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  • Dissociation of functional and structural plasticity of dendritic spines during NMDAR and mGluR-dependent long-term synaptic depression in wild-type and fragile X model mice MOLECULAR PSYCHIATRY Thomazeau, A., Bosch, M., Essayan-Perez, S., Barnes, S. A., De Jesus-Cortes, H., Bear, M. F. 2021; 26 (9): 4652-4669


    Many neurodevelopmental disorders are characterized by impaired functional synaptic plasticity and abnormal dendritic spine morphology, but little is known about how these are related. Previous work in the Fmr1-/y mouse model of fragile X (FX) suggests that increased constitutive dendritic protein synthesis yields exaggerated mGluR5-dependent long-term synaptic depression (LTD) in area CA1 of the hippocampus, but an effect on spine structural plasticity remains to be determined. In the current study, we used simultaneous electrophysiology and time-lapse two photon imaging to examine how spines change their structure during LTD induced by activation of mGluRs or NMDA receptors (NMDARs), and how this plasticity is altered in Fmr1-/y mice. We were surprised to find that mGluR activation causes LTD and AMPA receptor internalization, but no spine shrinkage in either wildtype or Fmr1-/y mice. In contrast, NMDAR activation caused spine shrinkage as well as LTD in both genotypes. Spine shrinkage was initiated by non-ionotropic (metabotropic) signaling through NMDARs, and in wild-type mice this structural plasticity required activation of mTORC1 and new protein synthesis. In striking contrast, NMDA-induced spine plasticity in Fmr1-/y mice was no longer dependent on acute activation of mTORC1 or de novo protein synthesis. These findings reveal that the structural consequences of mGluR and metabotropic NMDAR activation differ, and that a brake on spine structural plasticity, normally provided by mTORC1 regulation of protein synthesis, is absent in FX. Increased constitutive protein synthesis in FX appears to modify functional and structural plasticity induced through different glutamate receptors.

    View details for DOI 10.1038/s41380-020-0821-6

    View details for Web of Science ID 000544588500002

    View details for PubMedID 32606374

    View details for PubMedCentralID PMC8095717

  • Modeling Alzheimer's disease with human iPS cells: advancements, lessons, and applications. Neurobiology of disease Essayan-Perez, S. n., Zhou, B. n., Nabet, A. M., Wernig, M. n., Huang, Y. A. 2019: 104503


    One in three people will develop Alzheimer's disease (AD) or another dementia and, despite intense research efforts, treatment options remain inadequate. Understanding the mechanisms of AD pathogenesis remains our principal hurdle to developing effective therapeutics to tackle this looming medical crisis. In light of recent discoveries from whole-genome sequencing and technical advances in humanized models, studying disease risk genes with induced human neural cells presents unprecedented advantages. Here, we first review the current knowledge of the proposed mechanisms underlying AD and focus on modern genetic insights to inform future studies. To highlight the utility of human pluripotent stem cell-based innovations, we then present an update on efforts in recapitulating the pathophysiology by induced neuronal, non-neuronal and a collection of brain cell types, departing from the neuron-centric convention. Lastly, we examine the translational potentials of such approaches, and provide our perspectives on the promise they offer to deepen our understanding of AD pathogenesis and to accelerate the development of intervention strategies for patients and risk carriers.

    View details for DOI 10.1016/j.nbd.2019.104503

    View details for PubMedID 31202913