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.