RESUMEN
Mitochondria are integrative hubs central to cellular adaptive pathways. Such pathways are critical in highly differentiated postmitotic neurons, the plasticity of which sustains brain function. Consequently, defects in mitochondria and in their dynamics appear instrumental in neurodegenerative diseases and may also participate in cognitive impairments. To directly test this hypothesis, we analyzed cognitive performances in a mouse mitochondria-based disease model, because of haploinsufficiency in the mitochondrial optic atrophy type 1 (OPA1) protein involved in mitochondrial dynamics. In males, we evaluated adult hippocampal neurogenesis parameters using immunohistochemistry. We performed a battery of tests to assess basal behavioral characteristics and cognitive performances, and tested putative treatments. While in dominant optic atrophy (DOA) mouse models, the known main symptoms are late onset visual deficits, we discovered early impairments in hippocampus-dependent spatial memory attributable to defects in adult neurogenesis. Moreover, less connected adult-born hippocampal neurons showed a decrease in mitochondrial content. Remarkably, voluntary exercise or pharmacological treatment targeting mitochondrial dynamics restored spatial memory in DOA mice. Altogether, our study identifies a crucial role for OPA1-dependent mitochondrial functions in adult neurogenesis, and thus in hippocampal-dependent cognitive functions. More generally, our findings show that adult neurogenesis is highly sensitive to mild mitochondrial defects, generating impairments in spatial memory that can be detected at an early stage and counterbalanced by physical exercise and pharmacological targeting of mitochondrial dynamics. Thus, amplification of mitochondrial function at an early stage appears beneficial for late-onset neurodegenerative diseases.
Asunto(s)
Enfermedades Neurodegenerativas , Atrofia Óptica Autosómica Dominante , Masculino , Ratones , Animales , Memoria Espacial , Mitocondrias/metabolismo , Neurogénesis/fisiología , Neuronas/metabolismo , Atrofia Óptica Autosómica Dominante/metabolismo , Hipocampo/metabolismo , Enfermedades Neurodegenerativas/metabolismoRESUMEN
Dominant optic atrophy (DOA) is mainly caused by OPA1 mutations and is characterized by the degeneration of retinal ganglion cells (RGCs), whose axons form the optic nerve. The penetrance of DOA is incomplete and the disease is marked by highly variable expressivity, ranging from asymptomatic patients to some who are totally blind or who suffer from multisystemic effects. No clear genotype-phenotype correlation has been established to date. Taken together, these observations point toward the existence of modifying genetic and/or environmental factors that modulate disease severity. Here, we investigated the influence of genetic background on DOA expressivity by switching the previously described DOA mouse model bearing the c.1065 + 5G â A Opa1 mutation from mixed C3H; C57BL/6 J to a pure C57BL/6 J background. We no longer observed retinal and optic nerve abnormalities; the findings indicated no degeneration, but rather a sex-dependent negative effect on RGC connectivity. This highlights the fact that RGC synaptic alteration might precede neuronal death, as has been proposed in other neurodegenerative diseases, providing new clinical considerations for early diagnosis as well as a new therapeutic window for DOA. Furthermore, our results demonstrate the importance of secondary genetic factors in the variability of DOA expressivity and offer a model for screening for aggravating environmental and genetic factors.
RESUMEN
Chromatin acetylation, a critical regulator of synaptic plasticity and memory processes, is thought to be altered in neurodegenerative diseases. Here, we demonstrate that spatial memory and plasticity (LTD, dendritic spine formation) deficits can be restored in a mouse model of tauopathy following treatment with CSP-TTK21, a small-molecule activator of CBP/p300 histone acetyltransferases (HAT). At the transcriptional level, CSP-TTK21 re-established half of the hippocampal transcriptome in learning mice, likely through increased expression of neuronal activity genes and memory enhancers. At the epigenomic level, the hippocampus of tauopathic mice showed a significant decrease in H2B but not H3K27 acetylation levels, both marks co-localizing at TSS and CBP enhancers. Importantly, CSP-TTK21 treatment increased H2B acetylation levels at decreased peaks, CBP enhancers, and TSS, including genes associated with plasticity and neuronal functions, overall providing a 95% rescue of the H2B acetylome in tauopathic mice. This study is the first to provide in vivo proof-of-concept evidence that CBP/p300 HAT activation efficiently reverses epigenetic, transcriptional, synaptic plasticity, and behavioral deficits associated with Alzheimer's disease lesions in mice.
