Baoji Xu

Brain-derived neurotrophic factor (BDNF) is essential for nervous system development and function and exerts its effects primarily through the tropomyosin receptor kinase B (TrkB). The Ntrk2 gene encodes a full-length receptor (TrkB.FL) and two truncated isoforms (TrkB.T1 and TrkB.T2, collectively TrkB.T) that lack the intracellular tyrosine kinase domain. TrkB.T is expressed predominantly in astrocytes and is thought to inhibit BDNF-TrkB.FL signaling by sequestering BDNF and forming signaling-deficient heterodimers with TrkB.FL. Here, we investigated whether selective ablation of astrocytic TrkB.T could ameliorate Alzheimer’s disease (AD) pathology by enhancing endogenous BDNF-TrkB.FL signaling. Astrocyte-specific deletion of the Ntrk2 gene at 5 weeks of age reduced cortical TrkB.T expression by more than 80% without affecting TrkB.FL levels. TrkB.T ablation increased the size of Bassoon-positive presynaptic active zones, consistent with enhanced BDNF-TrkB.FL signaling. Remarkably, astrocytic TrkB.T ablation reduced β-amyloid plaque burden by more than 60% in the cortex, hippocampus, and subiculum of 6-month-old 5xFAD mice, despite having no detectable effect on microgliosis or astrogliosis. Furthermore, TrkB.T ablation prevented reductions in the density and size of PSD-95-positive postsynaptic sites in the cortex and hippocampus of 5xFAD mice at 1 year old. Together, these findings identify astrocytic TrkB.T as an important regulator of amyloid pathology and synaptic integrity in an AD mouse model. Our results suggest that selectively reducing TrkB.T expression represents a promising therapeutic strategy to enhance endogenous neuroprotective BDNF-TrkB.FL signaling, reduce amyloid pathology, and preserve synaptic integrity in AD. Significance Statement: Alzheimer’s disease (AD) is characterized by progressive synaptic loss and neuronal degeneration, yet effective therapies that preserve synaptic integrity remain limited. Brain-derived neurotrophic factor (BDNF) signaling through its receptor TrkB promotes neuronal survival and synaptic plasticity, but this neuroprotective pathway is impaired in AD. Here, we demonstrate that selective ablation of truncated TrkB receptors in astrocytes markedly reduces β-amyloid plaque burden and prevents synaptic loss in 5XFAD mice without altering microgliosis or astrogliosis. These findings reveal an unexpected role for astrocytic truncated TrkB receptors in regulating amyloid pathology and synaptic integrity. Our study identifies astrocytic truncated TrkB receptors as promising therapeutic targets for AD and suggests that removing an endogenous inhibitor of BDNF signaling may provide a novel neuroprotective strategy.

SUMMARY: Parabrachial nucleus (PBN) CGRP neurons mediate aversive feeding suppression, but PBN circuitry governing homeostatic, non-aversive feeding suppression remains poorly understood. Here, we identify a circuit in which paraventricular hypothalamus (PVH) neurons innervate BDNF-expressing ventrolateral/dorsolateral PBN (vl/dlPBN ^BDNF ) neurons, which project to multiple hypothalamic nuclei. Refeeding strengthens excitatory and weakens inhibitory synaptic transmission in LPBN-projecting PVH neurons and preferentially induced Bdnf and Fos in vl/dlPBN ^BDNF neurons compared with elPBN ^CGRP neurons, whereas noxious LPS preferentially activated elPBN ^CGRP neurons. Gain- and loss-of-function experiments demonstrated that vl/dlPBN ^BDNF neurons are sufficient and necessary for feeding suppression without inducing conditioned taste aversion and that this effect require BDNF-TrkB signaling. In addition to hypothalamic inputs, vl/dlPBN ^BDNF neurons receive dense inputs from major downstream targets of elPBN ^CGRP neurons. Thus, vl/dlPBN ^BDNF neurons define a non-aversive feeding-suppression circuit positioned to integrate hypothalamic homeostatic signals with aversive signals, thereby coordinating food intake with internal energy needs and potentially harmful physiological conditions.

