RESUMEN
Ketamine has been found to have rapid and potent antidepressant activity. However, despite the ubiquitous brain expression of its molecular target, the N-methyl-d-aspartate receptor (NMDAR), it was not clear whether there is a selective, primary site for ketamine's antidepressant action. We found that ketamine injection in depressive-like mice specifically blocks NMDARs in lateral habenular (LHb) neurons, but not in hippocampal pyramidal neurons. This regional specificity depended on the use-dependent nature of ketamine as a channel blocker, local neural activity, and the extrasynaptic reservoir pool size of NMDARs. Activating hippocampal or inactivating LHb neurons swapped their ketamine sensitivity. Conditional knockout of NMDARs in the LHb occluded ketamine's antidepressant effects and blocked the systemic ketamine-induced elevation of serotonin and brain-derived neurotrophic factor in the hippocampus. This distinction of the primary versus secondary brain target(s) of ketamine should help with the design of more precise and efficient antidepressant treatments.
Asunto(s)
Antidepresivos , Depresión , Habénula , Ketamina , Receptores de N-Metil-D-Aspartato , Animales , Masculino , Ratones , Antidepresivos/farmacología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Factor Neurotrófico Derivado del Encéfalo/genética , Depresión/tratamiento farmacológico , Depresión/metabolismo , Habénula/efectos de los fármacos , Habénula/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Ketamina/farmacología , Ketamina/administración & dosificación , Ratones Endogámicos C57BL , Ratones Noqueados , Células Piramidales/efectos de los fármacos , Células Piramidales/metabolismo , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/genética , Serotonina/metabolismoRESUMEN
Substantial clinical evidence has unravelled the superior antidepressant efficacy of ketamine: in comparison to traditional antidepressants targeting the monoamine systems, ketamine, as an N-methyl-d-aspartate receptor (NMDAR) antagonist, acts much faster and more potently. Surrounding the antidepressant mechanisms of ketamine, there is ample evidence supporting an NMDAR-antagonism-based hypothesis. However, alternative arguments also exist, mostly derived from the controversial clinical results of other NMDAR inhibitors. In this article, we first summarize the historical development of the NMDAR-centred hypothesis of rapid antidepressants. We then classify different NMDAR inhibitors based on their mechanisms of inhibition and evaluate preclinical as well as clinical evidence of their antidepressant effects. Finally, we critically analyse controversies and arguments surrounding ketamine's NMDAR-dependent and NMDAR-independent antidepressant action. A better understanding of ketamine's molecular targets and antidepressant mechanisms should shed light on the future development of better treatment for depression. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.
Asunto(s)
Antidepresivos , Ketamina , Receptores de N-Metil-D-Aspartato , Ketamina/farmacología , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Humanos , Animales , Depresión/tratamiento farmacológicoRESUMEN
Major depressive disorder, a prevalent and severe psychiatric condition, necessitates development of new and fast-acting antidepressants. Genetic suppression of astrocytic inwardly rectifying potassium channel 4.1 (Kir4.1) in the lateral habenula ameliorates depression-like phenotypes in mice. However, Kir4.1 remains an elusive drug target for depression. Here, we discovered a series of Kir4.1 inhibitors through high-throughput screening. Lys05, the most potent one thus far, effectively suppressed native Kir4.1 channels while displaying high selectivity against established targets for rapid-onset antidepressants. Cryogenic-electron microscopy structures combined with electrophysiological characterizations revealed Lys05 directly binds in the central cavity of Kir4.1. Notably, a single dose of Lys05 reversed the Kir4.1-driven depression-like phenotype and exerted rapid-onset (as early as 1 hour) antidepressant actions in multiple canonical depression rodent models with efficacy comparable to that of (S)-ketamine. Overall, we provided a proof of concept that Kir4.1 is a promising target for rapid-onset antidepressant effects.