Asunto(s)
Activadores de Enzimas/farmacología , Memoria , Plasticidad Neuronal/efectos de los fármacos , Tauopatías/fisiopatología , Factores de Transcripción p300-CBP/metabolismo , Acetilación/efectos de los fármacos , Animales , Modelos Animales de Enfermedad , Epigénesis Genética/efectos de los fármacos , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Histonas/metabolismo , Inflamación/patología , Memoria/efectos de los fármacos , Ratones Endogámicos C57BL , Ratones Transgénicos , Tauopatías/genética , Transcriptoma/efectos de los fármacos , Transcriptoma/genética , TransgenesRESUMEN
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory loss and impaired cognitive functions. The higher incidence of AD among women indicates that sex is one of the main risk factor for developing the disease. Using the transgenic amyloid precursor protein × presenilin 1 (APPxPS1) mouse model of AD, we investigated sex inequality with regards to memory capacities and hippocampal plasticity. We report that spatial memory is strongly affected in APPxPS1 females while remarkably spared in males, at all ages tested. Given the contribution of adult neurogenesis to hippocampal-dependent memory processes, we examined whether impaired neurogenesis could account for age-related decline of memory functions in APPxPS1 mice. We show that not only limited numbers of new neurons are generated in these mice, but also, that new granule cells display reduced capacity for synaptic connectivity, a default that is exacerbated in females. Moreover, high densities of hypertrophic astrocytes are observed in the dentate gyrus of APPxPS1 females specifically. By revealing sex-dependent hippocampal alterations, our data may provide causal explanation to APPxPS1 females' memory deficits.
Asunto(s)
Envejecimiento/fisiología , Envejecimiento/psicología , Enfermedad de Alzheimer/fisiopatología , Hipocampo/fisiopatología , Plasticidad Neuronal/fisiología , Caracteres Sexuales , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/psicología , Animales , Astrocitos/patología , Giro Dentado/citología , Modelos Animales de Enfermedad , Femenino , Hipocampo/patología , Humanos , Hipertrofia , Masculino , Memoria/fisiología , Ratones Transgénicos , Neurogénesis/fisiología , Neuronas/fisiología , Factores de Riesgo , Transmisión Sináptica/fisiologíaRESUMEN
During memory formation, structural rearrangements of dendritic spines provide a mean to durably modulate synaptic connectivity within neuronal networks. New neurons generated throughout the adult life in the dentate gyrus of the hippocampus contribute to learning and memory. As these neurons become incorporated into the network, they generate huge numbers of new connections that modify hippocampal circuitry and functioning. However, it is yet unclear as to how the dynamic process of memory formation influences their synaptic integration into neuronal circuits. New memories are established according to a multistep process during which new information is first acquired and then consolidated to form a stable memory trace. Upon recall, memory is transiently destabilized and vulnerable to modification. Using contextual fear conditioning, we found that learning was associated with an acceleration of dendritic spines formation of adult-born neurons, and that spine connectivity becomes strengthened after memory consolidation. Moreover, we observed that afferent connectivity onto adult-born neurons is enhanced after memory retrieval, while extinction training induces a change of spine shapes. Together, these findings reveal that the neuronal activity supporting memory processes strongly influences the structural dendritic integration of adult-born neurons into pre-existing neuronal circuits. Such change of afferent connectivity is likely to impact the overall wiring of hippocampal network, and consequently, to regulate hippocampal function.
