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The coordination of dendritic spine morphogenesis and function during synaptic plasticity and pathology

Final Report Summary - MORPHINGSYNAPSES (The coordination of dendritic spine morphogenesis and function during synaptic plasticity and pathology)


Synaptic plasticity is thought to underlie learning and memory, tuning of neural circuitry and information storage. Alterations of dendritic spine morphology and synaptic plasticity are thought to contribute to the pathogenesis of neuropsychiatric diseases such as autism spectrum disorders and schizophrenia. The objectives of ‘Morphing Synapses’ were to study dendritic spine morphology in the context of neuropsychiatric disease using cutting edge imaging techniques, to assess the role of genetic risk factors in dendritic spine morphology impairment in neuropsychiatric disease. To do this, key proteins that have been associated with neuropsychiatric diseases in genetic studies were studied at the cellular level to understand their functions in neurons and how they control spine morphology. These proteins include ankyrin-G (a key bipolar/schizophrenia risk gene) and cadherin-10 (CDH10; an autism risk factor).

To achieve these objectives Dr. Katharine Smith has been studying these proteins in neurons using a variety of state-of-the-art imaging techniques, combined with biochemistry, electrophysiology and in vivo studies. This has been very successful with part of the project being published in the high-profile journal Neuron (October 2014). The fellow showed that ankyrin-G has an important function in mediating dendritic spine maintenance, proper AMPAR clustering and synaptic plasticity (Smith et al., Neuron 2014). Specifically, the fellow utilized a super-resolution imaging technique, Structured-Illumination Microscopy (SIM), to define synaptic nanodomains of ankyrin-G that localize to the dendritic spine head and neck, and impact the dimensions of these structures. This paper was important for a number of reasons: (1) we discovered a novel synaptic function for ankyrin-G, which was originally thought to be restricted to the axon; (2) we found that ankyrin-G is one of a handful of proteins shown to function at the spine neck; and (3) we provided a possible mechanism for synaptic dysfunction in bipolar disorder (see attached figure).
In addition to this, the fellow characterized the cellular function of an autism-associated cadherin, CDH10, which she found to be localized to both excitatory and inhibitory synaptic sites: knock-down of CDH10 causes a shift in the E/I balance in neurons (Smith et al., manuscript submitted). The fellow is currently working on revisions for this publication and it is hoped it will be published within the next few months.

The impact of this project to date is underlined by the publication of the first part of it in the high-profile journal Neuron, where it will be read by a broad readership. Further, this paper was the subject of press releases by Northwestern University Feinberg School of Medicine and many local and online publications, indicating the potential impact of the work for mental health.

The fellow is now collaborating with another post-doc in the Penzes lab to finish a second publication looking at the role of ankyrin-G in spine maturation and how a palmitoylation-deficient mutation of Ankyrin-G can disrupt this. This manuscript will be submitted by the end of 2016.