# BDNF signaling via astrocyte Trkb.T1 drives morphogenesis and maturation of astrocytes, a dysregulated feature of Rett syndrome

> **NIH NIH F99** · VIRGINIA POLYTECHNIC INST AND ST UNIV · 2021 · $40,847

## Abstract

PROJECT SUMMARY
Astrocyte morphological maturation is a critical step for healthy central nervous system development. Immature
astrocytes elaborate their processes and infiltrate the neuropil with fine, terminal, leaflet processes. These
processes allow for cell-cell communication with neighboring astrocytes, ensheathment of the vasculature and
enwrapping synapses, and where astrocytes participate in neurotransmitter uptake, synapse development and
stabilization. Astrocyte morphogenesis coincides with neuronal maturation and synaptogenesis, implicating a
common mechanism between these two events. Brain-derived neurotrophic factor (BDNF) is one developmental
molecule crucial for development and activity-dependent plasticity in neurons. Our lab has shown that BDNF
interacts with astrocytes through a TrkB receptor isoform (TrkB.T1) to promote astrocyte morphological
maturation. Our published work demonstrates astrocyte deletion of TrkB.T1 results in a 25% reduction in
astrocyte volume and branching complexity, a change that persists through adulthood. Our discovery is
relevant to health, as neurodevelopmental disorders (NDDs) are associated with BDNF dysregulation,
including the X-linked NDD, Rett Syndrome (RTT). Preliminary evidence demonstrates that astrocytes in RTT
mouse models have volume deficits similar to TrKB.T1 knockout accompanied by dysregulated gene expression.
Reports demonstrate that the TrkB.T1 isoform uniquely interacts with a small RhoGTPase inhibitor, though its
functional significance is relatively unknown. We propose to evaluate astrocyte RhoGTPase signaling and
cytoskeletal dynamics in response to BDNF and potentially therapeutic TrkB activators utilizing in vitro
and in situ genetic, molecular, and imaging techniques. Furthermore, we will assess if TrkB therapeutics
rescue RTT astrocyte morphology deficits and gene dysregulation. My specific aims seek to (1) determine
signaling consequences of TrkB.T1 activation and (2) the role of TrkB.T1 activation on morphological change in
astrocytes as well as to expand upon our discovery by (3) evaluating astrocyte TrkB.T1 in a relevant NDD model.
This proposal meets the priorities of the BRAIN Initiate 2.0 of (1) demonstrating causality of relationships and (2)
identifying fundamental principles of observable brain properties.

## Key facts

- **NIH application ID:** 10319356
- **Project number:** 1F99NS124179-01
- **Recipient organization:** VIRGINIA POLYTECHNIC INST AND ST UNIV
- **Principal Investigator:** Raymundo Daniel Hernandez
- **Activity code:** F99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $40,847
- **Award type:** 1
- **Project period:** 2021-07-10 → 2023-07-09

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10319356

## Citation

> US National Institutes of Health, RePORTER application 10319356, BDNF signaling via astrocyte Trkb.T1 drives morphogenesis and maturation of astrocytes, a dysregulated feature of Rett syndrome (1F99NS124179-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10319356. Licensed CC0.

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