Asunto(s)
Antidepresivos , Canales de Potasio de Rectificación Interna , Antidepresivos/farmacología , Antidepresivos/química , Canales de Potasio de Rectificación Interna/antagonistas & inhibidores , Canales de Potasio de Rectificación Interna/metabolismo , Animales , Ratones , Masculino , Ratas , Humanos , Trastorno Depresivo Mayor/tratamiento farmacológico , Trastorno Depresivo Mayor/metabolismo , Depresión/tratamiento farmacológico , Depresión/metabolismo , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Bloqueadores de los Canales de Potasio/farmacología , Bloqueadores de los Canales de Potasio/químicaRESUMEN
BACKGROUND: Icariin, a traditional Chinese medicine, has demonstrated anti-osteoporotic properties in ovariectomized mice. However, its effectiveness in preventing bone loss induced by ketogenic diet (KD), which mimics osteoporosis in human, remains unexplored. This study aims to investigate icariin's impact on KD-induced bone loss in mice. METHODS: Thirty mice were divided into: sham, KD, and KD + icariin groups. Post a 12-week intervention, evaluation including bone microstructures, serum concentrations of tartrate-resistant acid phosphatase (TRAP) and bone-specific alkaline phosphatase (ALP), and femoral tissue expression levels of osteocalcin (OCN) and TRAP. The expression levels of mammalian target of rapamycin (mTOR), ALP, peroxisome proliferator-activated receptor gamma (PPAR-γ), phosphorylated mTOR (p-mTOR), and the autophagy adaptor protein (p62) were also analyzed. Alizarin granule deposition and cellular ALP levels were measured following the induction of bone marrow mesenchymal stem cells (BMSCs) into osteogenesis. RESULTS: The study found that KD significantly impaired BMSCs' osteogenic differentiation, leading to bone loss. Icariin notably increased bone mass, stimulated osteogenesis, and reduced cancellous bone loss. In the KD + icariin group, measures such as bone tissue density (TMD), bone volume fraction (BV/TV), trabecular number (Tb.N), and trabecular thickness (Tb.Th) were significantly higher than in the KD group. Additionally, bone trabecular separation (Tb.Sp) was markedly lower in the KD + icariin group. Moreover, icariin increased OCN and ALP levels while suppressing PPAR-γ, TRAP, p62, and p-mTOR. In cellular studies, icariin encouraged osteogenic development in BMSCs under KD conditions. CONCLUSIONS: Icariin effectively counteracts bone thinning and improves bone microstructure. Its mechanism likely involves stimulating BMSCs osteogenic differentiation and inhibiting bone resorption, potentially through mTOR downregulation. These findings suggest icariin's potential as an alternative treatment for KD-induced bone loss.
Asunto(s)
Enfermedades Óseas Metabólicas , Dieta Cetogénica , Flavonoides , Células Madre Mesenquimatosas , Osteoporosis , Humanos , Ratones , Animales , Osteogénesis , Receptores Activados del Proliferador del Peroxisoma/metabolismo , Receptores Activados del Proliferador del Peroxisoma/farmacología , Osteoporosis/tratamiento farmacológico , Osteoporosis/etiología , Osteoporosis/metabolismo , Diferenciación Celular , Enfermedades Óseas Metabólicas/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Autofagia , Células Madre Mesenquimatosas/metabolismo , Células de la Médula Ósea/metabolismo , Células Cultivadas , MamíferosRESUMEN
Melanoma cells, deriving from neuroectodermal melanocytes, may exploit the nervous system's immune privilege for growth. Here we show that nerve growth factor (NGF) has both melanoma cell intrinsic and extrinsic immunosuppressive functions. Autocrine NGF engages tropomyosin receptor kinase A (TrkA) on melanoma cells to desensitize interferon γ signaling, leading to T and natural killer cell exclusion. In effector T cells that upregulate surface TrkA expression upon T cell receptor activation, paracrine NGF dampens T cell receptor signaling and effector function. Inhibiting NGF, either through genetic modification or with the tropomyosin receptor kinase inhibitor larotrectinib, renders melanomas susceptible to immune checkpoint blockade therapy and fosters long-term immunity by activating memory T cells with low affinity. These results identify the NGF-TrkA axis as an important suppressor of anti-tumor immunity and suggest larotrectinib might be repurposed for immune sensitization. Moreover, by enlisting low-affinity T cells, anti-NGF reduces acquired resistance to immune checkpoint blockade and prevents melanoma recurrence.
