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1.
Chem Biol Interact ; 341: 109452, 2021 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-33785315

RESUMO

Current strategies for the treatment of Alzheimer's disease (AD) focus on the pathology in the later stages of disease progression. Early microglia abnormality and ß-amyloid (Aß) deposition trigger disease development before identical symptoms emerge, which leads to poor clinical treatment effects in the later stages. In the early stage of disease progression, microglia in brains of 5XFAD mice have been activated by Aß plaques to secrete more pro-inflammatory cytokines. In the meantime, these cytokines up-regulate Aß via increasing the APP processing. Sodium butyrate (NaB), as one of the short chain fatty acid (SCFA) generated by gut microbiota, is the inhibitor of histone deacetylase (HDAC), which reduces the secretion of pro-inflammatory cytokines. In our experiment, 8-week-old 5XFAD mice and their litter WT mice were treated with NaB or normal saline for 2 weeks (WT + Vehicle group, WT + NaB group, AD + Vehicle group and AD + NaB group). After treatment, behavioral tests were carried out. The novel object recognition (NOR) and Morris water maze (MWM) tests demonstrated that there was no significant difference between four groups of mice. The results of long-term potentiation (LTP) and depotentiation (DEP) illustrated that the synaptic plasticity was promoted in 5XFAD mice after treatment with NaB. Compared to the AD + Vehicle group, the dendritic spines were more abundant in other groups of mice. Furthermore, the synapse-associated proteins (PSD-95, SYP, NR2B) were reduced and the pro-inflammatory cytokines (TNF-α, IL-6, IL-1ß) were increased in the AD + Vehicle group. These phenomena were reversed after treatment with NaB. Moreover, our results suggested that NaB suppressed the over-activation of microglia and the accumulation of Aß in AD mice. Altogether, all results illustrated that HDAC inhibitor NaB could ameliorate the synaptic plasticity by reducing neuroinflammation in 5XFAD mice in the early stage of the disease.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Encéfalo/efeitos dos fármacos , Ácido Butírico/farmacologia , Inflamação/tratamento farmacológico , Plasticidade Neuronal/efeitos dos fármacos , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Disfunção Cognitiva/tratamento farmacológico , Modelos Animais de Doenças , Proteína 4 Homóloga a Disks-Large/metabolismo , Inflamação/patologia , Potenciação de Longa Duração/efeitos dos fármacos , Camundongos Transgênicos , Microglia/efeitos dos fármacos , Microglia/patologia , Plasticidade Neuronal/fisiologia , Sinaptofisina/metabolismo
3.
J Neurosci ; 41(6): 1218-1241, 2021 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-33402421

RESUMO

Critical periods are developmental windows during which neural circuits effectively adapt to the new sensory environment. Animal models of fragile X syndrome (FXS), a common monogenic autism spectrum disorder (ASD), exhibit profound impairments of sensory experience-driven critical periods. However, it is not known whether the causative fragile X mental retardation protein (FMRP) acts uniformly across neurons, or instead manifests neuron-specific functions. Here, we use the genetically-tractable Drosophila brain antennal lobe (AL) olfactory circuit of both sexes to investigate neuron-specific FMRP roles in the odorant experience-dependent remodeling of the olfactory sensory neuron (OSN) innervation during an early-life critical period. We find targeted OSN class-specific FMRP RNAi impairs innervation remodeling within AL synaptic glomeruli, whereas global dfmr1 null mutants display relatively normal odorant-driven refinement. We find both OSN cell autonomous and cell non-autonomous FMRP functions mediate odorant experience-dependent remodeling, with AL circuit FMRP imbalance causing defects in overall glomerulus innervation refinement. We find OSN class-specific FMRP levels bidirectionally regulate critical period remodeling, with odorant experience selectively controlling OSN synaptic terminals in AL glomeruli. We find OSN class-specific FMRP loss impairs critical period remodeling by disrupting responses to lateral modulation from other odorant-responsive OSNs mediating overall AL gain control. We find that silencing glutamatergic AL interneurons reduces OSN remodeling, while conversely, interfering with the OSN class-specific GABAA signaling enhances remodeling. These findings reveal control of OSN synaptic remodeling by FMRP with neuron-specific circuit functions, and indicate how neural circuitry can compensate for global FMRP loss to reinstate normal critical period brain circuit remodeling.SIGNIFICANCE STATEMENT Fragile X syndrome (FXS), the leading monogenic cause of intellectual disability and autism spectrum disorder (ASD), manifests severe neurodevelopmental delays. Likewise, FXS disease models display disrupted neurodevelopmental critical periods. In the well-mapped Drosophila olfactory circuit model, perturbing the causative fragile X mental retardation protein (FMRP) within a single olfactory sensory neuron (OSN) class impairs odorant-dependent remodeling during an early-life critical period. Importantly, this impairment requires activation of other OSNs, and the olfactory circuit can compensate when FMRP is removed from all OSNs. Understanding the neuron-specific FMRP requirements within a developing neural circuit, as well as the FMRP loss compensation mechanisms, should help us engineer FXS treatments. This work suggests FXS treatments could use homeostatic mechanisms to alleviate circuit-level deficits.


