Enhanced Glutamatergic Currents at Birth in Shank3 KO Mice

Abstract

Autism spectrum disorders (ASD) are neurodevelopmental disorders induced by genetic and environmental factors. In our recent studies, we showed that the GABA developmental shifts during delivery and the second postnatal week are abolished in two rodent models of ASD. Maternal treatment around birth with bumetanide restored the GABA developmental sequence and attenuated the autism pathogenesis in offspring. Clinical trials conducted in parallel confirmed the usefulness of bumetanide treatment to attenuate the symptoms in children with ASD. Collectively, these observations suggest that an alteration of the GABA developmental sequence is a hallmark of ASD. Here, we investigated whether similar alterations occur in the Shank3 mouse model of ASD. We report that in CA3 pyramidal neurons, the driving force and inhibitory action of GABA are not different in naïve and Shank3-mutant age-matched animals at birth and during the second postnatal week. In contrast, the frequency of spontaneous excitatory postsynaptic currents is already enhanced at birth and persists through postnatal day 15. Therefore, in CA3 pyramidal neurons of Shank3-mutant mice, glutamatergic but not GABAergic activity is affected at early developmental stages, hence reflecting the heterogeneity of mechanisms underlying the pathogenesis of ASD.

Autism-Associated Shank3 Is Essential for Homeostatic Compensation in Rodent V1

“…As a second means of testing the necessity of Shank3 in synaptic scaling, we made cultures from visual cortices of Shank3b À/À (Figures 4F and 4G), Shank3b +/À , or WT littermate mice (Figure S4E). Although neurons from Shank3b À/À and Shank3b +/À mice had similar basal mEPSC amplitudes as WT littermate neurons (as reported previously; Chiesa et al, 2019;Peç a et al, 2011), in KO neurons, TTX induced only a small and non-significant increase in mEPSC amplitude (Figures 1F and 1G;Figure S4E).…”

Swimming exercise is a promising early intervention for autism‐like behavior in Shank3 deletion rats

“…Glutathione increases in hippocampal CA3 neurons of Shank3 knockout mice during early development. 62 The MRS results showed that Shank3 gene knockout reduced Glu/Gln in the hippocampus of rats, which was consistent with some previous studies, but they did not show differences in other metabolites. This may be related to the specific knockout fragment in this study, which needs further study.…”

“…Fatemi et al 61 demonstrated that in the brains of ASD patients, the levels of GAD 65 kDa and GAD 67 kDa proteins (both involved in the conversion of Glu to GABA) decreased, resulting in increased Glu levels in the brain. Glutathione increases in hippocampal CA3 neurons of Shank3 knockout mice during early development 62 . The MRS results showed that Shank3 gene knockout reduced Glu/Gln in the hippocampus of rats, which was consistent with some previous studies, but they did not show differences in other metabolites.…”

Shankopathies in the Developing Brain in Autism Spectrum Disorders

“…et al, 2015 ; Lim et al, 2017 ), with fewer studies examining developing hippocampal synapses in pre-weaned animals ( Kouser et al, 2013 ; Jaramillo et al, 2016 ; Wegener et al, 2018 ; Chung et al, 2019 ). Shank3- Δ e 13–16–/– mice show enhanced glutamatergic network activity in CA3 pyramidal neurons from birth to the second postnatal week ( Chiesa et al, 2019 ). Shank2- Δ e 6–7–/– mice exhibit a developmental switch in NMDAR function at Schaffer collateral-CA1 synapses, from hyperfunction at P14 to hypofunction beyond P21, that was not observed in other Shank2 mutant mice such as Shank2- Δ e 7–/– or Shank2- Δ e 24–/– mice ( Chung et al, 2019 ).…”