Influence of maternal zinc supplementation on the development of autism-associated behavioural and synaptic deficits in offspring Shank3-knockout mice

Abstract

Autism Spectrum Disorders (ASD) are characterised by deficits in social interactions and repetitive behaviours. Multiple ASD-associated mutations have been identified in the Shank family of proteins that play a critical role in the structure and plasticity of glutamatergic synapses, leading to impaired synapse function and the presentation of ASD-associated behavioural deficits in mice. Shank proteins are highly regulated by zinc, where zinc binds the Shank SAM domain to drive synaptic protein recruitment and synaptic maturation. Here we have examined the influence of maternal dietary zinc supplementation during pregnancy and lactation on the development of ASD-associated behavioural and synaptic changes in the offspring Shank3 knockout ( Shank3 −/− ) mice. Behavioural and electrophysiological experiments were performed in juvenile and adult Shank3 −/− and wildtype littermate control mice born from mothers fed control (30 ppm, ppm) or supplemented (150 ppm) dietary zinc. We observed that the supplemented maternal zinc diet prevented ASD-associated deficits in social interaction and normalised anxiety behaviours in Shank3 −/− offspring mice. These effects were maintained into adulthood. Repetitive grooming was also prevented in adult Shank3 −/− offspring mice. At the synaptic level, maternal zinc supplementation altered postsynaptic NMDA receptor-mediated currents and presynaptic function at glutamatergic synapses onto medium spiny neurons in the cortico-striatal pathway of the Shank3 −/− offspring mice. These data show that increased maternal dietary zinc during pregnancy and lactation can alter the development of ASD-associated changes at the synaptic and the behavioural levels, and that zinc supplementation from the beginning of brain development can prevent ASD-associated deficits in Shank3 −/− mice long term.

Comparison of SHANK3 deficiency in animal models: phenotypes, treatment strategies, and translational implications

“…Increased self grooming and other repetitive behaviors have been consistently reported in the models ex4-22|ALL [ 128 – 130 ], ex11|SH3 [ 123 ], ex13|PDZ [ 139 , 176 ], ex13-16|PDZ [ 83 , 90 , 155 , 159 , 160 , 162 – 164 , 166 , 168 , 181 – 183 ], ex14-16|PDZ [ 131 ], ex21|PRO [ 125 , 178 , 179 ], and ex11-21|SH3-PRO in rats [ 135 ]. Interestingly, in murine models ex21|PRO-InsG3680 [ 127 ] and ex8|ANK-Q321R [ 132 ], which mimick ASD-associated mutations, increased repetitive behavior was observed, whereas this was not the case in ex21|PRO-R1117X [ 127 ] mice, which harbor a schizophrenia-associated mutation.…”

“…In conditional KO-models targeting somatosensory neurons in ex13-16|PDZ-Advillin Cre or the caudal embryo, including the neural tube in ex13-16|PDZ-Cdx2 Cre abnormal social recognition was recapitulated [ 140 ]. Mixed evidence concerning the ability to recognize familiar conspecifics was observed in the model ex13-16|PDZ [ 90 , 155 , 161 , 164 , 166 , 168 ], where some studies found aberrant social recognition, while it seemed to be intact in others. No deficits of social recognition were found in the murine models ex4-9|ANK [ 78 , 80 , 167 ], ex9|ANK [ 82 , 175 ], ex14-16|PDZ [ 131 ], and ex21|PRO-InsG3728 [ 126 ].…”

“…High levels of anxiety were reported in models with the deletions ex4-22|ALL [ 128 – 130 ], ex13-16|PDZ [ 83 , 90 , 155 , 159 , 160 , 163 , 164 , 168 , 183 , 188 , 189 ], ex11-21|SH3-PRO in rats [ 135 ], and in mice with schizophrenia- or ASD-associated mutations (ex21|PRO-R1117X, -InsG3680 [ 127 ] or -InsG3728 [ 126 ]), while only slight differences were observed in the models ex13|PDZ [ 139 , 176 ] and ex14-16|PDZ [ 131 ]. Elevated anxiety levels were also replicated in conditional KO-strategies, inducing SHANK3 deficiency in somatosensory neurons or cells derived from the caudal embryo (ex13-16|PDZ-Advillin Cre or -Cdx2 Cre [ 140 ]), but also in GABAergic (ex14-16|PDZ-Viaat Cre [ 131 ]) or DRD1-positive neurons (ex4-22|ALL-Drd1 Cre [ 129 ]).…”

Molecular Mechanisms of Aberrant Neuroplasticity in Autism Spectrum Disorders (Review)

“…Some researchers [72,73] studied the level of mercury in plasma, erythrocytes, reviews brain, hair, and urine of patients with ASD and healthy people and have established that impaired processes of detoxication and metal excretion in the sick people resulted in its accumulation in tissues, stimulation of neuroinflammation, and disease development. In other investigations, abnormal concentration of chromium, magnesium, and zinc in hair and/or blood have been detected in patients with ASD compared to the control group [74], special importance was attached to zinc deficiency [75][76][77].…”

The Gut-Microbiota-Brain Axis in Autism Spectrum Disorder

“…Increasing dietary zinc in Shank3 mouse models of ASD reverses ASD-related behaviors in young mice and offspring of mice fed a zinc-supplemented diet (155,156). Whether these dietary zinc effects partially or fully stem from changes in the gut, including gut permeability or the gut microbiome, is of significant interest.…”