Background: Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders characterized by deficits in social communication and interaction, and restricted interests or repetitive behaviors. ASD is approximately four times more prevalent in males than in females. In this study, we investigated whether sex hormones or sex chromosomes underlie the male bias in ASD susceptibility. Methods: We used the MG ^4E mouse model, in which microglial eIF4E overexpression produces robust male-biased ASD-like phenotypes. To distinguish the contributions of sex hormones and sex chromosomes, MG ^4E mice were crossed with four-core-genotype (FCG) mice carrying Sry gene manipulations, generating eight genotypes of experimental mice. Social interaction and repetitive behaviors were assessed using standard behavioral assays. Dendritic spine density was quantified in Thy1-GFP mice. Expression of estrogen receptors (ERs) and androgen receptor (AR) was examined in microglia isolated from control and MG ^4E mice. Results: Sex hormones, rather than non- Sry genes on sex chromosomes, are responsible for the male-biased deficits in social interaction and the increase in dendritic spine density. At postnatal day 14, ERs were undetectable in microglia, whereas ER expression was readily detected in neurons. Conclusions: These findings demonstrate that sex hormones are a major determinant of the increased susceptibility of males to ASD-like phenotypes in MG ^4E mice. The absence of ER expression in microglia suggests that sex hormones may act indirectly through hormone- responsive neurons to regulate microglia-neuron interactions during neurodevelopment.

Emotionally salient associative memories can endure for long periods, yet the mechanisms that determine their long-term stability remain unclear. Here we show that the prelimbic (PL) cortex integrates temporally structured translational programs to control both the consolidation and reconsolidation of cued threat memories. Using Pavlovian threat conditioning with in vivo fiber photometry, we found that PL calcium dynamics tightly track memory strength: discrete threat-predictive cues evoked robust activity during recent and single-timepoint remote retrieval, whereas prior retrieval selectively weakened remote expression, independent of contextual influences. Translational profiling of PL Camk2a⁺ cells uncovered a biphasic consolidation program, with an early phase characterized by ER stress-linked translational repression and robust oligodendrocyte plasticity, followed by a delayed phase engaging synaptic growth pathways. Loss- and gain-of-function approaches demonstrated that eIF2α-regulated, cap-independent translation is essential for recent consolidation and for the enduring stabilization of remote memory, whereas retrieval-induced destabilization engages a mechanistically distinct, eIF4E-dependent translational pathway required for reconsolidation. These findings identify the PL cortex as a dynamic node in which discrete modes of translational control govern the long-term persistence of emotional memories.

Fragile X syndrome (FXS) results from loss of FMR1-encoded FMRP and is associated with reduced density of parvalbumin (PV) neurons; however, the mechanism underlying this abnormality remains unknown. Here we report that microglial FMRP regulates PV neuron density through lysosomal function. Mice with Fmr1 deletion in microglia exhibited audiogenic seizures (AGS) and decreased PV neuron density in the cortex and AGS-associated inferior colliculus (IC). FMRP increased the expression of lysosomal genes in microglia, including the progranulin-encoding Grn gene. Its loss in microglia led to impaired lysosomal function and increased apoptosis in microglia and PV neurons. Furthermore, PV neuron density in the IC was reduced similarly in male Grn ^+/- , Fmr1 ^-/y , and Grn ^+/- ; Fmr1 ^-/y mice, and AAV8-mediated overexpression of progranulin rescued AGS and PV neuron loss in Fmr1 ^-/y mice. This indicates that progranulin insufficiency is a determinant for PV neuron loss in FXS and elevating progranulin is a therapeutic strategy for FXS.

At the center of the hippocampal tri-synaptic loop are synapses formed between mossy fiber (MF) terminals from granule cells in the dentate gyrus (DG) and proximal dendrites of CA3 pyramidal neurons. However, the molecular mechanism regulating the development and function of these synapses is poorly understood. In this study, we showed that neurotrophin-3 (NT3) was expressed in nearly all mature granule cells but not CA3 cells. We selectively deleted the NT3-encoding Ntf3 gene in the DG during the first two postnatal weeks to generate a Ntf3 conditional knockout (Ntf3-cKO). Ntf3-cKO mice of both sexes had normal hippocampal cytoarchitecture but displayed impairments in contextual memory, spatial reference memory, and nest building. Furthermore, male Ntf3-cKO mice exhibited anxiety-like behaviors, whereas female Ntf3-cKO showed some mild depressive symptoms. As MF-CA3 synapses are essential for encoding of contextual memory, we examined synaptic transmission at these synapses using ex vivo electrophysiological recordings. We found that Ntf3-cKO mice had impaired basal synaptic transmission due to deficits in excitatory postsynaptic currents mediated by AMPA receptors but normal presynaptic function and intrinsic excitability of CA3 pyramidal neurons. Consistent with this selective postsynaptic deficit, Ntf3-cKO mice had fewer and smaller thorny excrescences on proximal apical dendrites of CA3 neurons and lower GluR1 levels in the stratum lucidum area where MF-CA3 synapses reside but normal MF terminals, compared with control mice. Thus, our study indicates that NT3 expressed in the dentate gyrus is crucial for the postsynaptic structure and function of MF-CA3 synapses and hippocampal-dependent memory.

