Re-expression of SynGAP protein in adulthood improves translatable measures of brain function and behavior

Abstract

It remains unclear to what extent neurodevelopmental disorder (NDD) risk genes retain functions into adulthood and how they may influence disease phenotypes. SYNGAP1 haploinsufficiency causes a severe NDD defined by autistic traits, cognitive impairment, and epilepsy. To determine if this gene retains therapeutically-relevant biological functions into adulthood, we performed a gene restoration technique in a mouse model for SYNGAP1 haploinsufficiency. Adult restoration of SynGAP protein improved behavioral and electrophysiological measures of memory and seizure. This included the elimination of interictal events that worsened during sleep. These events may be a biomarker for generalized cortical dysfunction in SYNGAP1 disorders because they also worsened during sleep in the human patient population. We conclude that SynGAP protein retains biological functions throughout adulthood and that non-developmental functions may contribute to disease phenotypes. Thus, treatments that target debilitating aspects of severe NDDs, such as medically-refractory seizures and cognitive impairment, may be effective in adult patients.

Low-Dose Perampanel Rescues Cortical Gamma Dysregulation Associated With Parvalbumin Interneuron GluA2 Upregulation in Epileptic Syngap1+/− Mice

“…indicating a high incidence of seizures. Progressive worsening of sleep dysfunction and increasing NREM IIS frequency in 100% of the mice are also common features of several developmental disorders associated with epilepsy (53)(54)(55)(56)(57)(58)(59).…”

SYNGAP1 mutations: Clinical, genetic, and pathophysiological features

“…Reversal of haploinsufficiency in adult mice leads to a partial improvement in certain deficits. A recent study demonstrated that gene restoration in adult mice with SYNGAP1 haploinsufficiency improved memory and reduced seizure threshold (Creson et al, 2018). These observations demonstrate that non‐developmental functions of SYNGAP contribute to the pathology seen in SYNGAP1 haploinsufficiency and therapies directed at these functions enable age‐related improvements.…”

Splicing of the SynGAP Carboxyl-Terminus Enables Isoform-Specific Tuning of NMDA Receptor Signaling Linked to Cognitive Function

“…4G) (Komiyama et al, 2002), disrupted associative memory in a remote contextual fear conditioning test ( Fig. 4H) (Creson et al, 2019;Ozkan et al, 2014) and altered working memory during spontaneous alternation ( Fig. 4I) (Clement et al, 2012;Muhia et al, 2010), in Syngap1 PBM/PBM mice.…”

“…However, additional research is required to determine how re-expression of individual SynGAP C-terminal isoforms in animal models impact reversible phenotypes associated with the human disorder (Aceti et al, 2015;Clement et al, 2012;Creson et al, 2019;Ozkan et al, 2014). designed experiments, interpreted data, and edited the manuscript.…”