Assuntos
Período Crítico Psicológico , Proteína do X Frágil de Retardo Mental/metabolismo , Síndrome do Cromossomo X Frágil/metabolismo , Plasticidade Neuronal/fisiologia , Neurônios/fisiologia , Córtex Olfatório/crescimento & desenvolvimento , Córtex Olfatório/metabolismo , Animais , Animais Geneticamente Modificados , Drosophila , Feminino , Proteína do X Frágil de Retardo Mental/genética , Síndrome do Cromossomo X Frágil/genética , Masculino , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/química , Neurônios/efeitos dos fármacos , Odorantes , Bulbo Olfatório/química , Bulbo Olfatório/metabolismo , Córtex Olfatório/química , Neurônios Receptores Olfatórios/química , Neurônios Receptores Olfatórios/metabolismo , Optogenética/métodos
4.
J Neurosci ; 41(5): 845-854, 2021 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-33472820

RESUMO

Spinal interneurons are important facilitators and modulators of motor, sensory, and autonomic functions in the intact CNS. This heterogeneous population of neurons is now widely appreciated to be a key component of plasticity and recovery. This review highlights our current understanding of spinal interneuron heterogeneity, their contribution to control and modulation of motor and sensory functions, and how this role might change after traumatic spinal cord injury. We also offer a perspective for how treatments can optimize the contribution of interneurons to functional improvement.


Assuntos
Interneurônios/metabolismo , Doenças do Sistema Nervoso/metabolismo , Plasticidade Neuronal/fisiologia , Traumatismos da Medula Espinal/metabolismo , Medula Espinal/metabolismo , Animais , Agonistas GABAérgicos/farmacologia , Agonistas GABAérgicos/uso terapêutico , Humanos , Interneurônios/efeitos dos fármacos , Interneurônios/patologia , Doenças do Sistema Nervoso/tratamento farmacológico , Doenças do Sistema Nervoso/patologia , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Medula Espinal/efeitos dos fármacos , Medula Espinal/patologia , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/patologia
5.
Proc Natl Acad Sci U S A ; 118(1)2021 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-33443211

RESUMO

Hippocampal synaptic plasticity is important for learning and memory formation. Homeostatic synaptic plasticity is a specific form of synaptic plasticity that is induced upon prolonged changes in neuronal activity to maintain network homeostasis. While astrocytes are important regulators of synaptic transmission and plasticity, it is largely unclear how they interact with neurons to regulate synaptic plasticity at the circuit level. Here, we show that neuronal activity blockade selectively increases the expression and secretion of IL-33 (interleukin-33) by astrocytes in the hippocampal cornu ammonis 1 (CA1) subregion. This IL-33 stimulates an increase in excitatory synapses and neurotransmission through the activation of neuronal IL-33 receptor complex and synaptic recruitment of the scaffold protein PSD-95. We found that acute administration of tetrodotoxin in hippocampal slices or inhibition of hippocampal CA1 excitatory neurons by optogenetic manipulation increases IL-33 expression in CA1 astrocytes. Furthermore, IL-33 administration in vivo promotes the formation of functional excitatory synapses in hippocampal CA1 neurons, whereas conditional knockout of IL-33 in CA1 astrocytes decreases the number of excitatory synapses therein. Importantly, blockade of IL-33 and its receptor signaling in vivo by intracerebroventricular administration of its decoy receptor inhibits homeostatic synaptic plasticity in CA1 pyramidal neurons and impairs spatial memory formation in mice. These results collectively reveal an important role of astrocytic IL-33 in mediating the negative-feedback signaling mechanism in homeostatic synaptic plasticity, providing insights into how astrocytes maintain hippocampal network homeostasis.


Assuntos
Astrócitos/metabolismo , Região CA1 Hipocampal/metabolismo , Interleucina-33/metabolismo , Plasticidade Neuronal , Transdução de Sinais/efeitos dos fármacos , Memória Espacial/efeitos dos fármacos , Animais , Astrócitos/efeitos dos fármacos , Proteína 4 Homóloga a Disks-Large/metabolismo , Técnicas de Inativação de Genes , Hipocampo/metabolismo , Homeostase , Interleucina-33/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Células Piramidais/efeitos dos fármacos , Células Piramidais/metabolismo , Ratos , Sinapses/efeitos dos fármacos , Sinapses/genética , Sinapses/metabolismo , Transmissão Sináptica/efeitos dos fármacos , Tetrodotoxina/farmacologia
6.
Biochem Pharmacol ; 184: 114366, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33310049

RESUMO

Alzheimer's disease (AD) is one of the most prevalent neurodegenerative disorders characterized by memory deficits. Although no drug has given promising results, synaptic dysfunction-modulating agents might be considered potential candidates for alleviating this disorder. Pinoresinol, a lignan found in Forsythia suspensa, is a memory-enhancing agent with excitatory synaptic activation. In the present study, we tested whether pinoresinol reduces learning and memory and excitatory synaptic deficits in an amyloid ß (Aß)-induced AD-like mouse model. Pinoresinol enhanced hippocampal long-term potentiation (LTP) through calcium-permeable AMPA receptor, which was mediated by Akt activation. Moreover, pinoresinol ameliorated LTP deficits in amyloid ß (Aß)-treated hippocampal slices via Akt signaling. Oral administration of pinoresinol ameliorated Aß-induced memory deficits without sensory dysfunction. Moreover, AD-like pathology, including neuroinflammation and synaptic deficit, were ameliorated by pinoresinol administration. Collectively, pinoresinol may be a good candidate for AD therapy by modulating synaptic functions.