Asunto(s)
Melanoma , Receptor de Factor de Crecimiento Nervioso , Humanos , Receptor de Factor de Crecimiento Nervioso/genética , Receptor de Factor de Crecimiento Nervioso/metabolismo , Factor de Crecimiento Nervioso/genética , Factor de Crecimiento Nervioso/metabolismo , Tropomiosina , Melanoma/terapia , Receptor trkA/genética , Receptor trkA/metabolismo , Citoprotección , Inhibidores de Puntos de Control Inmunológico , Células T de Memoria , Terapia de Inmunosupresión , Inmunoterapia , Receptores de Antígenos de Linfocitos TRESUMEN
Social isolation is a risk factor for multiple mood disorders. Specifically, social isolation can remodel the brain, causing behavioral abnormalities, including sociability impairments. Here, we investigated social behavior impairment in mice following chronic social isolation stress (CSIS) and conducted a screening of susceptible brain regions using functional readouts. CSIS enhanced synaptic inhibition in the anterior cingulate cortex (ACC), particularly at inhibitory synapses of cholecystokinin (CCK)-expressing interneurons. This enhanced synaptic inhibition in the ACC was characterized by CSIS-induced loss of presynaptic cannabinoid type-1 receptors (CB1Rs), resulting in excessive axonal calcium influx. Activation of CCK-expressing interneurons or conditional knockdown of CB1R expression in CCK-expressing interneurons specifically reproduced social impairment. In contrast, optogenetic activation of CB1R or administration of CB1R agonists restored sociability in CSIS mice. These results suggest that the CB1R may be an effective therapeutic target for preventing CSIS-induced social impairments by restoring synaptic inhibition in the ACC.
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Cannabinoides , Giro del Cíngulo , Animales , Masculino , Ratones , Cannabinoides/metabolismo , Cannabinoides/farmacología , Giro del Cíngulo/metabolismo , Interneuronas/fisiología , Receptor Cannabinoide CB1/genética , Receptor Cannabinoide CB1/metabolismo , Aislamiento Social , Sinapsis/fisiologíaRESUMEN
Ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist1, has revolutionized the treatment of depression because of its potent, rapid and sustained antidepressant effects2-4. Although the elimination half-life of ketamine is only 13 min in mice5, its antidepressant activities can last for at least 24 h6-9. This large discrepancy poses an interesting basic biological question and has strong clinical implications. Here we demonstrate that after a single systemic injection, ketamine continues to suppress burst firing and block NMDARs in the lateral habenula (LHb) for up to 24 h. This long inhibition of NMDARs is not due to endocytosis but depends on the use-dependent trapping of ketamine in NMDARs. The rate of untrapping is regulated by neural activity. Harnessing the dynamic equilibrium of ketamine-NMDAR interactions by activating the LHb and opening local NMDARs at different plasma ketamine concentrations, we were able to either shorten or prolong the antidepressant effects of ketamine in vivo. These results provide new insights into the causal mechanisms of the sustained antidepressant effects of ketamine. The ability to modulate the duration of ketamine action based on the biophysical properties of ketamine-NMDAR interactions opens up new opportunities for the therapeutic use of ketamine.
