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Sci Rep ; 8(1): 13046, 2018 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-30158644


Reelin protein (RELN), an extracellular matrix protein, plays multiple roles that range from embryonic neuronal migration to spine formation in the adult brain. Results from genetic studies have suggested that RELN is associated with the risk of psychiatric disorders, including schizophrenia (SCZ). We previously identified a novel exonic deletion of RELN in a patient with SCZ. High-resolution copy number variation analysis revealed that this deletion included exons 52 to 58, which truncated the RELN in a similar manner to the Reln Orleans mutation (Relnrl-Orl). We examined the clinical features of this patient and confirmed a decreased serum level of RELN. To elucidate the pathophysiological role of the exonic deletion of RELN in SCZ, we conducted behavioral and neurochemical analyses using heterozygous Relnrl-Orl/+ mice. These mice exhibited abnormalities in anxiety, social behavior, and motor learning; the deficits in motor learning were ameliorated by antipsychotics. Methamphetamine-induced hyperactivity and dopamine release were significantly reduced in the Relnrl-Orl/+ mice. In addition, the levels of GABAergic markers were decreased in the brain of these mice. Taken together, our results suggest that the exonic deletion of RELN plays a pathological role, implicating functional changes in the dopaminergic and GABAergic systems, in the pathophysiology of SCZ.

Glia ; 66(5): 1034-1052, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29380419


In the central nervous system, major histocompatibility complex class I (MHCI) molecules are mainly expressed in neurons, and neuronal MHCI have roles in synapse elimination and plasticity. However, the pathophysiological significance of astroglial MHCI remains unclear. We herein demonstrate that MHCI expression is up-regulated in astrocytes in the medial prefrontal cortex (mPFC) following systemic immune activation by an intraperitoneal injection of polyinosinic-polycytidylic acid (polyI:C) or hydrodynamic interferon (IFN)-γ gene delivery in male C57/BL6J mice. In cultured astrocytes, MHCI/H-2D largely co-localized with exosomes. To investigate the role of astroglial MHCI, H-2D, or sH-2D was expressed in the mPFC of male C57/BL6J mice using an adeno-associated virus vector under the control of a glial fibrillary acidic protein promoter. The expression of astroglial MHCI in the mPFC impaired sociability and recognition memory in mice. Regarding neuropathological changes, MHCI expression in astrocytes significantly activated microglial cells, decreased parvalbumin-positive cell numbers, and reduced dendritic spine density in the mPFC. A treatment with GW4869 that impairs exosome synthesis ameliorated these behavioral and neuropathological changes. These results suggest that the overexpression of MHCI in astrocytes affects microglial proliferation as well as neuronal numbers and spine densities, thereby leading to social and cognitive deficits in mice, possibly via exosomes created by astrocytes.

Astrócitos/imunologia , Genes MHC Classe I/fisiologia , Inflamação/metabolismo , Recognição (Psicologia)/fisiologia , Comportamento Social , Animais , Astrócitos/patologia , Comportamento Animal/fisiologia , Células Cultivadas , Espinhas Dendríticas/imunologia , Espinhas Dendríticas/patologia , Exossomos/imunologia , Exossomos/patologia , Hipocampo/imunologia , Hipocampo/patologia , Inflamação/patologia , Inflamação/psicologia , Interneurônios/imunologia , Interneurônios/patologia , Masculino , Camundongos Endogâmicos C57BL , Microglia/imunologia , Microglia/patologia , Córtex Pré-Frontal/imunologia , Córtex Pré-Frontal/patologia , RNA Mensageiro/metabolismo
J Pharmacol Sci ; 127(4): 439-45, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25850380