Assuntos
Furanos/farmacologia , Hipocampo/efeitos dos fármacos , Lignanas/farmacologia , Transtornos da Memória/tratamento farmacológico , Plasticidade Neuronal/efeitos dos fármacos , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/toxicidade , Animais , Modelos Animais de Doenças , Hipocampo/metabolismo , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Transtornos da Memória/etiologia , Transtornos da Memória/patologia , Camundongos Endogâmicos , Plasticidade Neuronal/fisiologia , Fragmentos de Peptídeos/toxicidade , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de AMPA/metabolismo
7.
Nature ; 590(7846): 451-456, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33361810

RESUMO

Reinforcement learning models postulate that neurons that release dopamine encode information about action and action outcome, and provide a teaching signal to striatal spiny projection neurons in the form of dopamine release1. Dopamine is thought to guide learning via dynamic and differential modulation of protein kinase A (PKA) in each class of spiny projection neuron2. However, the real-time relationship between dopamine and PKA in spiny projection neurons remains untested in behaving animals. Here we monitor the activity of dopamine-releasing neurons, extracellular levels of dopamine and net PKA activity in spiny projection neurons in the nucleus accumbens of mice during learning. We find positive and negative modulation of dopamine that evolves across training and is both necessary and sufficient to explain concurrent fluctuations in the PKA activity of spiny projection neurons. Modulations of PKA in spiny projection neurons that express type-1 and type-2 dopamine receptors are dichotomous, such that these neurons are selectively sensitive to increases and decreases, respectively, in dopamine that occur at different phases of learning. Thus, PKA-dependent pathways in each class of spiny projection neuron are asynchronously engaged by positive or negative dopamine signals during learning.


Assuntos
Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Dopamina/metabolismo , Aprendizagem , Animais , Proteínas Quinases Dependentes de AMP Cíclico/antagonistas & inibidores , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/enzimologia , Neurônios Dopaminérgicos/metabolismo , Feminino , Fluorescência , Neurônios GABAérgicos/efeitos dos fármacos , Neurônios GABAérgicos/enzimologia , Neurônios GABAérgicos/metabolismo , Aprendizagem/efeitos dos fármacos , Masculino , Camundongos , Plasticidade Neuronal/efeitos dos fármacos , Núcleo Accumbens/citologia , Fotometria , Receptores Dopaminérgicos/classificação , Receptores Dopaminérgicos/metabolismo
8.
Cells ; 9(12)2020 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-33321704

RESUMO

Neurotrophin nerve growth factor (NGF) has been demonstrated to upregulate the gene expression of bradykinin receptor 2 (B2R) on sensory neurons, thus facilitating nociceptive signals. The aim of the present study is to investigate the involvement of B2R in the NGF mechanism of action in nonsensory neurons in vitro by using rat mixed cortical primary cultures (CNs) and mouse hippocampal slices, and in vivo in Alzheimer's disease (AD) transgenic mice (5xFAD) chronically treated with NGF. A significant NGF-mediated upregulation of B2R was demonstrated by microarray, Western blot, and immunofluorescence analysis in CNs, indicating microglial cells as the target of this modulation. The B2R involvement in the NGF mechanism of action was also demonstrated by using a selective B2R antagonist which was able to reverse the neuroprotective effect of NGF in CNs, as revealed by viability assay, and the NGF-induced long-term potentiation (LTP) in hippocampal slices. To confirm in vitro observations, B2R upregulation was observed in 5xFAD mouse brain following chronic intranasal NGF treatment. This study demonstrates for the first time that B2R is a key element in the neuroprotective activity and synaptic plasticity mediated by NGF in brain cells.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Fator de Crescimento Neural/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Receptor B2 da Bradicinina/genética , Receptor B2 da Bradicinina/metabolismo , Administração Intranasal , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Animais , Sobrevivência Celular , Células Cultivadas , Córtex Cerebral/citologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Camundongos , Camundongos Transgênicos , Microglia/citologia , Microglia/efeitos dos fármacos , Microglia/metabolismo , Fator de Crescimento Neural/farmacologia , Plasticidade Neuronal/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Cultura Primária de Células , Ratos , Regulação para Cima
9.
Int J Mol Sci ; 21(24)2020 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-33352646

