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1.
Cell Mol Neurobiol ; 44(1): 4, 2023 Dec 17.
Artículo en Inglés | MEDLINE | ID: mdl-38104054

RESUMEN

Brain-derived neurotrophic factor (BDNF) acting upon its receptor Neurotrophic tyrosine kinase receptor 2 (NTRK2, TRKB) plays a central role in the development and maintenance of synaptic function and activity- or drug-induced plasticity. TRKB possesses an inverted cholesterol recognition and alignment consensus sequence (CARC), suggesting this receptor can act as a cholesterol sensor. We have recently shown that antidepressant drugs directly bind to the CARC domain of TRKB dimers, and that this binding as well as biochemical and behavioral responses to antidepressants are lost with a mutation in the TRKB CARC motif (Tyr433Phe). However, it is not clear if this mutation can also compromise the receptor function and lead to behavioral alterations. Here, we observed that Tyr433Phe mutation does not alter BDNF binding to TRKB, or BDNF-induced dimerization of TRKB. In this line, primary cultures from embryos of heterozygous Tyr433Phe mutant mice (hTRKB.Tyr433Phe) are responsive to BDNF-induced activation of TRKB, and samples from adult mice do not show any difference on TRKB activation compared to wild-type littermates (TRKB.wt). The behavioral phenotype of hTRKB.Tyr433Phe mice is indistinguishable from the wild-type mice in cued fear conditioning, contextual discrimination task, or the elevated plus maze, whereas mice heterozygous to BDNF null allele show a phenotype in context discrimination task. Taken together, our results indicate that Tyr433Phe mutation in the TRKB CARC motif does not show signs of loss-of-function of BDNF responses, while antidepressant binding to TRKB and responses to antidepressants are lost in Tyr433Phe mutants, making them an interesting mouse model for antidepressant research.


Asunto(s)
Factor Neurotrófico Derivado del Encéfalo , Receptor trkB , Ratones , Animales , Factor Neurotrófico Derivado del Encéfalo/genética , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Receptor trkB/metabolismo , Antidepresivos/farmacología , Proteínas Tirosina Quinasas Receptoras/metabolismo , Transducción de Señal , Mutación/genética
2.
Nat Neurosci ; 26(6): 1032-1041, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-37280397

RESUMEN

Psychedelics produce fast and persistent antidepressant effects and induce neuroplasticity resembling the effects of clinically approved antidepressants. We recently reported that pharmacologically diverse antidepressants, including fluoxetine and ketamine, act by binding to TrkB, the receptor for BDNF. Here we show that lysergic acid diethylamide (LSD) and psilocin directly bind to TrkB with affinities 1,000-fold higher than those for other antidepressants, and that psychedelics and antidepressants bind to distinct but partially overlapping sites within the transmembrane domain of TrkB dimers. The effects of psychedelics on neurotrophic signaling, plasticity and antidepressant-like behavior in mice depend on TrkB binding and promotion of endogenous BDNF signaling but are independent of serotonin 2A receptor (5-HT2A) activation, whereas LSD-induced head twitching is dependent on 5-HT2A and independent of TrkB binding. Our data confirm TrkB as a common primary target for antidepressants and suggest that high-affinity TrkB positive allosteric modulators lacking 5-HT2A activity may retain the antidepressant potential of psychedelics without hallucinogenic effects.


Asunto(s)
Antidepresivos , Alucinógenos , Dietilamida del Ácido Lisérgico , Psilocibina , Receptor trkB , Alucinógenos/metabolismo , Humanos , Células HEK293 , Sitios de Unión , Simulación de Dinámica Molecular , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Transducción de Señal , Receptor trkB/metabolismo , Plasticidad Neuronal/efectos de los fármacos , Antidepresivos/metabolismo , Regulación Alostérica , Masculino , Femenino , Animales , Ratones , Ratones Endogámicos C57BL , Embrión de Mamíferos/citología , Neuronas/efectos de los fármacos , Dietilamida del Ácido Lisérgico/química , Dietilamida del Ácido Lisérgico/metabolismo , Dietilamida del Ácido Lisérgico/farmacología , Psilocibina/química , Psilocibina/metabolismo , Psilocibina/farmacología
3.
Front Syst Neurosci ; 17: 1160083, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37064160

RESUMEN

Despite fine tuning voluntary movement as the most prominently studied function of the cerebellum, early human studies suggested cerebellar involvement emotion regulation. Since, the cerebellum has been associated with various mood and anxiety-related conditions. Research in animals provided evidence for cerebellar contributions to fear memory formation and extinction. Fear and anxiety can broadly be referred to as defensive states triggered by threat and characterized by multimodal adaptations such as behavioral and cardiac responses integrated into an intricately orchestrated defense reaction. This is mediated by an evolutionary conserved, highly interconnected network of defense-related structures with functional connections to the cerebellum. Projections from the deep cerebellar nucleus interpositus to the central amygdala interfere with retention of fear memory. Several studies uncovered tight functional connections between cerebellar deep nuclei and pyramis and the midbrain periaqueductal grey. Specifically, the fastigial nucleus sends direct projections to the ventrolateral PAG to mediate fear-evoked innate and learned freezing behavior. The cerebellum also regulates cardiovascular responses such as blood pressure and heart rate-effects dependent on connections with medullary cardiac regulatory structures. Because of the integrated, multimodal nature of defensive states, their adaptive regulation has to be highly dynamic to enable responding to a moving threatening stimulus. In this, predicting threat occurrence are crucial functions of calculating adequate responses. Based on its role in prediction error generation, its connectivity to limbic regions, and previous results on a role in fear learning, this review presents the cerebellum as a regulator of integrated cardio-behavioral defensive states.

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