Essential role for TrkB receptors in hippocampus-mediated learning

Brain-derived neurotrophic factor (BDNF) and its receptor TrkB regulate both short-term synaptic functions and long-term potentiation (LTP) of brain synapses, raising the possibility that BDNF/TrkB may be involved in cognitive functions. We have generated conditionally gene targeted mice in which the knockout of the trkB gene is restricted to the forebrain and occurs only during postnatal development. Adult mutant mice show increasingly impaired learning behavior or inappropriate coping responses when facing complex and/or stressful learning paradigms but succeed in simple passive avoidance learning. Homozygous mutants show impaired LTP at CA1 hippocampal synapses. Interestingly, heterozygotes show a partial but substantial reduction of LTP but appear behaviorally normal. Thus, CA1 LTP may need to be reduced below a certain threshold before behavioral defects become apparent.     

A novel trimeric peptide, Neuropep-1-stimulating brain-derived neurotrophic factor expression in rat brain improves spatial learning and memory as measured by the Y-maze and Morris water maze

Abundant studies have shown possible links between low levels of brain-derived neurotrophic factor (BDNF) and neurological diseases such as Alzheimer's disease, Parkinson's disease, and depression, as well as stress and anxiety; therefore, BDNF could be a therapeutic target for neurological disorders. In the present study, a positional scanning-synthetic peptide combinatorial library was utilized to identify a peptide modulator of BDNF expression in the hippocampal neuronal cell line, H19-7. A novel tripeptide (Neuropep-1) induced a significant increase of BDNF mRNA and protein levels in H19-7 cells. Pre-treatment of TrkB inhibitor (K252a) did not block Neuropep-1-induced BDNF up-regulation. These results indicate that Neuropep-1 may up-regulate BDNF expression that might be independent of the TrkB receptor pathway. Tail vein injection of Neuropep-1 significantly up-regulated BDNF expression, TrkB phosphorylation, and its downstream signals including activation of Akt, ERK, and cAMP response element binding in the rat hippocampus. To evaluate improvement of spatial learning and memory (SLM) by Neuropep-1-induced BDNF up-regulation, the Y-maze and Morris water maze tests were performed. These results showed Neuropep-1 injection improved SLM performance with increase of BDNF and TrkB expression, activation of TrkB downstream signals in rat hippocampus compared with the control group. However, phosphorylation levels of TrkB were not changed when it was normalized to the level of TrkB expression. The difference on TrkB phosphorylation in Neuropep-1-injected rats may be affected by behavioral tests. These results suggest that Neuropep-1 may improve SLM via activation of the BDNF/TrkB signaling pathway in the rat hippocampus. Therefore, our findings represent that Neuropep-1 might be a potential candidate for treatment of learning and memory disorders as well as neurological diseases involving the abnormal expression of BDNF.     

Differential effects of transient and sustained activation of BDNF‐TrkB signaling

Brain‐derived neurotrophic factor (BDNF) serves a pleiotropic role in the central nervous system, ranging from promoting neuronal survival and differentiation during development and synaptic modulation in the adult. An important, yet unanswered question is how BDNF could serve such diverse functions, sometimes in the same cell. At least two modes of BDNF actions have been elucidated so far based on BDNF signaling kinetics and/or the activity status of the responding neurons. Acute and gradual increases in extracellular BDNF concentrations elicit, respectively, transient and sustained activation of TrkB receptor and its downstream signaling, leading to differential molecular and cellular functions. In cultured neurons, sustained TrkB activation promotes neuronal dendritic arborization and spinogenesis, whereas transient TrkB activation facilitates dendritic growth and spine morphogenesis. In hippocampal slices, slow delivery of BDNF facilitates LTP, whereas fast application of BDNF enhances basal synaptic transmission in schaffer collateral synapses. High‐frequency stimulation of neurons converts BDNF‐induced TrkB signaling from a transient to a sustained mode. These initial insights lay the foundation for future investigation of the BDNF‐TrkB pathway, and analogous signaling pathways to gain a comprehensive understanding to enable translational research. © 2018 Wiley Periodicals, Inc. Develop Neurobiol 78: 647–659, 2018     