RESUMO

Chronic neuroinflammation is a common pathogenetic link in the development of various neurological and neurodegenerative diseases. Thus, a detailed study of neuroinflammation and the development of drugs that reduce or eliminate the negative effect of neuroinflammation on cognitive processes are among the top priorities of modern neurobiology. N-docosahexanoylethanolamine (DHEA, synaptamide) is an endogenous metabolite and structural analog of anandamide, an essential endocannabinoid produced from arachidonic acid. Our study aims to elucidate the pharmacological activity of synaptamide in lipopolysaccharide (LPS)-induced neuroinflammation. Memory deficits in animals were determined using behavioral tests. To study the effects of LPS (750 µg/kg/day, 7 days) and synaptamide (10 mg/kg/day, 7 days) on synaptic plasticity, long-term potentiation was examined in the CA1 area of acute hippocampal slices. The Golgi-Cox method allowed us to assess neuronal morphology. The production of inflammatory factors and receptors was assessed using ELISA and immunohistochemistry. During the study, functional, structural, and plastic changes within the hippocampus were identified. We found a beneficial effect of synaptamide on hippocampal synaptic plasticity and morphological characteristics of neurons. Synaptamide treatment recovered hippocampal neurogenesis, suppressed microglial activation, and significantly improved hippocampus-dependent memory. The basis of the phenomena described above is probably the powerful anti-inflammatory activity of synaptamide, as shown in our study and several previous works.


Assuntos
Modelos Animais de Doenças , Encefalite/tratamento farmacológico , Etanolaminas/farmacologia , Hipocampo/efeitos dos fármacos , Transtornos da Memória/tratamento farmacológico , Microglia/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Animais , Ácidos Docosa-Hexaenoicos/química , Encefalite/metabolismo , Encefalite/patologia , Hipocampo/metabolismo , Hipocampo/patologia , Potenciação de Longa Duração , Masculino , Transtornos da Memória/metabolismo , Transtornos da Memória/patologia , Camundongos , Camundongos Endogâmicos C57BL , Microglia/metabolismo , Microglia/patologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia
10.
Science ; 369(6505): 858-862, 2020 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-32792401

RESUMO

The conversion of neural stem cells into neurons is associated with the remodeling of organelles, but whether and how this is causally linked to fate change is poorly understood. We examined and manipulated mitochondrial dynamics during mouse and human cortical neurogenesis. We reveal that shortly after cortical stem cells have divided, daughter cells destined to self-renew undergo mitochondrial fusion, whereas those that retain high levels of mitochondria fission become neurons. Increased mitochondria fission promotes neuronal fate, whereas induction of mitochondria fusion after mitosis redirects daughter cells toward self-renewal. This occurs during a restricted time window that is doubled in human cells, in line with their increased self-renewal capacity. Our data reveal a postmitotic period of fate plasticity in which mitochondrial dynamics are linked with cell fate.


Assuntos
Córtex Cerebral/crescimento & desenvolvimento , Mitocôndrias/fisiologia , Dinâmica Mitocondrial , Mitose , Células-Tronco Neurais/citologia , Neurogênese/fisiologia , Neurônios/citologia , Animais , Córtex Cerebral/citologia , Feminino , Células HEK293 , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Humanos , Masculino , Camundongos , Plasticidade Neuronal/efeitos dos fármacos , Plasticidade Neuronal/fisiologia , Sirtuínas/metabolismo
11.
Adv Pharmacol ; 89: 43-78, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32616214

RESUMO

There has been much recent progress in understanding of the mechanism of ketamine's rapid and enduring antidepressant effects. Here we review recent insights from clinical and preclinical studies, with special emphasis of ketamine-induced changes in GABAergic synaptic transmission that are considered essential for its antidepressant therapeutic effects. Subanesthetic ketamine is now understood to exert its initial action by selectively blocking a subset of NMDA receptors on GABAergic interneurons, which results in disinhibition of glutamatergic target neurons, a surge in extracellular glutamate and correspondingly elevated glutamatergic synaptic transmission. This surge in glutamate appears to be corroborated by the rapid metabolism of ketamine into hydroxynorketamine, which acts at presynaptic sites to disinhibit the release of glutamate. Preclinical studies indicate that glutamate-induced activity triggers the release of BDNF, followed by transient activation of the mTOR pathway and increased expression of synaptic proteins, along with functional strengthening of glutamatergic synapses. This drug-on phase lasts for approximately 2h and is followed by a period of days characterized by structural maturation of newly formed glutamatergic synapses and prominently enhanced GABAergic synaptic inhibition. Evidence from mouse models with constitutive antidepressant-like phenotypes suggests that this phase involves strengthened inhibition of dendrites by somatostatin-positive GABAergic interneurons and correspondingly reduced NMDA receptor-mediated Ca2+ entry into dendrites, which activates an intracellular signaling cascade that converges with the mTOR pathway onto increased activity of the eukaryotic elongation factor eEF2 and enhanced translation of dendritic mRNAs. Newly synthesized proteins such as BDNF may be important for the prolonged therapeutic effects of ketamine.