Asunto(s)
Conducta Animal , Hipocampo/fisiología , Memoria , Neurogénesis , Neuronas/fisiología , Animales , Condicionamiento Psicológico , Espinas Dendríticas/metabolismo , Espinas Dendríticas/fisiología , Estimulación Eléctrica , Miedo , Genes Reporteros , Proteínas Fluorescentes Verdes/biosíntesis , Proteínas Fluorescentes Verdes/genética , Hipocampo/citología , Hipocampo/metabolismo , Proteínas Luminiscentes/biosíntesis , Proteínas Luminiscentes/genética , Masculino , Ratones Endogámicos C57BL , Vías Nerviosas/metabolismo , Vías Nerviosas/fisiología , Técnicas de Trazados de Vías Neuroanatómicas , Neuronas/metabolismo , Factores de Tiempo , Proteína Fluorescente RojaRESUMEN
AIM: Chronic consumption of a high-fat (HF) diet contributes to peripheral insulin resistance and elevated plasma corticosterone. However, the effect of HF consumption on the neurofunctional insulin receptors and neuronal corticosterone level is unclear. We tested the hypothesis that HF consumption can lead to peripheral insulin resistance, elevated neuronal corticosterone, and impaired neuronal responses to insulin. MAIN METHODS: Male Wistar rats were fed with normal diet or HF diet for 4, 8 or 12weeks. At the end of each dietary period, plasma was collected for investigating peripheral insulin resistance parameters and corticosterone. Brains were then rapidly removed for studying the function of neuronal insulin receptors (IRs) by extracellular recording in CA1 hippocampus, neuronal IR signaling by immunoblot technique and neuronal corticosterone. KEY FINDINGS: Elevated plasma corticosterone level was initially seen in 4-week HF-fed rats. Peripheral insulin resistance developed at 8-week HF-fed rats. However, the elevated neuronal corticosterone level was found at 12-week HF consumption. The neuronal IR response demonstrated by insulin-mediated long-term depression in CA1 hippocampus was diminished in 12-week HF-fed rats. The phosphorylation levels of neuronal IR, IR substrate 1 and Akt/PKB were decreased in 12-week HF-fed rats with no change in these proteins. There was a correlation among peripheral insulin resistance, neuronal stress (elevated neuronal corticosterone), and neuronal insulin resistance in HF group. SIGNIFICANCE: Our findings suggest that HF consumption can lead to the elevation of corticosterone and peripheral insulin resistance, which could contribute to neuronal insulin resistance and neuronal stress.
Asunto(s)
Región CA1 Hipocampal/metabolismo , Corticosterona/metabolismo , Grasas de la Dieta/efectos adversos , Resistencia a la Insulina , Neuronas/metabolismo , Receptor de Insulina/fisiología , Animales , Corticosterona/sangre , Dieta , Grasas de la Dieta/administración & dosificación , Electroforesis en Gel de Poliacrilamida , Prueba de Tolerancia a la Glucosa , Immunoblotting , Inmunoprecipitación , Proteínas Sustrato del Receptor de Insulina/metabolismo , Masculino , Fosforilación , Ratas , Ratas Wistar , Receptor de Insulina/metabolismo , Factores de TiempoRESUMEN
The benefits of omega-3 (ie, eicosapentaenoic acid and docosahexaenoic acid [DHA]) and omega-6 (ie, linoleic acid and arachidonic acid [AA]) fatty acids on reducing cardiac mortality are still debated. In this study, we tested the hypothesis that high levels of omega-3 and omega-6 fatty acids in heart tissues are associated with low cardiac mortality in Thai cadavers. One hundred fresh cadavers were examined in this study. The cause of death, history of coronary heart disease (CHD), and fish consumption habits were obtained from death certificates, cadaver medical record profiles, and a questionnaire to a person who lived with the subject before death. In each cadaver, biopsies of cardiac tissues were taken from the interventricular septum for measurement of fatty acid. Of the 100 cadavers (average age, 69 +/- 13 years), 60 were men. The frequency of fish consumption was directly associated with omega-3 and omega-6 fatty acids in heart tissues (P < .01). History of CHD and cause of death (cardiac vs noncardiac) were not significantly associated with levels of omega-3 or omega-6 fatty acids. However, in cadavers with a history of CHD, high levels of omega-3 and omega-6, particularly DHA and AA, were associated with low cardiac mortality (P < .05). Fish consumption is associated with levels of omega-3 and omega-6 fatty acids in heart tissues. Although omega-3 and omega-6 fatty acids are not associated with cardiac mortality in the overall studied population, their low levels (especially DHA and AA) in heart tissues are associated with high cardiac mortality in cadavers with a history of CHD.