Zinc deficiency dysregulates the synaptic ProSAP/Shank scaffold and might contribute to autism spectrum disorders

Abstract

Proteins of the ProSAP/Shank family act as major organizing scaffolding elements within the postsynaptic density of excitatory synapses. Deletions, mutations or the downregulation of these molecules has been linked to autism spectrum disorders, the related Phelan McDermid Syndrome or Alzheimer's disease. ProSAP/Shank proteins are targeted to synapses depending on binding to zinc, which is a prerequisite for the assembly of the ProSAP/Shank scaffold. To gain insight into whether the previously reported assembly of ProSAP/Shank through zinc ions provides a crossing point between genetic forms of autism spectrum disorder and zinc deficiency as an environmental risk factor for autism spectrum disorder, we examined the interplay between zinc and ProSAP/Shank in vitro and in vivo using neurobiological approaches. Our data show that low postsynaptic zinc availability affects the activity dependent increase in ProSAP1/Shank2 and ProSAP2/Shank3 levels at the synapse in vitro and that a loss of synaptic ProSAP1/Shank2 and ProSAP2/Shank3 occurs in a mouse model for acute and prenatal zinc deficiency. Zinc-deficient animals displayed abnormalities in behaviour such as over-responsivity and hyperactivity-like behaviour (acute zinc deficiency) and autism spectrum disorder-related behaviour such as impairments in vocalization and social behaviour (prenatal zinc deficiency). Most importantly, a low zinc status seems to be associated with an increased incidence rate of seizures, hypotonia, and attention and hyperactivity issues in patients with Phelan-McDermid syndrome, which is caused by haploinsufficiency of ProSAP2/Shank3. We suggest that the molecular underpinning of prenatal zinc deficiency as a risk factor for autism spectrum disorder may unfold through the deregulation of zinc-binding ProSAP/Shank family members.

Shank3 Is Part of a Zinc-Sensitive Signaling System That Regulates Excitatory Synaptic Strength

“…This was associated with a modest change in Shank3 levels (ϳ10%), which may reflect plasmid overexpression of Shank3, creating a larger pool of extrasynaptic Shank3 that masks changes in synaptic levels. However, our observed changes were similar to those seen for endogenous Shank3 (Grabrucker et al, 2014). Functionally, the decreased mobility associated with the addition of TPEN was inversely correlated to AMPAR-mediated synaptic transmission and the synaptic levels of VGLUT1 and Homer1b.…”

“…Importantly, zinc homeostasis is disrupted in neuropsychiatric disorders including ASD (Curtis and Patel, 2008;Grabrucker et al, 2011a;Russo and Devito, 2011;Yasuda et al, 2011). Elevation of zinc has been shown to rescue normal social interaction via Src and NMDAR activation in Shank2 and Tbr1 ASD mouse models (Lee et al, 2015), whereas chronic zinc deficiency induces the loss of Shank2/3 and increases the incidence of ASD-related behaviors (Grabrucker et al, 2014). Together with our results, these data suggest that environmental/ dietary factors such as changes in zinc levels could alter the Shank3-signaling system and reduce the optimal performance of Shank3-dependent excitatory synaptic function.…”

“…Zinc enters the postsynaptic neuron via different channels, including calciumpermeable AMPA receptors, NMDA receptors, voltage-gated calcium channels, and TRPM7 channels (Manzerra et al, 2001;Kim et al, 2002;Huang et al, 2008;Paoletti et al, 2009;Inoue et al, 2010;Watt et al, 2013), where it is highly enriched within dendritic spines (Li et al, 2001;Grabrucker et al, 2011b) and modulates synaptic transmission and plasticity (Mayer and Vyklicky, 1989;Izumi et al, 2006;Takeda et al, 2010;Lorca et al, 2011;Pan et al, 2011) through mechanisms that are poorly understood. Once in the spine, buffers such as metallothionein III likely facilitate the sequestration of free zinc (Ebadi et al, 1990;Masters et al, 1994;Grabrucker et al, 2014).…”

Gestational marginal zinc deficiency impaired fetal neural progenitor cell proliferation by disrupting the ERK1/2 signaling pathway

“…Some of these effects may be irreversible because marginal zinc deficiency during gestation and lactation leads to impaired working memory performance on the radial arm maze after dietary zinc repletion [41]. Similarly, gestational zinc deficiency with repletion at birth leads to an impairment in social behavior consistent with models of autism in mice [42]. Although neurogenesis is not limited to the developmental period and continues in the hippocampus and the subventricular zone throughout life, most of the neurons in the adult brain are born during the embryonic stage.…”

Oxidative Stress and Dietary Interventions in Autism: Exploring the Role of Zinc, Antioxidant Enzymes and Other Micronutrients in the Neurobiology of Autism

“…Zinc deficiency magnifies the defect. Supplementation with zinc has recently been found to protect the integrity of the blood vessel cell lining which helps maintain immune function in the elderly [100]. Within two months of zinc supplementation, resistance improves, and the chances of surviving an infection increase [101].…”