Assuntos
Antidepressivos/farmacologia , Neurônios GABAérgicos/fisiologia , Ketamina/farmacologia , Inibição Neural/efeitos dos fármacos , Animais , Depressão/fisiopatologia , Neurônios GABAérgicos/efeitos dos fármacos , Humanos , Metaboloma/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos
12.
Adv Pharmacol ; 89: 79-99, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32616215

RESUMO

Major depressive disorder is a prevalent and serious form of mental illness. While traditional antidepressants ameliorate some of the symptoms associated with depression, the onset of action typically takes several weeks leaving severely depressed individuals vulnerable to self-injurious behavior and possibly suicide. There has been a major unmet need for the development of pharmacological therapies that can quickly alleviate symptoms associated with depression. Clinical data shows that a single sub-psychomimetic dose of ketamine, a noncompetitive glutamatergic N-methyl-d-aspartate (NMDA) receptor antagonist, has rapid antidepressant responses in patients with treatment-resistant major depressive disorder. We have studied key signaling pathways and synaptic mechanisms underlying the rapid antidepressant action of ketamine. Our studies show ketamine blocks synaptic NMDA receptors involved in spontaneous synaptic transmission, which deactivates calcium/calmodulin-dependent kinase eukaryotic elongation factor 2 kinase (eEF2K), resulting in dephosphorylation of eukaryotic elongation factor 2 (eEF2), and the subsequent desuppression of brain-derived neurotrophic factor (BDNF) protein synthesis in the hippocampus. This signaling pathway then potentiates synaptic α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor responses that results in a novel form of synaptic potentiation which corresponds with antidepressant efficacy. In this chapter, we focus on our studies examining ketamine's action and the instructive role of eEF2K in rapid antidepressant action. Our recent studies highlight eEF2K as a major molecular substrate mediating synaptic plasticity and the rapid antidepressant effects of ketamine.


Assuntos
Antidepressivos/farmacologia , Quinase do Fator 2 de Elongação/metabolismo , Ketamina/farmacologia , Animais , Depressão/tratamento farmacológico , Depressão/fisiopatologia , Humanos , Ketamina/uso terapêutico , Plasticidade Neuronal/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/metabolismo
13.
Psychopharmacology (Berl) ; 237(8): 2499-2508, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32483676

RESUMO

Evidence indicates that neuroplasticity-based cognitive training can improve cognition in patients with schizophrenia, but the individual response to training varies greatly between subjects. Hence, there is a need to understand the neurological underpinnings of cognitive training to reveal predictors of treatment response. D-serine is a crucial modulator of neuroplasticity, and decreased levels of D-serine may contribute to deficits in neuroplasticity in schizophrenia. Interestingly, we observed that training mice to identify auditory oddballs increased extracellular levels of D-serine in the hippocampus during training. Serine racemase (Srr) is the only source of brain D-serine; thus, it is possible that Srr may mediate the response to training. To test this hypothesis, we trained mice that have a mutated version of Srr (SrrY269*/SrrY269*) and reduced levels of D-serine in the same auditory training. SrrY269*/SrrY269* mice showed decreased performance during auditory training (defined as the capacity to discriminate an oddball during a sequence of tones). Importantly, auditory training improved prepulse inhibition (PPI) in SrrY269*/SrrY269* but not in wild-type mice. Finally, D-serine (100 mg/kg i.p.) given 30 min before training sessions to SrrY269*/SrrY269* mice improved training performance, but it did not enhance PPI. Taken together, our results show that D-serine is involved in the response to neuroplasticity-based auditory training and that PPI deficits can be improved by auditory oddball training even in the presence of neuroplasticity deficits.


Assuntos
Estimulação Acústica/métodos , Cognição/fisiologia , Inibição Pré-Pulso/fisiologia , Racemases e Epimerases/genética , Racemases e Epimerases/metabolismo , Animais , Cognição/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Plasticidade Neuronal/efeitos dos fármacos , Plasticidade Neuronal/fisiologia , Inibição Pré-Pulso/efeitos dos fármacos , Esquizofrenia/genética , Esquizofrenia/metabolismo , Serina/farmacologia
14.
Neuron ; 106(5): 715-726, 2020 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-32497508

RESUMO

Ketamine exerts rapid antidepressant action in depressed and treatment-resistant depressed patients within hours. At the same time, ketamine elicits a unique form of functional synaptic plasticity that shares several attributes and molecular mechanisms with well-characterized forms of homeostatic synaptic scaling. Lithium is a widely used mood stabilizer also proposed to act via synaptic scaling for its antimanic effects. Several studies to date have identified specific forms of homeostatic synaptic plasticity that are elicited by these drugs used to treat neuropsychiatric disorders. In the last two decades, extensive work on homeostatic synaptic plasticity mechanisms have shown that they diverge from classical synaptic plasticity mechanisms that process and store information and thus present a novel avenue for synaptic regulation with limited direct interference with cognitive processes. In this review, we discuss the intersection of the findings from neuropsychiatric treatments and homeostatic plasticity studies to highlight a potentially wider paradigm for treatment advance.


