• Phelan-McDermid
• SHANK3
• visual processing

Visual processing alteration in Phelan McDermid Syndrome mouse model and patients


Phelan McDermid syndrome (PMS) is a rare neurodevelopmental disorder characterised by intellectual and speech delay, hypotonia, mental retardation and symptoms of the autism spectrum disorder (ASD). This pathology, also called 22q13 deletion syndrome, is caused by a haploinsufficiency of the SHANK3 gene. Similarly to other genes associated with autism, its product is a synaptic protein. Precisely, Shank/ProSAP is a scaffold protein involved in the assembly of the postsynaptic density (PSD) of glutamatergic synapses, and it is indirectly connected to the actin cytoskeleton and to the main molecular characters of the glutamatergic transmission: NMDA receptors, AMPA receptors and metabotropic glutamate receptors (mGluRs). Moreover, the last-mentioned class of receptors has been proven to be involved in autism since an alteration of mGluR5-dependent response has been assessed in mouse models of fragile X syndrome (FXS) and tuberous sclerosis (TSC). Specifically to PMS, the PSD of a Shank3 knock down in vitro model shows reduced expression level and functionality of mGluRs. Interestingly, Vicidomini et al found that administration of an mGluR5 positive allosteric modulator can rescue the deficits of SHANK3 KO mice in behavioural tests.

In order to investigate the physiology of the central nervous system of SHANK3 KO mice, the laboratory team used the visual system as a model of neural computation. Visual Evoked Potentials (VEPs) were measured in anesthetized mice via local field potential (LFP) recording. Stimulus contrast was changed among different recordings so that a contrast transfer function was produced (i.e, VEP amplitudes against versus stimulus contrast). The contrast transfer function of SHANK3 KO mice showed a higher gain control than the one from wild type (Wt) mice, which was interpreter ad a symptom of a reduced recruitment of inhibitory neurons.
Moreover, given the positive effect of mGluR positive allosteric regulators on behavioural tests in SHANK3 KO mice, we investigated the effect of VU0409551 on the contrast transfer function of these animals.
We are also trying to record VEPs in human PMD patients via electroencephalography (EEG, looking for similarities with the phenotype observed in the mouse model. This part of the study is performed at Meyer Children Hospital in collaboration with an equip of neuropsychiatrists. For standardizing the recording procedure and for reducing the effect of patients limited attention levels, commonly reported in PMD patients, visual stimuli are presented via a virtual reality headset instead of a screen.