RESUMO
Parkinson's disease (PD) is a progressive neurological disease, one of the pathological characteristics is a gradual loss of midbrain dopaminergic (mDA) neurons in the substantia nigra pars compacta (SNpc). In animals, PD-like symptoms can be induced by genetic mutations or by neurotoxins such as 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP). It has been reported that deletion of autophagy-related gene 5 (Atg5) in the brain can disrupt neural function and is accompanied by the accumulation of cytoplasmic inclusions. However, the exact role of autophagy in PD etiology has not fully been asserted. In this study, we used tyrosine hydroxylase (TH)-Cre mice to generate conditional knockouts (CKO) with the specific deletion of Atg5 in mDA neurons, and found that adult Atg5 CKO mice contained ubiquitin- and p62-positive inclusions and fewer TH-positive mDA neurons compared with wild-type controls. Interestingly, MPTP-induced loss of mDA neurons was not observed in Atg5 CKO mice. Thus, Atg5-associated autophagy is required for the survival of mDA neurons, and may be involved in MPTP-induced neuronal degeneration.
Assuntos
Proteína 5 Relacionada à Autofagia/genética , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/patologia , Intoxicação por MPTP/genética , Mesencéfalo/efeitos dos fármacos , Animais , Sobrevivência Celular , Neurônios Dopaminérgicos/metabolismo , Intoxicação por MPTP/patologia , Mesencéfalo/metabolismo , Mesencéfalo/patologia , Camundongos Knockout , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
Parkinson's disease (PD) is a neurodegenerative disease caused by a gradual loss of midbrain dopaminergic (mDA) neurons in the substantia nigra pars compacta (SNpc) during aging. 1-Methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) is one of the neurotoxins used widely to induce PD-like symptoms in PD animal models, including rodents and non-human primates. It has been reported that deletion of autophagy-related gene 7 (Atg7) in the brain results in a reduction of mDA neurons in adulthood. In this study, we used tyrosine hydroxylase (TH)-Cre mice to generate conditional knockout (CKO) mice with the specific deletion of Atg7 in mDA neurons. Consistent with previous reports, adult Atg7 CKO mice contained fewer TH-positive mDA neurons compared with wild-type (WT) controls. TH-expressing neurons containing puncta-like structures with p62 and ubiquitin immunoreactivity were observed in the midbrain of Atg7 CKO mice but were not detected in control mice. However, MPTP-induced loss of mDA neurons was not observed in Atg7 CKO mice. Our results indicate that Atg7-involved autophagy is required not only for the survival of mDA neurons in the mouse brain, but also for MPTP-induced mDA neuron degeneration.
Assuntos
Proteína 7 Relacionada à Autofagia/deficiência , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Intoxicação por MPTP/metabolismo , Envelhecimento/efeitos dos fármacos , Envelhecimento/metabolismo , Animais , Autofagia/efeitos dos fármacos , Autofagia/fisiologia , Proteína 7 Relacionada à Autofagia/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Neurônios Dopaminérgicos/patologia , Marcha/efeitos dos fármacos , Marcha/fisiologia , Intoxicação por MPTP/patologia , Mesencéfalo/efeitos dos fármacos , Mesencéfalo/metabolismo , Mesencéfalo/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neuroproteção/efeitos dos fármacos , Neuroproteção/fisiologia , Tirosina 3-Mono-Oxigenase/metabolismo , Ubiquitina/metabolismoRESUMO
Early-life sensory input plays a crucial role in brain development. Although deprivation of orofacial sensory input at perinatal stages disrupts the establishment of the barrel cortex and relevant callosal connections, its long-term effect on adult behavior remains elusive. In this study, we investigated the behavioral phenotypes in adult mice with unilateral transection of the infraorbital nerve (ION) at postnatal day 3 (P3). Although ION-transected mice had normal locomotor activity, motor coordination, olfaction, anxiety-like behaviors, novel object memory, preference for social novelty and sociability, they presented deficits in social memory and spatial memory compared with control mice. In addition, the social memory deficit was associated with reduced oxytocin (OXT) levels in the hypothalamus and could be partially restored by intranasal administration of OXT. Thus, early sensory deprivation does result in behavioral alterations in mice, some of which may be associated with the disruption of oxytocin signaling.
Assuntos
Transtornos da Memória/metabolismo , Transtornos da Memória/fisiopatologia , Ocitocina/metabolismo , Privação Sensorial , Comportamento Social , Animais , Ansiedade/complicações , Ansiedade/fisiopatologia , Comportamento Animal , Hipotálamo/metabolismo , Hipotálamo/fisiopatologia , Aprendizagem em Labirinto , Transtornos da Memória/complicações , Camundongos Endogâmicos C57BL , Atividade Motora , Ocitocina/administração & dosagem , Ocitocina/farmacologia , OlfatoRESUMO
The blood-brain barrier (BBB) is critical to the health of the central nervous system (CNS). The possibility that 5-hydroxytryptamine (5-HT) participates in the alteration of the BBB has been previously demonstrated. Tryptophan hydroxylase 2 (TPH2) is a unique genetic enzyme isoform that catalyzes the rate-limiting step in the biosynthesis of 5-HT in the CNS; however, its role in the permeability changes of the BBB remains unclear. In the present study, TPH2-knockout mice were utilized in the assessment of BBB disruption, as measured by the Evans Blue (EB) extravasation or fluorescein isothiocyanate-albumin leakage assay in the brain. EB was not found to be retained in the brain in the TPH2-knockout mice or the wild-type controls. The results of the study demonstrate that TPH2 knockout has no effect on BBB permeability, indicating that TPH2 and the 5-HT system in the CNS are not sufficient to influence the BBB leakage.
RESUMO
The canonical Wnt signaling pathway is critical for the development of midbrain dopaminergic (DA) neurons, and recent studies have suggested that disruption of this signaling cascade may underlie the pathogenesis of Parkinson's disease (PD). However, the exact role of the canonical Wnt signaling pathway, including low-density lipoprotein receptor-related protein 5 and 6 (LRP5/6) and ß-catenin components, in a mouse model of PD remains unclear. In the present study, the tyrosine hydroxylase (TH)-Cre transgenic mouse line was used to generate mice with the specific knockout of LRP5, LRP6 or ß-catenin in DA neurons. Following inactivation of LRP5, LRP6 or ß-catenin, TH-immunohistochemical staining was performed. The results indicated that ß-catenin is required for the development or maintenance of these neurons; however, LRP5 and LRP6 were found to be dispensable. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice, the depletion of LRP5, LRP6 or ß-catenin was found to be protective for the midbrain DA neurons to a certain extent. These in vivo results provide a novel perspective for the function of the canonical Wnt signaling pathway in a mouse model of PD.