Asunto(s)
Antidepresivos , Depresión , Habénula , Ketamina , Receptores de N-Metil-D-Aspartato , Animales , Ratones , Antidepresivos/administración & dosificación , Antidepresivos/metabolismo , Antidepresivos/farmacocinética , Antidepresivos/farmacología , Depresión/tratamiento farmacológico , Depresión/metabolismo , Habénula/efectos de los fármacos , Habénula/metabolismo , Semivida , Ketamina/administración & dosificación , Ketamina/metabolismo , Ketamina/farmacocinética , Ketamina/farmacología , Neuronas/fisiología , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Factores de Tiempo , Unión ProteicaRESUMEN
Relief, the appetitive state after the termination of aversive stimuli, is evolutionarily conserved. Understanding the behavioral role of this well-conserved phenomenon and its underlying neurobiological mechanisms are open and important questions. Here, we discover that the magnitude of relief from physical stress strongly correlates with individual resilience to depression-like behaviors in chronic stressed mice. Notably, blocking stress relief causes vulnerability to depression-like behaviors, whereas natural rewards supplied shortly after stress promotes resilience. Stress relief is mediated by reward-related mesolimbic dopamine neurons, which show minute-long, persistent activation after stress termination. Circuitry-wise, activation or inhibition of circuits downstream of the ventral tegmental area during the transient relief period bi-directionally regulates depression resilience. These results reveal an evolutionary function of stress relief in depression resilience and identify the neural substrate mediating this effect. Importantly, our data suggest a behavioral strategy of augmenting positive valence of stress relief with natural rewards to prevent depression.
Asunto(s)
Núcleo Accumbens , Resiliencia Psicológica , Ratones , Animales , Núcleo Accumbens/fisiología , Depresión , Área Tegmental Ventral/fisiología , RecompensaRESUMEN
Following the publication of the above article, the authors have contacted the Editorial Office to explain that they had assembled the cellular morphological images in Fig. 1A on p. 819 incorrectly; essentially, the cell morphology of 2 passages of hBMSCs (centre panel) should have been shown as the data panel for 3 passages of hBMSCs (right-hand panel), and likewise, the cell morphology of 3 passages of hBMSCs should have been shown as the data panel for 2 passages of hBMSCs. The revised version of Fig. 1 is shown below. The authors confirm that the errors associated with this figure did not have any significant impact on either the results or the conclusions reported in this study, and are grateful to the Editor of International Journal of Molecular Medicine for allowing them the opportunity to publish this Corrigendum. Furthermore, they apologize to the readership of the Journal for any inconvenience caused. [International Journal of Molecular Medicine 45: 816-824, 2020; DOI: 10.3892/ijmm.2020.4470].
RESUMEN
Downward social mobility is a well-known mental risk factor for depression, but its neural mechanism remains elusive. Here, by forcing mice to lose against their subordinates in a non-violent social contest, we lower their social ranks stably and induce depressive-like behaviors. These rank-decline-associated depressive-like behaviors can be reversed by regaining social status. In vivo fiber photometry and single-unit electrophysiological recording show that forced loss, but not natural loss, generates negative reward prediction error (RPE). Through the lateral hypothalamus, the RPE strongly activates the brain's anti-reward center, the lateral habenula (LHb). LHb activation inhibits the medial prefrontal cortex (mPFC) that controls social competitiveness and reinforces retreats in contests. These results reveal the core neural mechanisms mutually promoting social status loss and depressive behaviors. The intertwined neuronal signaling controlling mPFC and LHb activities provides a mechanistic foundation for the crosstalk between social mobility and psychological disorder, unveiling a promising target for intervention.
Asunto(s)
Habénula , Estatus Social , Ratones , Animales , Recompensa , Conducta Social , Habénula/fisiología , DepresiónRESUMEN
BACKGROUND: Oxidative stress is involved in many musculoskeletal diseases, such as osteoarthritis. However, the effect of oxidative stress on intervertebral disc degeneration (IDD) is still unclear. This study was aimed to provide an evidence of oxidative stress involved in IDD, and propose a new insight into pathogenesis of IDD. METHODS: Sixteen rats were randomly divided into sham and cervical muscle section (CMS) groups. The intervertebral disc degeneration scores (DDS) were assessed by histological staining at 8 weeks. Intracellular reactive oxygen species mainly comes from nicotinamide adenine dinucleotide phosphate oxidases (NOXs), while its clearance relies on antioxidant enzymes which regulated by forkhead transcription factor O (FOXOs). Thus, the oxidative stress was evaluated by the expression of NOXs and FOXOs. Meanwhile, the protein expression of Aggrecan, matrix metalloproteinase-13 (MMP-13), NOXs, FOXOs and antioxidant proteins (Manganese superoxide dismutase: MnSOD and Catalase) were tested in nucleus pulposus cells (NPCs) under tert-butyl hydroperoxide (TBHP) intervention. RESULTS: CMS induced IDD by enhancing DDS in 8 weeks, and the expression of NOX2 and NOX4 were significantly increased and the expression of FOXO3 and FOXO4 were remarkably decreased in the CMS rats. With the stimulation of TBHP, the contents of NOX2 and NOX4 in NPCs increased significantly, and the antioxidant proteins of FOXO1, FOXO3, FOXO4, MnSOD and Catalase and the matrix proteins of Aggrecan decreased remarkably, while MMP-13 significantly increased after TBHP intervention. CONCLUSIONS: The present study proposed that regulation of NOXs and FOXOs alters oxidative stress in intervertebral disc, which indicates that the intervention of oxidative stress would provide a new strategy to the treatment of IDD.