The brain-derived neurotrophic factor (BDNF) and its high-affinity receptor tropomyosin-related kinase receptor B (TrkB) are widely expressed in the central nervous system. It is well documented that neurons express BDNF and full-length TrkB (TrkB.FL) as well as a lower level of truncated TrkB (TrkB.T). However, there are conflicting reports regarding the expression of BDNF and TrkB in glial cells, particularly microglia. In this study, we employed a sensitive and reliable genetic method to characterize the expression of BDNF and TrkB in glial cells in the mouse brain. We utilized three Cre mouse strains in which Cre recombinase is expressed in the same cells as BDNF, TrkB.FL, or all TrkB isoforms, and crossed them to Cre-dependent reporter mice to label BDNF- or TrkB-expressing cells with soma-localized EGFP. We performed immunohistochemistry with glial cell markers to examine the expression of BDNF and TrkB in microglia, astrocytes, and oligodendrocytes. Surprisingly, we found no BDNF- or TrkB-expressing microglia in examined CNS regions, including the somatomotor cortex, hippocampal CA1, and spinal cord. Consistent with previous studies, most astrocytes only express TrkB.T in the hippocampus of adult brains. Moreover, there are a small number of astrocytes and oligodendrocytes that express BDNF in the hippocampus, the function of which is to be determined. We also found that oligodendrocyte precursor cells, but not mature oligodendrocytes, express both TrkB.FL and TrkB.T in the hippocampus of adult mice. These results not only clarify the expression of BDNF and TrkB in glial cells but also open opportunities to investigate previously unidentified roles of BDNF and TrkB in astrocytes and oligodendrocytes.

At the center of the hippocampal tri-synaptic loop are synapses formed between mossy fiber (MF) terminals from granule cells in the dentate gyrus (DG) and proximal dendrites of CA3 pyramidal neurons. However, the molecular mechanism regulating the development and function of these synapses is poorly understood. In this study, we showed that neurotrophin-3 (NT3) was expressed in nearly all mature granule cells but not CA3 cells. We selectively deleted the NT3-encoding Ntf3 gene in the DG during the 1 ^st two postnatal weeks to generate a Ntf3 conditional knockout (Ntf3-cKO). Ntf3-cKO mice had normal hippocampal cytoarchitecture but displayed elevated anxiety level and impairments in contextual memory, spatial reference memory and nest building. As MF-CA3 synapses are essential for encoding of contextual memory, we examined synaptic transmission at these synapses using ex vivo electrophysiological recordings. We found that Ntf3-cKO mice showed impaired basal synaptic transmission due to deficits in excitatory postsynaptic currents mediated by AMPA receptors but normal presynaptic function and intrinsic excitability of CA3 pyramidal neurons. Consistent with this selective postsynaptic deficit, Ntf3-cKO mice had fewer and smaller thorny excrescences on proximal apical dendrites of CA3 neurons and lower GluR1 levels in the stratum lucidum area where MF-CA3 synapses reside but normal MF terminals, compared with control mice. Thus, our study indicates that NT3 expressed in the dentate gyrus is crucial for the postsynaptic structure and function of MF-CA3 synapses and hippocampal-dependent memory.

The brain-derived neurotrophic factor (BDNF) and its high-affinity receptor tropomyosin-related kinase receptor B (TrkB) are widely expressed in the central nervous system. It is well documented that neurons express BDNF and full-length TrkB (TrkB.FL), and a lower level of truncated TrkB (TrkB.T). With conflicting results, glial cells also have been reported to express BDNF and TrkB. In the current study, we employed a more sensitive and reliable genetic method to characterize the expression of BDNF and TrkB in glial cells in the mouse brain. We utilized three Cre mouse strains in which Cre recombinase is expressed in the same cells as BDNF, TrkB.FL, or all TrkB isoforms, and crossed them to Cre-dependent EGFP reporter mice to label BDNF- or TrkB-expressing cells. We performed immunohistochemistry with glial cell markers to examine the expression of BDNF and TrkB in microglia, astrocytes, and oligodendrocytes. Surprisingly, we found no BDNF- or TrkB-expressing microglia in the brain and spinal cord. Consistent with previous studies, most astrocytes only express TrkB.T in the adult brain. Moreover, there are a small number of astrocytes and oligodendrocytes that express BDNF, the function of which is to be determined. We also found that oligodendrocyte precursor cells, but not mature oligodendrocytes, express both TrkB.FL and TrkB.T in the adult brain. These results not only clarify the expression of BDNF and TrkB in glial cells, but also open opportunities to investigate previously unidentified roles of BDNF and TrkB in glial cells.