BDNF-induced recruitment of TrkB receptor into neuronal lipid rafts: roles in synaptic modulation

Brain-derived neurotrophic factor (BDNF) plays an important role in synaptic plasticity but the underlying signaling mechanisms remain unknown. Here, we show that BDNF rapidly recruits full-length TrkB (TrkB-FL) receptor into cholesterol-rich lipid rafts from nonraft regions of neuronal plasma membranes. Translocation of TrkB-FL was blocked by Trk inhibitors, suggesting a role of TrkB tyrosine kinase in the translocation. Disruption of lipid rafts by depleting cholesterol from cell surface blocked the ligand-induced translocation. Moreover, disruption of lipid rafts prevented potentiating effects of BDNF on transmitter release in cultured neurons and synaptic response to tetanus in hippocampal slices. In contrast, lipid rafts are not required for BDNF regulation of neuronal survival. Thus, ligand-induced TrkB translocation into lipid rafts may represent a signaling mechanism selective for synaptic modulation by BDNF in the central nervous system.     

BDNF modulates heart contraction force and long-term homeostasis through truncated TrkB.T1 receptor activation

Brain-derived neurotrophic factor (BDNF) is critical for mammalian development and plasticity of neuronal circuitries affecting memory, mood, anxiety, pain sensitivity, and energy homeostasis. Here we report a novel unexpected role of BDNF in regulating the cardiac contraction force independent of the nervous system innervation. This function is mediated by the truncated TrkB.T1 receptor expressed in cardiomyocytes. Loss of TrkB.T1 in these cells impairs calcium signaling and causes cardiomyopathy. TrkB.T1 is activated by BDNF produced by cardiomyocytes, suggesting an autocrine/paracrine loop. These findings unveil a novel signaling mechanism in the heart that is activated by BDNF and provide evidence for a global role of this neurotrophin in the homeostasis of the organism by signaling through different TrkB receptor isoforms.     

Memory impairment of chewing-side preference mice is associated with 5-HT-BDNF signal pathway

Although tooth loss is a known risk factor of cognitive function, whether and how the chewing-side preference (CSP) affects memory impairment still remains unclear. This study evaluates the behavior changes in mice after the loss of teeth on one side and explores the role of serotonin (5-HT) and brain-derived neurotrophic factor (BDNF) signal pathway within these changes. To this end, CSP mouse models with either the removal of left unilateral molars (CSP-L) or right unilateral molars (CSP-R) were established. Morris water maze test and passive avoidance test were performed to evaluate the mice’s learning and memory capacity in the 4th and 8th weeks. The correlation between CSP and brain function changes was validated with changes in 5-HT and BDNF levels. CSP mice’s cognitive function was found to be decreased, along with a significant decline in 5-HT1A level, especially in CSP-R mice. BDNF and TrkB levels in CSP-R mice were also significantly lowered. These findings suggest that CSP results in memory impairment, which is associated with the 5-HT-BDNF signaling pathway.

     

A role for BDNF/TrkB signaling in behavioral and physiological consequences of social defeat stress

