BDNF Activates Postsynaptic TrkB Receptors to Induce Endocannabinoid Release and Inhibit Presynaptic Calcium Influx at a Calyx-Type Synapse.

Brain-derived neurotropic factor (BDNF) has been shown to play critical roles in neural development, plasticity, and neurodegenerative diseases. The main function of BDNF in the brain is widely accepted to be synaptic regulation. However, how BDNF modulates synaptic transmission, especially the underlying signaling cascades between presynaptic and postsynaptic neurons, remains controversial. In the present study, we investigated the actions of BDNF at rat calyx-type synapses of either sex by measuring the excitatory postsynaptic current (EPSC) and presynaptic calcium current and capacitance changes. We found that BDNF inhibits the EPSC, presynaptic calcium influx, and exocytosis/endocytosis via activation of the presynaptic cannabinoid Type 1 receptors (CB1Rs). Inhibition of the CB1Rs abolished the BDNF-induced presynaptic inhibition, whereas CB1R agonist mimicked the effect of BDNF. Exploring the underlying signaling cascade, we found that BDNF specifically activates the postsynaptic TrkB receptors, inducing the release of endocannabinoids via the PLCγ/DGL pathway and retrogradely activating presynaptic CB1Rs. We also reported the involvement of AC/PKA in modulating vesicle endocytosis, which may account for the BDNF-induced calcium-dependent and -independent regulation of endocytosis. Thus, our study provides new insights into the BDNF/endocannabinoid-associated modulation of neurotransmission in physiological and pathologic processes.SIGNIFICANCE STATEMENT BDNF plays critical roles in the modulation of synaptic strength. However, how BDNF regulates synaptic transmission and its underlying signaling cascade(s) remains elusive. By measuring EPSC and the presynaptic calcium current and capacitance changes at rat calyces, we found that BDNF inhibits synaptic transmission via BDNF-TrkB-eCB signaling pathway. Activation of postsynaptic TrkB receptors induces endocannabinoid release via the PLCγ/DGL pathway, retrogradely activating the presynaptic CB1Rs, inhibiting the AC/PKA, and suppressing calcium influx. Our findings provide a comprehensive understanding of BDNF/endocannabinoid-associated modulation of neuronal activities.

Glucocorticoids modulate neural activity via a rapid non-genomic effect on Kv2.2 channels in the central nervous system.

Glucocorticoids are primary stress hormones that exert neuronal effects via both genomic and non-genomic signaling pathways. However, their rapid non-genomic effects and underlying mechanisms on neural activities remain elusive. In the present study, we investigated the rapid non-genomic effect of glucocorticoids on Kv2.2 channels in cultured HEK293 cells and acute brain slices including cortical pyramidal neurons and calyx-type synapses in the brain stem. We found that cortisol, the endogenous glucocorticoids, rapidly increased Kv2.2 currents by increasing the single-channel open probability in Kv2.2-expressing HEK293 cells through activation of the membrane-associated glucocorticoid receptor. Bovine serum albumin-conjugated dexamethasone, a membrane-impermeable agonist of the glucocorticoid receptor, could mimic the effect of cortisol on Kv2.2 channels. The cortisol-increased Kv2.2 currents were induced by activation of the extracellular signal-regulated protein kinase (ERK) 1/2 kinase, which could be inhibited by U0126, an antagonist of the ERK signaling pathway. In layer 2 cortical pyramidal neurons and the calyx of Held synapses, cortisol suppressed the action potential firing frequency during depolarization and reduced the successful rate upon high-frequency stimulation by activating Kv2.2 channels. We further examined the postsynaptic responses and found that cortisol did not affect the mEPSC and evoked EPSC, but increased the activity-dependent synaptic depression induced by a high-frequency stimulus train. In conclusion, glucocorticoids can rapidly activate Kv2.2 channels through membrane-associated glucocorticoid receptors via the ERK1/2 signaling pathway, suppress presynaptic action potential firing, and inhibit synaptic transmission and plasticity. This may be a universal mechanism of the glucocorticoid-induced non-genomic effects in the central nervous system.

Therapeutic Strategies Against Metabolic Imbalance in a Male Mouse Model With 5-HT2CR Loss-of-Function.

The serotonin 2C receptor (5-HT2CR)-melanocortin pathway plays well-established roles in the regulation of feeding behavior and body weight homeostasis. Dysfunctions in this system, such as loss-of-function mutations in the Htr2c gene, can lead to hyperphagia and obesity. In this study, we aimed to investigate the potential therapeutic strategies for ameliorating hyperphagia, hyperglycemia, and obesity associated with a loss-of-function mutation in the Htr2c gene (Htr2cF327L/Y). We demonstrated that reexpressing functional 5-HT2CR solely in hypothalamic pro-opiomelanocortin (POMC) neurons is sufficient to reduce food intake and body weight in Htr2cF327L/Y mice subjected to a high-fat diet (HFD). In addition, 5-HT2CR expression restores the responsiveness of POMC neurons to lorcaserin, a selective agonist for 5-HT2CR. Similarly, administration of melanotan II, an agonist of the melanocortin receptor 4 (MC4R), effectively suppresses feeding and weight gain in Htr2cF327L/Y mice. Strikingly, promoting wheel-running activity in Htr2cF327L/Y mice results in a decrease in HFD consumption and improved glucose homeostasis. Together, our findings underscore the crucial role of the melanocortin system in alleviating hyperphagia and obesity related to dysfunctions of the 5-HT2CR, and further suggest that MC4R agonists and lifestyle interventions might hold promise in counteracting hyperphagia, hyperglycemia, and obesity in individuals carrying rare variants of the Htr2c gene.

5-HT Neurons Integrate GABA and Dopamine Inputs to Regulate Meal Initiation.

Obesity is a growing global health epidemic with limited effective therapeutics. Serotonin (5-HT) is one major neurotransmitter which remains an excellent target for new weight-loss therapies, but there remains a gap in knowledge on the mechanisms involved in 5-HT produced in the dorsal Raphe nucleus (DRN) and its involvement in meal initiation. Using a closed-loop optogenetic feeding paradigm, we showed that the 5-HTDRN→arcuate nucleus (ARH) circuit plays an important role in regulating meal initiation. Incorporating electrophysiology and ChannelRhodopsin-2-Assisted Circuit Mapping, we demonstrated that 5-HTDRN neurons receive inhibitory input partially from GABAergic neurons in the DRN, and the 5-HT response to GABAergic inputs can be enhanced by hunger. Additionally, deletion of the GABAA receptor subunit in 5-HT neurons inhibits meal initiation with no effect on the satiation process. Finally, we identified the instrumental role of dopaminergic inputs via dopamine receptor D2 in 5-HTDRN neurons in enhancing the response to GABA-induced feeding. Thus, our results indicate that 5-HTDRN neurons are inhibited by synergistic inhibitory actions of GABA and dopamine, which allows for the initiation of a meal.