aim, the localization of these molecules will first be determined. Then, the expression of each will be manipulated to determine whether specific synaptic types can be affected by perturbing SynCAM expression. In conclusion, these studies aim to elucidate fundamental mechanisms mediating induction and differentiation of synapses. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Fragile X syndrome (FXS) is the leading single gene cause of intellectual disability and autism. Study of FXS thus provides insights into conditions that affect large populations of Americans. FXS is caused by mutations in the gene encoding the RNA binding protein FMRP. In the absence of FMRP, synaptic plasticity is altered. Both intellectual disability and autism likely result from impairments in a restricted set of neural circuits. A large body of work has shown that FMRP is expressed in the somatodendritic domain of virtually every neuron. However, we have recently described a novel structure, the Fragile X granule (FXG), that is expressed presynaptically in a subset of circuits, including some implicated in the etiology of autism such as frontal cortex, cerebellum and amygdala. Importantly, FXG expression is developmentally regulated. Our results suggest that some of the symptoms of FXS and autism may arise from perturbations in presynaptic FMRP. In my proposed work, I will extend and deepen our understanding of presynaptic FMRP and FXGs by addressing three goals: 1) To characterize the expression and activity-dependent regulation of presynaptic FMRP in vivo;2) To identify FXG-associated RNAs;3) To determine domains of FMRP required for FXG formation and presynaptic differentiation. Findings from these studies will elucidate how presynaptic FMRP contributes to normal cognition and how its loss contributes to the phenotypes observed in FXS and potentially autistic patients. My career objective is to become an independent researcher at an academic institution where I can combine teaching and research. My long-term research interests are on how the environment shapes the structure and ultimately the function of the nervous system. My research as a doctoral student at Yale University studying Neuroscience focused on the anatomy of the olfactory system and how its structure can be used to understand its function. For my postdoctoral studies, I have been broadening my technical expertise to include molecular biological, cell biological, and biochemical approaches. The acquisition of this expertise will be crucial to the establishment of my independent lab. I am working with Dr. Justin Fallon at Brown University due to his well-established expertise with these approaches as well as his scientific interest in the structural plasticity of synapses in response to interactions with the environment. The technical and intellectual environments of his lab are thus ideal for my continued progress. The proposed K99 phase of the research will involve learning new techniques both from Dr. Fallon and from collaborations with faculty at Brown and outside institutions. Prof. Fallon has been very supportive in the establishment of these collaborations. My progress through this phase will be monitored by Dr. Fallon and will be supported by an advisory committee comprising Drs. Gilad Barnea, Julie Kauer, and Kim Mowry. Their support, along with the broader institutional support including the outstanding research facilities required for the conduct of my research, will greatly facilitate the execution of my planned experiments and my subsequent transition to independence. PUBLIC HEALTH RELEVANCE: Fragile X syndrome (FXS), the leading single gene cause of both mental retardation and autism, arises from mutations in the gene encoding the protein FMRP. Our recent work has indicated that some of the deficits seen in FXS may arise from loss of FMRP function at presynaptic sites. The proposed work will address this possibility and may lead to treatments for FXS and autism.