Astrocytes contribute to many facets of ?normal? central nervous system (CNS) physiology, including regulation of neurotransmitters and K+ ions concentration, synaptic development, and synapse stabilization. These functions are largely mediated at distal, fine, peripheral astrocyte processes (PAPs). It is at these processes that astrocytes communicate with their neighbors, regulate ion and neurotransmitter levels and contribute to synapse development and stabilization. Despite decades of research indicating astrocytes enwrap or contact excitatory and inhibitory synaptic elements, with increased coverage of mature synapses, there is little known regarding signals that recruit astrocyte PAPs to synaptic structures. RNA sequencing data we have generated (and confirmed using multiple public resources) indicate astrocytes express very high levels of the BDNF receptor, TrkB. Isoform specific identification demonstrates astrocytes predominately express the truncated form, TrkB.T1. In cortex, TrkB.T1 is found almost exclusively in astrocytes. Global and astrocyte specific genetic deletion of TrkB.T1 results in astrocytes with significantly reduced volume and branching complexities. Astrocytes lacking TrkB.T1 show dysregulated expression of both perisynaptic genes associated with mature astrocyte function and pro-synaptogenic genes. In vitro and in vivo we observed that TrkB.T1 KO astrocytes do not support normal excitatory synaptogenesis or function as assessed by evaluation of pre and post synaptic excitatory elements and neuronal mEPSC analysis. Preliminary in vitro data also indicate that TrkB.T1 KO astrocytes fail to enwrap glutamatergic synapses, a phenotype we readily observe in WT astrocytes. In the current proposal we test the hypothesis that BDNF signaling through the astrocytic TrkB.T1 receptor serves as a key signaling pathway in recruiting astrocyte perisynaptic processes to glutamatergic synapses thus facilitating actin mediated structural plasticity. In the current work we use ultrastructural imaging in WT and astrocyte specific TrkB.T1 KO mice to determine if BDNF/TrkB.T1 signaling in astrocytes is necessary for astrocyte structural plasticity and function at glutamatergic synapses (Aim 1). We evaluate the loss of astrocyte TrkB.T1 on neuronal synapse development and function (Aim 2) and we use a combination of in vitro and in vivo approaches to identify the key signaling mechanisms by which BDNF binding to astrocyte TrkB.T1 receptors engage downstream signaling mechanisms, providing a molecular mechanistic framework linking astrocyte BDNF/TrkB.T1 signaling to actin cytoskeletal reorganization, morphological refinement, process outgrowth and synapse enwrapment. These studies identify a completely novel signaling pathway in astrocyte structural plasticity and have the potential to significantly advance our understanding of astrocyte-synapse interactions. While disrupted BDNF/TrkB signaling is implicated in many CNS disorders the relevance of BDNF/astrocytic TrkB.T1 signaling has not been considered.

Public Health Relevance

BDNF is the most well-studied neurotrophic factor in the central nervous system and its role in maturation and synapse development in neurons is well characterized. To date, no study has evaluated a role for BDNF in the development or morphological maturation in a non-neuronal cell type, even though astrocytes express the highest levels of the receptor for BDNF, TrkB. Successful completion of these studies have the potential to advance our understanding of a novel molecular signaling that serves to recruit astrocytes perisynaptic processes to glutamatergic synapses. These studies lay the groundwork for novel inquiries into aberrant BDNF/TrkB signaling in a growing list of neurodevelopmental and neurological disorders whereby BDNF and astrocytes are increasingly implicated.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Lavaute, Timothy M
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Virginia Polytechnic Institute and State University
Schools of Arts and Sciences
United States
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