Asunto(s)
Degeneración del Disco Intervertebral , Disco Intervertebral , Animales , Ratas , Agrecanos/metabolismo , Agrecanos/farmacología , Antioxidantes/farmacología , Apoptosis , Catalasa/metabolismo , Catalasa/farmacología , Factores de Transcripción Forkhead , Disco Intervertebral/patología , Degeneración del Disco Intervertebral/patología , Metaloproteinasa 13 de la Matriz/metabolismo , Metaloproteinasa 13 de la Matriz/farmacología , Estrés Oxidativo , NADPH OxidasasRESUMEN
In humans, loss-of-function mutations of Kcnj10 in SeSAME/EAST syndrome, which encodes the inwardly rectifying K+ channel 4.1 (Kir 4.1), causes progressive neurological decline. Despite its rich expression in oligodendrocyte (OL) lineage cells and an emerging link with demyelinating disease, the function of Kir 4.1 in OLs is unclear. Here we show a novel role of Kir 4.1 in OL development. Kir 4.1 expression is markedly greater in OLs than in OL precursor cells (OPCs), and the down-regulation of Kir 4.1 impairs OL maturation by affecting OPC differentiation. Interestingly, Kir 4.1 regulates the intracellular pH of OPCs and OLs via the Na+ /H+ exchanger, which underlies impeded OPC differentiation by Kir 4.1 inhibition. Furthermore, Kir 4.1 regulates GSK3ß and SOX10, two molecules critical to OPC development. Collectively, our work opens a new avenue to understanding the functions of Kir 4.1 and intracellular pH in OLs.
Asunto(s)
Células Precursoras de Oligodendrocitos , Canales de Potasio de Rectificación Interna , Humanos , Concentración de Iones de Hidrógeno , Neurogénesis/fisiología , Células Precursoras de Oligodendrocitos/metabolismo , Oligodendroglía/metabolismo , Potasio/metabolismo , Canales de Potasio de Rectificación Interna/genética , Canales de Potasio de Rectificación Interna/metabolismoRESUMEN
In the brain, oscillatory strength embedded in network rhythmicity is important for processing experiences, and this process is disrupted in certain psychiatric disorders. The use of rhythmic network stimuli can change these oscillations and has shown promise in terms of improving cognitive function, although the underlying mechanisms are poorly understood. Here, we combine a two-layer learning model, with experiments involving genetically modified mice, that provides precise control of experience-driven oscillations by manipulating long-term potentiation of excitatory synapses onto inhibitory interneurons (LTPEâI). We find that, in the absence of LTPEâI, impaired network dynamics and memory are rescued by activating inhibitory neurons to augment the power in theta and gamma frequencies, which prevents network overexcitation with less inhibitory rebound. In contrast, increasing either theta or gamma power alone was less effective. Thus, inducing network changes at dual frequencies is involved in memory encoding, indicating a potentially feasible strategy for optimizing network-stimulating therapies.
