Brain-derived neurotrophic factor (BDNF) is a critical growth factor involved in the maturation of the CNS, including neuronal morphology and synapse refinement. Herein, we demonstrate astrocytes express high levels of BDNF’s receptor, TrkB (in the top 20 of protein-coding transcripts), with nearly exclusive expression of the truncated isoform, TrkB.T1, which peaks in expression during astrocyte morphological maturation. Using a novel culture paradigm, we show that astrocyte morphological complexity is increased in the presence of BDNF and is dependent upon BDNF/TrkB.T1 signaling. Deletion of TrkB.T1, globally and astrocyte-specifically, in mice revealed morphologically immature astrocytes with significantly reduced volume, as well as dysregulated expression of perisynaptic genes associated with mature astrocyte function. Indicating a role for functional astrocyte maturation via BDNF/TrkB.T1 signaling, TrkB.T1 KO astrocytes do not support normal excitatory synaptogenesis or function. These data suggest a significant role for BDNF/TrkB.T1 signaling in astrocyte morphological maturation, a critical process for CNS development.

Rett syndrome (RTT) is a rare, X-linked neurodevelopmental disorder typically affecting females, resulting in a range of symptoms including autistic features, intellectual impairment, motor deterioration, and autonomic abnormalities. RTT is primarily caused by the genetic mutation of the Mecp2 gene. Initially considered a neuronal disease, recent research shows that glial dysfunction contributes to the RTT disease phenotype. In the following manuscript, we review the evidence regarding glial dysfunction and its effects on disease etiology.

CD38 is an ectoenzyme that converts NAD+ to NAM to help maintain bioenergetic homeostasis. CD38 dysregulation and gene variation is reported in neurodegenerative conditions such as Parkinson's disease (PD) and Alzheimer's disease (AD), highlighting the need to better understand CD38 biology within the brain. Here, we demonstrate enrichment of Cd38 in midbrain astrocytes and describe how CD38 deficiency influences brain metabolism, astrocytic gene expression, and bioenergetics. We demonstrate increased NAD content, decreased NAM content, and increased NAD/NAM in the midbrain and striatum of CD38‐deficient ( Cd38 ^−/− ) mice, indicating the dependence on CD38 for NAD to NAM conversion in the brain. RNA‐sequencing of isolated astrocytes revealed numerous differentially expressed genes in Cd38 ^+/− and Cd38 ^−/− mice, with alterations in mitochondrial, metabolic, senescence‐related, astrocyte reactivity, and other genes involved in PD and AD etiology. Furthermore, functional metabolic analysis of midbrain revealed changes in pyruvate oxidation, age‐dependent increase of citrate synthase (CS) activity, and reduction of cytochrome c oxidase‐to‐CS ratio in Cd38 deficiency. These findings identify a novel role for astrocytes in the regulation of CD38‐dependent NAD/NAM homeostasis in the brain and provide a framework for future studies evaluating the relationship between CD38 dysfunction, aging, and vulnerability of neuronal populations in neurodegenerative disease. Importantly, these studies underscore the necessity to better resolve the impact of CD38 deficiency on brain metabolism, considering ongoing clinical trials and discussions related to the use of CD38 modulators for the treatment of cancers, age‐related decline, and neurodegenerative disease.

Brain derived neurotrophic factor (BDNF) is a critical growth factor involved in the maturation of neurons, including neuronal morphology and synapse refinement. Herein, we demonstrate astrocytes express high levels of BDNF’s receptor, TrkB (in the top 20 of protein-coding transcripts), with nearly exclusive expression of the truncated isoform, TrkB.T1 which peaks in expression during astrocyte morphological maturation. Using a novel culture paradigm, we show that astrocyte morphological complexity is increased in the presence of BDNF and is dependent upon BDNF/TrkB.T1 signaling. Deletion of TrkB.T1 in vivo revealed morphologically immature astrocytes with significantly reduced volume and branching, as well as dysregulated expression of perisynaptic genes associated with mature astrocyte functions, including synaptogenic genes. Indicating a role for functional astrocyte maturation via BDNF/TrkB.T1 signaling, TrkB.T1 KO astrocytes do not support normal excitatory synaptogenesis. These data suggest a significant role for BDNF/TrkB.T1 signaling in astrocyte morphological maturation, a critical process for CNS development.