TY  - JOUR
AU  - Vyas, Yukti
AU  - Jung, Yewon
AU  - Lee, Kevin
AU  - Garner, Craig C
AU  - Montgomery, Johanna M
TI  - In vitro zinc supplementation alters synaptic deficits caused by autism spectrum disorder-associated Shank2 point mutations in hippocampal neurons.
JO  - Molecular brain
VL  - 14
IS  - 1
SN  - 1756-6606
CY  - London
PB  - BioMed Central
M1  - DZNE-2021-00643
SP  - 95
PY  - 2021
AB  - Autism Spectrum Disorders (ASDs) are neurodevelopmental disorders characterised by deficits in social interactions and repetitive behaviours. ASDs have a strong genetic basis with mutations involved in the development and function of neural circuitry. Shank proteins act as master regulators of excitatory glutamatergic synapses, and Shank mutations have been identified in people with ASD. Here, we have investigated the impact of ASD-associated Shank2 single nucleotide variants (SNVs) at the synaptic level, and the potential of in vitro zinc supplementation to prevent synaptic deficits. Dissociated rat hippocampal cultures expressing enhanced green fluorescent protein (EGFP) tagged Shank2-Wildtype (WT), and ASD-associated Shank2 single nucleotide variants (SNVs: S557N, V717F, and L1722P), were cultured in the absence or presence of 10 μM zinc. In comparison to Shank2-WT, ASD-associated Shank2 SNVs induced significant decreases in synaptic density and reduced the frequency of miniature excitatory postsynaptic currents. These structural and functional ASD-associated synaptic deficits were prevented by chronic zinc supplementation and further support zinc supplementation as a therapeutic target in ASD.
KW  - Animals
KW  - Animals, Newborn
KW  - Autism Spectrum Disorder: genetics
KW  - Autism Spectrum Disorder: pathology
KW  - Dietary Supplements
KW  - Female
KW  - Glutamic Acid: metabolism
KW  - Hippocampus: pathology
KW  - Male
KW  - Nerve Tissue Proteins: genetics
KW  - Neurons: drug effects
KW  - Neurons: metabolism
KW  - Neurons: pathology
KW  - Point Mutation: genetics
KW  - Rats
KW  - Synapses: drug effects
KW  - Synapses: pathology
KW  - Zinc: pharmacology
KW  - Autism (Other)
KW  - Glutamatergic synapses (Other)
KW  - Shank2 (Other)
KW  - Zinc supplementation (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:34167580
C2  - pmc:PMC8223320
DO  - DOI:10.1186/s13041-021-00809-3
UR  - https://pub.dzne.de/record/155437
ER  -