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Hipocampo , Interneuronas , Animales , Hipocampo/fisiología , Humanos , Interneuronas/fisiología , Aprendizaje , Potenciación a Largo Plazo/fisiología , Ratones , Periodicidad , Sinapsis/fisiologíaRESUMEN
The central nervous system has evolved to coordinate the regulation of both the behavior response to the external environment and homeostasis of energy expenditure. Recent studies have indicated the dorsomedial ventromedial hypothalamus (dmVMH) as an important hub that regulates both innate behavior and energy homeostasis for coping stress. However, how dmVMH neurons control neuronal firing pattern to regulate chronic stress-induced anxiety and energy expenditure remains poorly understood. Here, we found enhanced neuronal activity in VMH after chronic stress, which is mainly induced by increased proportion of burst firing neurons. This enhancement of VMH burst firing is predominantly mediated by Cav3.1 expression. Optogenetically evoked burst firing of dmVMH neurons induced anxiety-like behavior, shifted the respiratory exchange ratio toward fat oxidation, and decreased food intake, while knockdown of Cav3.1 in the dmVMH had the opposite effects, suggested that Cav 3.1 as a crucial regulator. Interestingly, we found that fluoxetine (anxiolytics) could block the increase of Cav3.1 expression to inhibit the burst firing, and then rescued the anxiety-like behaviors and energy expenditure changes. Collectively, our study first revealed an important role of Cav3.1-driven bursting firing of dmVMH neurons in the control of anxiety-like behavior and energy expenditure, and provided potential therapeutic targets for treating the chronic stress-induced emotional malfunction and metabolism disorders.
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Hipotálamo , Neuronas , Ansiedad , Metabolismo Energético , Neuronas/metabolismoRESUMEN
CaMKII is essential for long-term potentiation (LTP), a process in which synaptic strength is increased following the acquisition of information. Among the four CaMKII isoforms, γCaMKII is the one that mediates the LTP of excitatory synapses onto inhibitory interneurons (LTPEâI). However, the molecular mechanism underlying how γCaMKII mediates LTPEâI remains unclear. Here, we show that γCaMKII is highly enriched in cultured hippocampal inhibitory interneurons and opts to be activated by higher stimulating frequencies in the 10-30 Hz range. Following stimulation, γCaMKII is translocated to the synapse and becomes co-localized with the postsynaptic protein PSD-95. Knocking down γCaMKII prevents the chemical LTP-induced phosphorylation and trafficking of AMPA receptors (AMPARs) in putative inhibitory interneurons, which are restored by overexpression of γCaMKII but not its kinase-dead form. Taken together, these data suggest that γCaMKII decodes NMDAR-mediated signaling and in turn regulates AMPARs for expressing LTP in inhibitory interneurons.
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N-Metilaspartato , Receptores AMPA , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Hipocampo/metabolismo , Interneuronas/fisiología , Potenciación a Largo Plazo/fisiología , N-Metilaspartato/metabolismo , Receptores AMPA/fisiología , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapsis/fisiologíaRESUMEN
Chronic stress is a major risk factor for depression onset. However, it remains unclear how repeated stress sculpts neural circuits and finally elicits depression. Given the essential role of lateral habenula (LHb) in depression, here, we attempt to clarify how LHb-centric neural circuitry integrates stress-related information. We identify lateral hypothalamus (LH) as the most physiologically relevant input to LHb under stress. LH neurons fire with a unique pattern that efficiently drives postsynaptic potential summation and a closely followed LHb bursting (EPSP-burst pairing) in response to various stressors. We found that LH-LHb synaptic potentiation is determinant in stress-induced depression. Mimicking this repeated EPSP-burst pairings at LH-LHb synapses by photostimulation, we artificially induced an "emotional status" merely by potentiating this pathway in mice. Collectively, these results delineate the spatiotemporal dynamics of chronic stress processing from forebrain onto LHb in a pathway-, cell-type-, and pattern-specific manner, shedding light on early interventions before depression onset.