Accumulating evidences underlie the importance of the interplay between environmental and genetic factors in contributing to the risk to develop mental illness. Brain-derived neurotrophic factor (BDNF) and its Tyrosine receptor kinase B (TrkB) receptor play a fundamental contribution to brain development and plastic adaptations to life events. In the present study, the potential for the BDNF/TrkB contribution in increasing vulnerability to negative social experiences was assessed by subjecting TrkB.T1 overexpressing mice to a chronic social defeat model. TrkB.T1 mice overexpress the dominant-negative truncated splice variant of TrkB receptor leading to decreased BDNF signaling. After repeated social defeat, mice were assessed in a longitudinal study for behavioral, physiological, endocrine and immune responses potentially related to psychiatric endophenotypes. TrkB.T1 overexpression corresponded to smaller changes in metabolic parameters such as body weight, food intake, feed efficiency and peripheral ghrelin levels compared with wild-type (wt) littermates following social defeat. Interestingly, 4 weeks after the last defeat, TrkB.T1 overexpressing mice exhibited more consistent social avoidance effects than what observed in wt subjects. Finally, previously unreported effects of TrkB mutations could be observed on lymphoid organ weight and on peripheral immune biomarker levels, such as interleukin-1α and regulated on activation, normal, T-cell expressed, and secreted (RANTES), thus suggesting a systemic role of BDNF signaling in immune function. In conclusion, the present data support a contribution of TrkB to stress vulnerability that, given the established role of TrkB in the response to antidepressant treatment, calls for further studies addressing the link between stress susceptibility and variability in drug efficacy.     

NMDA receptor dysfunction contributes to impaired brain‐derived neurotrophic factor‐induced facilitation of hippocampal synaptic transmission in a Tau transgenic model

While the spatiotemporal development of Tau pathology has been correlated with occurrence of cognitive deficits in Alzheimer's patients, mechanisms underlying these deficits remain unclear. Both brain‐derived neurotrophic factor (BDNF) and its tyrosine kinase receptor TrkB play a critical role in hippocampus‐dependent synaptic plasticity and memory. When applied on hippocampal slices, BDNF is able to enhance AMPA receptor‐dependent hippocampal basal synaptic transmission through a mechanism involving TrkB and N‐methyl‐d‐Aspartate receptors (NMDAR). Using THY‐Tau22 transgenic mice, we demonstrated that hippocampal Tau pathology is associated with loss of synaptic enhancement normally induced by exogenous BDNF. This defective response was concomitant to significant memory impairments. We show here that loss of BDNF response was due to impaired NMDAR function. Indeed, we observed a significant reduction of NMDA‐induced field excitatory postsynaptic potential depression in the hippocampus of Tau mice together with a reduced phosphorylation of NR2B at the Y1472, known to be critical for NMDAR function. Interestingly, we found that both NR2B and Src, one of the NR2B main kinases, interact with Tau and are mislocalized to the insoluble protein fraction rich in pathological Tau species. Defective response to BDNF was thus likely related to abnormal interaction of Src and NR2B with Tau in THY‐Tau22 animals. These are the first data demonstrating a relationship between Tau pathology and synaptic effects of BDNF and supporting a contribution of defective BDNF response and impaired NMDAR function to the cognitive deficits associated with Tauopathies.     

Brain-derived neurotrophic factor: Its role in energy balance and cancer cachexia

Brain-derived neurotrophic factor (BDNF) plays an important role in the development of the central and peripheral nervous system during embryogenesis. In the mature central nervous system, BDNF is required for the maintenance and enhancement of synaptic transmissions and the survival of neurons. Particularly, it is involved in the modulation of neurocircuits that control energy balance through food intake, energy expenditure, and locomotion. Regulation of BDNF in the central nervous system is complex and environmental factors affect its expression in murine models which may reflect to phenotype dramatically. Furthermore, BDNF and its high-affinity receptor tropomyosin receptor kinase B (TrkB), as well as pan-neurotrophin receptor (p75^NTR) is expressed in peripheral tissues in adulthood and their signaling is associated with regulation of energy balance. BDNF/TrkB signaling is exploited by cancer cells as well and BDNF expression is increased in tumors. Intriguingly, previously demonstrated roles of BDNF in regulation of food intake, adipose tissue and muscle overlap with derangements observed in cancer cachexia. However, data about the involvement of BDNF in cachectic cancer patients and murine models are scarce and inconclusive. In the future, knock-in and/or knock-out experiments with murine cancer models could be helpful to explore potential new roles for BDNF in the development of cancer cachexia.