Assuntos
Antimaníacos/farmacologia , Transtorno Bipolar/tratamento farmacológico , Transtorno Depressivo Maior/tratamento farmacológico , Antagonistas de Aminoácidos Excitatórios/farmacologia , Homeostase/efeitos dos fármacos , Ketamina/farmacologia , Compostos de Lítio/farmacologia , Plasticidade Neuronal/efeitos dos fármacos , Animais , Antimaníacos/uso terapêutico , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Humanos , Ketamina/uso terapêutico , Compostos de Lítio/uso terapêutico , Transtornos do Humor/tratamento farmacológico , Sinapses/efeitos dos fármacos
15.
J Pharmacol Sci ; 143(4): 245-254, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32482409

RESUMO

The accumulation of insoluble amyloid ß (Aß) peptides is one of the pathological changes in Alzheimer's disease (AD), which induced synaptic plasticity impairment and excitatory amino acid toxicity associated with decreased memory function. Xingnaojing (XNJ), a well-known prescription in traditional Chinese medicine, has been used for the treatment of stroke for many years in China. In this study, we aim to investigate the therapeutic effects of XNJ in a hippocampus of Aß1-42 induced mouse model of AD which showed significant memory loss and impaired synaptic morphology and function. Treatment of XNJ could attenuate spatial and working memory dysfunction, increase dendritic spine density and improve long-term potential (LTP) induction. In addition, XNJ treatment significantly increased the level of N-methyl-d-aspartate receptors (NMDARs) and inhibit the NMDA/α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) ratio in AD mice. XNJ treatment also activated the AKT/mechanistic target of rapamycin (mTOR) pathway, while inhibition of the mTOR pathway by rapamycin could reverse the protective effects of XNJ treatment. In conclusion, XNJ protected against synaptic plasticity and memory impairment in AD mice via the activation of AKT/mTOR signaling pathway, suggesting XNJ as an alternative treatment for AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Transtornos da Memória/tratamento farmacológico , Plasticidade Neuronal/efeitos dos fármacos , Fragmentos de Peptídeos/metabolismo , Doença de Alzheimer/metabolismo , Animais , Modelos Animais de Doenças , Masculino , Camundongos Endogâmicos C57BL
16.
J Neurosci ; 40(27): 5161-5176, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32444385

RESUMO

Alterations of excitatory synaptic function are the strongest correlate to the pathologic disturbance of cognitive ability observed in the early stages of Alzheimer's disease (AD). This pathologic feature is driven by amyloid-ß oligomers (Aßos) and propagates from neuron to neuron. Here, we investigated the mechanism by which Aßos affect the function of synapses and how these alterations propagate to surrounding healthy neurons. We used complementary techniques ranging from electrophysiological recordings and molecular biology to confocal microscopy in primary cortical cultures, and from acute hippocampal and cortical slices from male wild-type and amyloid precursor protein (APP) knock-out (KO) mice to assess the effects of Aßos on glutamatergic transmission, synaptic plasticity, and dendritic spine structure. We showed that extracellular application of Aßos reduced glutamatergic synaptic transmission and long-term potentiation. These alterations were not observed in APP KO neurons, suggesting that APP expression is required. We demonstrated that Aßos/APP interaction increases the amyloidogenic processing of APP leading to intracellular accumulation of newly produced Aßos. Intracellular Aßos participate in synaptic dysfunctions as shown by pharmacological inhibition of APP processing or by intraneuronal infusion of an antibody raised against Aßos. Furthermore, we provide evidence that following APP processing, extracellular release of Aßos mediates the propagation of the synaptic pathology characterized by a decreased spine density of neighboring healthy neurons in an APP-dependent manner. Together, our data unveil a complementary role for Aßos in AD, while intracellular Aßos alter synaptic function, extracellular Aßos promote a vicious cycle that propagates synaptic pathology from diseased to healthy neurons.SIGNIFICANCE STATEMENT Here we provide the proof that a vicious cycle between extracellular and intracellular pools of Aß oligomers (Aßos) is required for the spreading of Alzheimer's disease (AD) pathology. We showed that extracellular Aßos propagate excitatory synaptic alterations by promoting amyloid precursor protein (APP) processing. Our results also suggest that subsequent to APP cleavage two pools of Aßos are produced. One pool accumulates inside the cytosol, inducing the loss of synaptic plasticity potential. The other pool is released into the extracellular space and contributes to the propagation of the pathology from diseased to healthy neurons. Pharmacological strategies targeting the proteolytic cleavage of APP disrupt the relationship between extracellular and intracellular Aß, providing a therapeutic approach for the disease.


Assuntos
Peptídeos beta-Amiloides/farmacologia , Precursor de Proteína beta-Amiloide/metabolismo , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/metabolismo , Sinapses/efeitos dos fármacos , Precursor de Proteína beta-Amiloide/antagonistas & inibidores , Animais , Anticorpos Bloqueadores/farmacologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Espaço Extracelular/efeitos dos fármacos , Espaço Extracelular/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Histidina/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/efeitos dos fármacos , Técnicas de Patch-Clamp , Cultura Primária de Células , Transmissão Sináptica/efeitos dos fármacos
17.
J Neurosci ; 40(19): 3707-3719, 2020 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-32269108