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Habénula , Animales , Depresión/etiología , Habénula/fisiología , Área Hipotalámica Lateral , Hipotálamo , Ratones , Sinapsis/fisiologíaRESUMEN
Social competition plays a pivotal role in determining individuals' social status. While the dorsomedial prefrontal cortex (dmPFC) is essential in regulating social competition, it remains unclear how information is processed within its local networks. Here, by applying optogenetic and chemogenetic manipulations in a dominance tube test, we reveal that, in accordance with pyramidal (PYR) neuron activation, excitation of the vasoactive intestinal polypeptide (VIP) or inhibition of the parvalbumin (PV) interneurons induces winning. The winning behavior is associated with sequential calcium activities initiated by VIP and followed by PYR and PV neurons. Using miniature two-photon microscopic (MTPM) and optrode recordings in awake mice, we show that VIP stimulation directly leads to a two-phased activity pattern of both PYR and PV neurons-rapid suppression followed by activation. The delayed activation of PV implies an embedded feedback tuning. This disinhibitory VIP-PV-PYR motif forms the core of a dmPFC microcircuit to control social competition.
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Interneuronas , Parvalbúminas , Animales , Interneuronas/fisiología , Ratones , Parvalbúminas/metabolismo , Corteza Prefrontal/fisiología , Células Piramidales/fisiología , Péptido Intestinal Vasoactivo/metabolismoRESUMEN
For network rewiring and information storage in the brain, late phase long-term synaptic depression (L-LTD) requires the long-lasting reorganization of cellular resources. We found that activation of GRIN/NMDAR recruits transcription-dependent autophagy for synaptic turnover to support L-LTD. Activity-dependent CRTC1 synapto-nuclear translocation increases nuclear CRTC1 that competes with FXR for binding to CREB; this in turn enhances the direct binding between CRTC1-CREB and macroautophagy/autophagy gene promoters. Synergistic actions of CRTC1-CREB are preferentially turned on by LTD-inducing stimuli and switched off by genetic knockdown of CREB or CRTC1, or acutely activating FXR. Disrupted CRTC1-CREB signaling impairs activity-driven loss of surface GRIA/AMPARs and DLG4/PSD-95, and selectively prevents GRIN/NMDAR-dependent L-LTD, which are rescued by enhancing MTOR-regulated autophagy. These findings suggest a novel mechanism in L-LTD, in which brief synaptic activities recruit long-lasting autophagy through excitation-transcription coupling for ensuing synaptic remodeling.
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Autofagia , Depresión Sináptica a Largo Plazo , Sinapsis/metabolismo , Animales , Autofagia/fisiología , Encéfalo/metabolismo , Encéfalo/fisiología , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Humanos , Depresión Sináptica a Largo Plazo/fisiología , Transducción de Señal , Sinapsis/fisiología , Factores de Transcripción/metabolismoRESUMEN
Cellular resources must be reorganized for long-term synaptic plasticity during brain information processing, in which coordinated gene transcription and protein turnover are required. However, the mechanism underlying this process remains elusive. Here, we report that activating N-methyl-d-aspartate receptors (NMDARs) induce transcription-dependent autophagy for synaptic turnover and late-phase long-term synaptic depression (L-LTD), which invokes cytoplasm-to-nucleus signaling mechanisms known to be required for late-phase long-term synaptic potentiation (L-LTP). Mechanistically, LTD-inducing stimuli specifically dephosphorylate CRTC1 (CREB-regulated transcription coactivator 1) at Ser-151 and are advantaged in recruiting CRTC1 from cytoplasm to the nucleus, where it competes with FXR (fed-state sensing nuclear receptor) for binding to CREB (cAMP response element-binding protein) and drives autophagy gene expression. Disrupting synergistic actions of CREB and CRTC1 (two essential L-LTP transcription factors) impairs transcription-dependent autophagy induction and prevents NMDAR-dependent L-LTD, which can be rescued by constitutively inducing mechanistic target of rapamycin (mTOR)-dependent autophagy. Together, these findings uncover mechanistic commonalities between L-LTP and L-LTD, suggesting that synaptic activity can tune excitation-transcription coupling for distinct long-lasting synaptic remodeling.