RESUMEN
Early Alzheimer's disease (AD) affects the brain non-uniformly, causing hippocampal memory deficits long before wide-spread brain degeneration becomes evident. Here we addressed whether mossy fiber inputs from the dentate gyrus onto CA3 principal cells are affected in an AD mouse model before amyloid ß plaque deposition. We recorded from CA3 pyramidal cells in a slice preparation from 6-month-old male APP/PS1 mice, and studied synaptic properties and intrinsic excitability. In parallel we performed a morphometric analysis of mossy fiber synapses following viral based labeling and 3D-reconstruction. We found that the basal structural and functional properties as well as presynaptic short-term plasticity at mossy fiber synapses are unaltered at 6 months in APP/PS1 mice. However, transient potentiation of synaptic transmission mediated by activity-dependent release of lipids was abolished. Whereas the presynaptic form of mossy fiber long-term potentiation (LTP) was not affected, the postsynaptic LTP of NMDAR-EPSCs was reduced. In addition, we also report an impairment in feedforward inhibition in CA3 pyramidal cells. This study, together with our previous work describing deficits at CA3-CA3 synapses, provides evidence that early AD affects synapses in a projection-dependent manner at the level of a single neuronal population.SIGNIFICANCE STATEMENT Because loss of episodic memory is considered the cognitive hallmark of Alzheimer's disease (AD), it is important to study whether synaptic circuits involved in the encoding of episodic memory are compromised in AD mouse models. Here we probe alterations in the synaptic connections between the dentate gyrus and CA3, which are thought to be critical for enabling episodic memories to be formed and stored in CA3. We found that forms of synaptic plasticity specific to these synaptic connections are markedly impaired at an early stage in a mouse model of AD, before deposition of ß amyloid plaques. Together with previous work describing deficits at CA3-CA3 synapses, we provide evidence that early AD affects synapses in an input-dependent manner within a single neuronal population.
Asunto(s)
Enfermedad de Alzheimer/fisiopatología , Región CA3 Hipocampal/fisiopatología , Fibras Musgosas del Hipocampo/fisiopatología , Células Piramidales/fisiología , Sinapsis/patología , Enfermedad de Alzheimer/patología , Animales , Modelos Animales de Enfermedad , Potenciales Postsinápticos Excitadores/fisiología , Potenciación a Largo Plazo/fisiología , Masculino , Ratones , Sinapsis/fisiologíaRESUMEN
Autism spectrum disorders (ASD) are a set of complex neurodevelopmental disorders for which there is currently no targeted therapeutic approach. It is thought that alterations of genes regulating migration and synapse formation during development affect neural circuit formation and result in aberrant connectivity within distinct circuits that underlie abnormal behaviors. However, it is unknown whether deviant developmental trajectories are circuit-specific for a given autism risk-gene. We used MRI to probe changes in functional and structural connectivity from childhood to adulthood in Fragile-X (Fmr1-/y) and contactin-associated (CNTNAP2-/-) knockout mice. Young Fmr1-/y mice (30 days postnatal) presented with a robust hypoconnectivity phenotype in corticocortico and corticostriatal circuits in areas associated with sensory information processing, which was maintained until adulthood. Conversely, only small differences in hippocampal and striatal areas were present during early postnatal development in CNTNAP2-/- mice, while major connectivity deficits in prefrontal and limbic pathways developed between adolescence and adulthood. These findings are supported by viral tracing and electron micrograph approaches and define 2 clearly distinct connectivity endophenotypes within the autism spectrum. We conclude that the genetic background of ASD strongly influences which circuits are most affected, the nature of the phenotype, and the developmental time course of the associated changes.
Asunto(s)
Trastorno Autístico , Encéfalo/crecimiento & desarrollo , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/genética , Proteínas de la Membrana/genética , Proteínas del Tejido Nervioso/genética , Vías Nerviosas/crecimiento & desarrollo , Vías Nerviosas/patología , Factores de Edad , Animales , Animales Recién Nacidos , Trastorno Autístico/complicaciones , Trastorno Autístico/genética , Trastorno Autístico/patología , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Encéfalo/ultraestructura , Mapeo Encefálico , Conectoma , Modelos Animales de Enfermedad , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/metabolismo , Procesamiento de Imagen Asistido por Computador , Proteínas Luminiscentes/genética , Proteínas Luminiscentes/metabolismo , Imagen por Resonancia Magnética , Proteínas de la Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas del Tejido Nervioso/metabolismo , Vías Nerviosas/diagnóstico por imagen , Oxígeno/sangre , Transducción Genética , Proteína Fluorescente RojaRESUMEN
Synaptic plasticity in the autoassociative network of recurrent connections among hippocampal CA3 pyramidal cells is thought to enable the storage of episodic memory. Impaired episodic memory is an early manifestation of cognitive deficits in Alzheimer's disease (AD). In the APP/PS1 mouse model of AD amyloidosis, we show that associative long-term synaptic potentiation (LTP) is abolished in CA3 pyramidal cells at an early stage. This is caused by activation of upregulated neuronal adenosine A2A receptors (A2AR) rather than by dysregulation of NMDAR signalling or altered dendritic spine morphology. Neutralization of A2AR by acute pharmacological inhibition, or downregulation driven by shRNA interference in a single postsynaptic neuron restore associative CA3 LTP. Accordingly, treatment with A2AR antagonists reverts one-trial memory deficits. These results provide mechanistic support to encourage testing the therapeutic efficacy of A2AR antagonists in early AD patients.
Asunto(s)
Antagonistas del Receptor de Adenosina A2/farmacología , Enfermedad de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Fármacos Neuroprotectores/farmacología , Presenilina-1/genética , Receptor de Adenosina A2A/genética , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/fisiopatología , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Región CA3 Hipocampal/efectos de los fármacos , Región CA3 Hipocampal/metabolismo , Región CA3 Hipocampal/patología , Espinas Dendríticas/efectos de los fármacos , Espinas Dendríticas/metabolismo , Espinas Dendríticas/ultraestructura , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Humanos , Potenciación a Largo Plazo , Memoria Episódica , Ratones , Ratones Transgénicos , Presenilina-1/metabolismo , Pirimidinas/farmacología , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Receptor de Adenosina A2A/metabolismo , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Transducción de Señal , Sinapsis/efectos de los fármacos , Sinapsis/metabolismo , Sinapsis/ultraestructura , Triazinas/farmacología , Triazoles/farmacologíaRESUMEN
Glycoprotein-deleted rabies virus (RABV ∆G) is a powerful tool for the analysis of neural circuits. Here, we demonstrate the utility of an anterograde RABV ∆G variant for novel neuroanatomical approaches involving either bulk or sparse neuronal populations. This technology exploits the unique features of RABV ∆G vectors, namely autonomous, rapid high-level expression of transgenes, and limited cytotoxicity. Our vector permits the unambiguous long-range and fine-scale tracing of the entire axonal arbor of individual neurons throughout the brain. Notably, this level of labeling can be achieved following infection with a single viral particle. The vector is effective over a range of ages (>14 months) aiding the studies of neurodegenerative disorders or aging, and infects numerous cell types in all brain regions tested. Lastly, it can also be readily combined with retrograde RABV ∆G variants. Together with other modern technologies, this tool provides new possibilities for the investigation of the anatomy and physiology of neural circuits.