RESUMO

Calcineurin inhibitors, such as tacrolimus (FK506) and cyclosporine, are widely used as standard immunosuppressants in organ transplantation recipients. However, these drugs can cause severe pain in patients, commonly referred to as calcineurin inhibitor-induced pain syndrome (CIPS). Although calcineurin inhibition increases NMDAR activity in the spinal cord, the underlying mechanism remains enigmatic. Using an animal model of CIPS, we found that systemic administration of FK506 in male and female mice significantly increased the amount of α2δ-1-GluN1 complexes in the spinal cord and the level of α2δ-1-bound GluN1 proteins in spinal synaptosomes. Treatment with FK506 significantly increased the frequency of mEPSCs and the amplitudes of monosynaptic EPSCs evoked from the dorsal root and puff NMDAR currents in spinal dorsal horn neurons. Inhibiting α2δ-1 with gabapentin or disrupting the α2δ-1-NMDAR interaction with α2δ-1Tat peptide completely reversed the effects of FK506. In α2δ-1 gene KO mice, treatment with FK506 failed to increase the frequency of NMDAR-mediated mEPSCs and the amplitudes of evoked EPSCs and puff NMDAR currents in spinal dorsal horn neurons. Furthermore, systemic administration of gabapentin or intrathecal injection of α2δ-1Tat peptide reversed thermal and mechanical hypersensitivity in FK506-treated mice. In addition, genetically deleting GluN1 in dorsal root ganglion neurons or α2δ-1 genetic KO similarly attenuated FK506-induced thermal and mechanical hypersensitivity. Together, our findings indicate that α2δ-1-bound NMDARs mediate calcineurin inhibitor-induced tonic activation of presynaptic and postsynaptic NMDARs at the spinal cord level and that presynaptic NMDARs play a prominent role in the development of CIPS.SIGNIFICANCE STATEMENT Calcineurin inhibitors are immunosuppressants used to prevent rejection of transplanted organs and tissues. However, these drugs can cause severe, unexplained pain. We showed that calcineurin inhibition enhances physical interaction between α2δ-1 and NMDARs and their synaptic trafficking in the spinal cord. α2δ-1 is essential for calcineurin inhibitor-induced aberrant activation of presynaptic and postsynaptic NMDARs in the spinal cord. Furthermore, inhibiting α2δ-1 or disrupting α2δ-1-NMDAR interaction reduces calcineurin inhibitor-induced pain hypersensitivity. Eliminating NMDARs in primary sensory neurons or α2δ-1 KO also attenuates calcineurin inhibitor-induced pain hypersensitivity. This new information extends our mechanistic understanding of the role of endogenous calcineurin in regulating synaptic plasticity and nociceptive transmission and suggests new strategies for treating this painful condition.


Assuntos
Inibidores de Calcineurina/toxicidade , Canais de Cálcio/metabolismo , Hiperalgesia/induzido quimicamente , Hiperalgesia/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Feminino , Masculino , Camundongos , Plasticidade Neuronal/efeitos dos fármacos , Plasticidade Neuronal/fisiologia , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo
18.
Neurobiol Aging ; 91: 66-75, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32224066

RESUMO

Cognitive impairments and circadian rhythm disorders are the main clinical manifestations of Alzheimer's disease (AD). Orexin has been reported as abnormally elevated in the cerebrospinal fluid of AD patients, accompanied with cognitive impairments. Our recent research revealed that suvorexant, a dual orexin receptor antagonist, could improve behavioral circadian rhythm disorders in 9-month-old APP/PS1 mice. Here we further observed whether suvorexant could ameliorate the cognitive decline in APP/PS1 mice by using behavioral tests, and investigated the possible mechanisms by in vivo electrophysiological recording, western blot, and immunochemistry. The results showed that suvorexant treatment effectively ameliorated the cognitive impairments, alleviated in vivo hippocampal long-term potentiation suppression, restored the circadian phosphorylated CREB expression in the hippocampus, and reduced amyloid-ß protein deposition in the hippocampus and cortex in APP/PS1 mice. These results indicate that the neuroprotective effects of suvorexant against AD are involved in the reduction of amyloid-ß plaques, improvement of synaptic plasticity, and circadian expression of phosphorylated CREB, suggesting that suvorexant could be beneficial to the prevention and treatment of AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Azepinas/farmacologia , Azepinas/uso terapêutico , Transtornos Cronobiológicos/tratamento farmacológico , Disfunção Cognitiva/tratamento farmacológico , Neuroprostanos , Antagonistas dos Receptores de Orexina , Triazóis/farmacologia , Triazóis/uso terapêutico , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/complicações , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/metabolismo , Animais , Transtornos Cronobiológicos/etiologia , Disfunção Cognitiva/líquido cefalorraquidiano , Disfunção Cognitiva/etiologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Modelos Animais de Doenças , Expressão Gênica/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Potenciação de Longa Duração/efeitos dos fármacos , Camundongos Transgênicos , Plasticidade Neuronal/efeitos dos fármacos , Orexinas/líquido cefalorraquidiano
19.
J Neurosci ; 40(16): 3231-3249, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-32144180

