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

• Published in: Brain (London, England : 1878) Vol. 137; no. Pt 1; pp. 137 - 152
• Main Authors: GRABRUCKER, Stefanie, JANNETTI, Linda, KREUTZ, Michael R, EHRET, Günter, BOECKERS, Tobias M, GRABRUCKER, Andreas M, ECKERT, Matti, GAUB, Simone, CHHABRA, Resham, PFAENDER, Stefanie, MANGUS, Katharina, PARAMESHWAR PASHAM REDDY, RANKOVIC, Vladan, SCHMEISSER, Michael J
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 2014
• Subjects: Alzheimer's disease; Animals; Attention Deficit Disorder with Hyperactivity - physiopathology; Behavior, Animal - physiology; Biological and medical sciences; Blotting, Western; Cells, Cultured; Child clinical studies; Child Development Disorders, Pervasive - metabolism; Child Development Disorders, Pervasive - physiopathology; Chromosome Deletion; Chromosome Disorders - metabolism; Chromosome Disorders - physiopathology; Chromosomes, Human, Pair 22 - metabolism; Developmental disorders; Diseases of striated muscles. Neuromuscular diseases; Female; Hippocampus - metabolism; Humans; Immunohistochemistry; Infantile autism; Medical sciences; Mice; Neurology; Organ Culture Techniques; Pregnancy; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Rats; Real-Time Polymerase Chain Reaction; RNA, Small Interfering - genetics; Saposins - metabolism; Spectrometry, Fluorescence; Synapses - physiology; Transfection; Vocalization, Animal - physiology; Zinc - deficiency; PSD; Autism; Nervous system diseases; Synapse; Pervasive developmental disorder; ASD; Shank3; Zn; Deficiency; Developmental disorder; Zinc; synapse; Zn2
• ISSN: 0006-8950; 1460-2156
• DOI: 10.1093/brain/awt303

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.