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Dendritic spine pathology in neuropsychiatric disorders

Nature Neuroscience volume 14, pages 285–293 (2011)Cite this article

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Abstract

Substantial progress has been made toward understanding the genetic architecture, cellular substrates, brain circuits and endophenotypic profiles of neuropsychiatric disorders, including autism spectrum disorders (ASD), schizophrenia and Alzheimer's disease. Recent evidence implicates spiny synapses as important substrates of pathogenesis in these disorders. Although synaptic perturbations are not the only alterations relevant for these diseases, understanding the molecular underpinnings of spine pathology may provide insight into their etiologies and may reveal new drug targets. Here we discuss recent neuropathological, genetic, molecular and animal model studies that implicate structural alterations at spiny synapses in the pathogenesis of major neurological disorders, focusing on ASD, schizophrenia and Alzheimer's disease as representatives of these categories across different ages of onset. We stress the importance of reverse translation, collaborative and multidisciplinary approaches, and the study of the spatio-temporal roles of disease molecules in the context of synaptic regulatory pathways and neuronal circuits that underlie disease endophenotypes.

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Figure 1: Putative lifetime trajectory of dendritic spine number in the in a normal subject (black), in ASD (pink), in schizophrenia (SZ, green) and in Alzheimer's disease (AD) (blue).
Figure 2: Model of molecular mechanisms of spine pathology in ASD.
Figure 3: Model of molecular mechanisms contributing to spine dysfunction in schizophrenia.
Figure 4: Model of molecular mechanisms involved in spine pathology in Alzheimer's disease.

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Acknowledgements

This work was supported by grants from the US National Institutes of Health (NIH) National Institute of Mental Health (MH071316, MH071533), National Alliance for Research on Schizophrenia and Depression and Alzheimer's Association (to P.P.), NIH 1F31AG031621 (M.E.C.), NIH 1F31MH085362 (K.A.J.), NIH 1F31MH087043 (J.V.) and a predoctoral American Heart Association fellowship (K.M.W.).

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  1. Michael E Cahill, Kelly A Jones, Jon-Eric VanLeeuwen and Kevin M Woolfrey: These authors contributed equally to this work.

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  1. Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA

    Peter Penzes, Michael E Cahill, Kelly A Jones, Jon-Eric VanLeeuwen & Kevin M Woolfrey

  2. Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA

    Peter Penzes

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Penzes, P., Cahill, M., Jones, K. et al. Dendritic spine pathology in neuropsychiatric disorders. Nat Neurosci 14, 285–293 (2011). https://doi.org/10.1038/nn.2741

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