Abstract
The SHANK family of synaptic proteins (SHANK1–3) are master regulators of the organizational structure of excitatory synapses in the brain. Mutations in SHANK1–3 are prevalent in patients with autism spectrum disorders (ASD), and loss of one copy of SHANK3 causes Phelan-McDermid Syndrome, a syndrome in which Autism occurs in >80% of cases. The synaptic stability of SHANK3 is highly regulated by zinc, driving the formation of postsynaptic protein complexes and increases in excitatory synaptic strength. As ASD-associated SHANK3 mutations retain responsiveness to zinc, here we investigated how increasing levels of dietary zinc could alter behavioral and synaptic deficits that occur with ASD. We performed behavioral testing together with cortico-striatal slice electrophysiology on a Shank3−/− mouse model of ASD (Shank3ex13–1616−/−), which displays ASD-related behaviors and structural and functional deficits at striatal synapses. We observed that 6 weeks of dietary zinc supplementation in Shank3ex13–16−/− mice prevented ASD-related repetitive and anxiety behaviors and deficits in social novelty recognition. Dietary zinc supplementation also increased the recruitment of zinc sensitive SHANK2 to synapses, reduced synaptic transmission specifically through N-methyl-D-aspartate (NMDA)-type glutamate receptors, reversed the slowed decay tau of NMDA receptor (NMDAR)-mediated currents and occluded long term potentiation (LTP) at cortico-striatal synapses. These data suggest that alterations in NMDAR function underlie the lack of NMDAR-dependent cortico-striatal LTP and contribute to the reversal of ASD-related behaviors such as compulsive grooming. Our data reveal that dietary zinc alters neurological function from synapses to behavior, and identifies dietary zinc as a potential therapeutic agent in ASD.
Highlights
The SHANK family of proteins (SHANK1–3) are localized at the core of the postsynaptic density (PSD) at glutamatergic synapses where they bind to structural proteins, glutamate receptors, and the actin cytoskeleton to modulate the structure, plasticity and maturation of excitatory synapses (Boeckers et al, 2002; Kreienkamp, 2008)
To determine whether chronic changes in dietary zinc can alter the autism spectrum disorders (ASD)-associated synaptic and behavioral deficits that occur in the striatum of the Shank3ex13–16−/− ASD mouse model (Peca et al, 2011), Shank3ex13–16−/− mice were fed normal (30 ppm) or high (150 ppm) dietary zinc levels for 6 weeks followed by analysis of ASD-related behaviors as well as glutamatergic excitatory synaptic transmission and plasticity in the cortico-striatal pathway
Zinc is a known modulator of ion channels, synaptic transmission, and the recruitment of postsynaptic signaling protein complexes including SHANK2 and SHANK3 (Westbrook and Mayer, 1987; Chen et al, 1997; Yamada et al, 2002; Baron et al, 2006; Grabrucker et al, 2014; Arons et al, 2016)
Summary
The SHANK family of proteins (SHANK1–3) are localized at the core of the postsynaptic density (PSD) at glutamatergic synapses where they bind to structural proteins, glutamate receptors, and the actin cytoskeleton to modulate the structure, plasticity and maturation of excitatory synapses (Boeckers et al, 2002; Kreienkamp, 2008). Mouse models expressing ASD mutations in Shank exhibit impaired glutamatergic synaptic function, decreased synaptic plasticity, increased anxiety and repetitive behaviors and impaired social interactions (Hung et al, 2008; Bozdagi et al, 2010; Peca et al, 2011; Schmeisser et al, 2012; Duffney et al, 2013; Lee et al, 2015; Speed et al, 2015; Mei et al, 2016). Restoring excitatory synaptic function (e.g., by altering NMDA or metabotropic-type glutamate receptor function, or restoring Shank expression) improves ASD-related behaviors (Won et al, 2012; Chung et al, 2015; Lee et al, 2015; Mei et al, 2016). Glutamatergic synapses are a major focus for developing treatments for the behavioral deficits associated with ASD
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