Antipsychotics are often used in conjunction with anti-Alzheimer drugs to treat the behavioral and psychological symptoms of dementia (BPSD). Here, we examined the effects of cholinesterase inhibitors (ChEIs), donepezil and galantamine, on antipsychotic-induced extrapyramidal side effects (EPS) in mice. The effects of serotonergic agents on the EPS drug interaction were also evaluated. Donepezil (0.3-3 mg/kg) did not induce EPS signs by itself; however, it significantly potentiated bradykinesia induction with a low dose of haloperidol (0.5 mg/kg) in dose-dependent and synergistic manners. Galantamine (0.3-3 mg/kg) elicited mild bradykinesia at a high dose and dose-dependently augmented haloperidol-induced bradykinesia. The EPS potentiation by galantamine was blocked by trihexyphenidyl (a muscarinic antagonist), but not by mecamylamine (a nicotinic antagonist). In addition, the bradykinesia potentiation by galantamine was significantly reduced by (±)-8-hydroxy-2-(di-n-propylamino)-tetralin (a 5-HT1A agonist), ritanserin (a 5-HT2 antagonist), and SB-258585 (a 5-HT6 antagonist). The present results give us a caution for the antipsychotics and ChEIs interaction in inducing EPS in the treatment of BPSD. In addition, second generation antipsychotics, which can stimulate 5-HT1A receptors or antagonize 5-HT2 and 5-HT6 receptors, seem to be favorable as an adjunctive therapy for BPSD.

Antipsicóticos/efeitos adversos , Doenças dos Gânglios da Base/induzido quimicamente , Inibidores da Colinesterase/efeitos adversos , Galantamina/efeitos adversos , Haloperidol/efeitos adversos , Indanos/efeitos adversos , Nootrópicos/efeitos adversos , Piperidinas/efeitos adversos , Doença de Alzheimer/tratamento farmacológico , Animais , Donepezila , Relação Dose-Resposta a Droga , Interações de Medicamentos , Hipocinesia/induzido quimicamente , Masculino , Camundongos Endogâmicos , Receptor 5-HT1A de Serotonina , Receptores Muscarínicos , Serotoninérgicos/efeitos adversos
Artigo em Inglês | MEDLINE | ID: mdl-23838274


We previously demonstrated that 5-HT stimulants, including selective serotonin reuptake inhibitors (SSRIs), potentiated antipsychotic-induced extrapyramidal symptoms (EPS) by stimulating 5-HT2A/2C, 5-HT3 and 5-HT6 receptors. Here, we studied the effects of the 5-HT1A agonist (±)-8-hydroxy-2-(di-n-propylamino) tetralin ((±)-8-OH-DPAT) on the fluoxetine enhancement of EPS (i.e., bradykinesia and catalepsy) to determine if the 5-HT1A agonist can counteract the serotonergic potentiation of EPS. Fluoxetine did not induce EPS signs by itself, but significantly potentiated haloperidol-induced bradykinesia in mice. (±)-8-OH-DPAT (0.1-1mg/kg, i.p.) significantly attenuated the fluoxetine enhancement of haloperidol-induced bradykinesia in a dose-dependent manner. A selective 5-HT1A antagonist (s)-WAY-100135 completely reversed the anti-EPS action of (±)-8-OH-DPAT. Microinjection studies using rats revealed that local application of (±)-8-OH-DPAT into the dorsolateral striatum or the motor cortex significantly diminished fluoxetine-enhanced catalepsy. In contrast, (±)-8-OH-DPAT injected into the medial raphe nucleus failed to affect EPS induction. The present results illustrate that 5-HT1A agonist can alleviate the SSRI enhancement of EPS by activating postsynaptic 5-HT1A receptors in the striatum and cerebral cortex.

Doenças dos Gânglios da Base/tratamento farmacológico , Doenças dos Gânglios da Base/metabolismo , Receptor 5-HT1A de Serotonina/metabolismo , Agonistas do Receptor 5-HT1 de Serotonina/administração & dosagem , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Masculino , Camundongos , Microinjeções/métodos , Ratos , Ratos Sprague-Dawley , Antagonistas do Receptor 5-HT1 de Serotonina/administração & dosagem