RESUMO

Endogenous neuropeptide Y (NPY) and corticotrophin-releasing factor (CRF) modulate the responses of the basolateral amygdala (BLA) to stress and are associated with the development of stress resilience and vulnerability, respectively. We characterized persistent effects of repeated NPY and CRF treatment on the structure and function of BLA principal neurons in a novel organotypic slice culture (OTC) model of male rat BLA, and examined the contributions of specific NPY receptor subtypes to these neural and behavioral effects. In BLA principal neurons within the OTCs, repeated NPY treatment caused persistent attenuation of excitatory input and induced dendritic hypotrophy via Y5 receptor activation; conversely, CRF increased excitatory input and induced hypertrophy of BLA principal neurons. Repeated treatment of OTCs with NPY followed by an identical treatment with CRF, or vice versa, inhibited or reversed all structural changes in OTCs. These structural responses to NPY or CRF required calcineurin or CaMKII, respectively. Finally, repeated intra-BLA injections of NPY or a Y5 receptor agonist increased social interaction, a validated behavior for anxiety, and recapitulated structural changes in BLA neurons seen in OTCs, while a Y5 receptor antagonist prevented NPY's effects both on behavior and on structure. These results implicate the Y5 receptor in the long-term, anxiolytic-like effects of NPY in the BLA, consistent with an intrinsic role in stress buffering, and highlight a remarkable mechanism by which BLA neurons may adapt to different levels of stress. Moreover, BLA OTCs offer a robust model to study mechanisms associated with resilience and vulnerability to stress in BLA.SIGNIFICANCE STATEMENT Within the basolateral amygdala (BLA), neuropeptide Y (NPY) is associated with buffering the neural stress response induced by corticotropin releasing factor, and promoting stress resilience. We used a novel organotypic slice culture model of BLA, complemented with in vivo studies, to examine the cellular mechanisms associated with the actions of NPY. In organotypic slice cultures, repeated NPY treatment reduces the complexity of the dendritic extent of anxiogenic BLA principal neurons, making them less excitable. NPY, via activation of Y5 receptors, additionally inhibits and reverses the increases in dendritic extent and excitability induced by the stress hormone, corticotropin releasing factor. This NPY-mediated neuroplasticity indicates that resilience or vulnerability to stress may thus involve neuropeptide-mediated dendritic remodeling in BLA principal neurons.


Assuntos
Complexo Nuclear Basolateral da Amígdala/efeitos dos fármacos , Hormônio Liberador da Corticotropina/farmacologia , Dendritos/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Neuropeptídeo Y/farmacologia , Receptores de Neuropeptídeo Y/agonistas , Comportamento Social , Animais , Complexo Nuclear Basolateral da Amígdala/metabolismo , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Calcineurina/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Dendritos/metabolismo , Masculino , Plasticidade Neuronal/fisiologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Ratos , Ratos Sprague-Dawley , Receptores de Neuropeptídeo Y/metabolismo , Resiliência Psicológica
20.
Pharmacol Rev ; 72(2): 439-465, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32139613

RESUMO

Recent studies have strived to find an association between rapid antidepressant effects and a specific subset of pharmacological targets and molecular pathways. Here, we propose a broader hypothesis of encoding, consolidation, and renormalization in depression (ENCORE-D), which suggests that, fundamentally, rapid and sustained antidepressant effects rely on intrinsic homeostatic mechanisms evoked as a response to the acute pharmacological or physiologic effects triggered by the treatment. We review evidence that supports the notion that various treatments with a rapid onset of action, such as ketamine, electroconvulsive therapy, and sleep deprivation, share the ability to acutely excite cortical networks, which increases synaptic potentiation, alters patterns of functional connectivity, and ameliorates depressive symptoms. We proceed to examine how the initial effects are short-lived and, as such, require both consolidation during wake and maintenance throughout sleep to remain sustained. Here, we incorporate elements from the synaptic homeostasis hypothesis and theorize that the fundamental mechanisms of synaptic plasticity and sleep, particularly the homeostatic emergence of slow-wave electroencephalogram activity and the renormalization of synaptic strength, are at the center of sustained antidepressant effects. We conclude by discussing the various implications of the ENCORE-D hypothesis and offer several considerations for future experimental and clinical research. SIGNIFICANCE STATEMENT: Proposed molecular perspectives of rapid antidepressant effects fail to appreciate the temporal distribution of the effects of ketamine on cortical excitation and plasticity as well as the prolonged influence on depressive symptoms. The encoding, consolidation, and renormalization in depression hypothesis proposes that the lasting clinical effects can be best explained by adaptive functional and structural alterations in neural circuitries set in motion in response to the acute pharmacological effects of ketamine (i.e., changes evoked during the engagement of receptor targets such as N-methyl-D-aspartate receptors) or other putative rapid-acting antidepressants. The present hypothesis opens a completely new avenue for conceptualizing and targeting brain mechanisms that are important for antidepressant effects wherein sleep and synaptic homeostasis are at the center stage.


Assuntos
Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Depressão/tratamento farmacológico , Plasticidade Neuronal/efeitos dos fármacos , Sono/efeitos dos fármacos , Animais , Depressão/patologia , Depressão/fisiopatologia , Homeostase/efeitos dos fármacos , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto
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