Neurodevelopmental disorders (NDDs), including intellectual disability (ID), autism spectrum disorder (ASD), and epilepsy result in treatment-resistant behavioral abnormalities. Many severe NDDs are characterized by cognitive impairments and medically-refractory seizures (Boyle et al., 2011; Jeste and Tuchman, 2015a). In some cases, seizures, and underlying circuit-level excitatory imbalances that trigger these events, are thought to contribute to worsening of cognitive and behavioral phenotypes (Scheffer et al., 2017). Therefore, it is crucial to develop treatment strategies that improve the function of neural circuits associated with seizure susceptibility and cognitive impairment in NDD patient populations.

Historically, the patho-neurobiology underlying NDD symptomatology is thought to arise from impaired brain development. However, studies in animal models of genetic risk factors causally-linked to syndromic NDDs have shown improvement in meaningful measures of brain function and behavior in response to adult-initiated therapeutic interventions (Guy et al., 2007; Ehninger et al., 2008a; Cui et al., 2008). These findings suggest that not all phenotypic consequences of NDDs arise through impaired neurodevelopment indicating that therapeutic intervention may be beneficial in adult NDD patients with fully mature brains (Zoghbi and Bear, 2012; Ehninger et al., 2008b). The potential impact of adult initiated treatments in NDD patients cannot be overstated, as there are currently no effective treatments for the most debilitating aspects of these disorders. Thus, hope remains that adults with NDDs could benefit from emerging therapeutic strategies.

Adult reversal studies have been carried out in animal models for only a few syndromic NDD genes (Ehninger et al., 2008b). In these models, with some notable exceptions, phenotypic reversal in adulthood is most effective in correcting social behaviors and/or motor function (Guy et al., 2007; Ehninger et al., 2008b; Marín, 2016; Mei et al., 2016). However, there is less evidence that adult-initiated treatments can improve both cognitive dysfunction and seizure susceptibility in animal models for human disorders that are defined by these core phenotypes. Over the past decade, hundreds of new genes have been linked to NDDs (Vorstman et al., 2017). Large-scale exome sequencing projects in children with classically undefined and sporadic NDDs have identified a pool of genes that infer 100% (i.e. causal) risk for developing a severe disorder caused by brain dysfunction (Deciphering Developmental Disorders Study, 2015; Deciphering Developmental Disorders Study, 2017; Kyle Satterstrom et al., 2018). Some of these newer NDD genes account for a significant fraction of total cases, and dramatic phenotypes, such as severe cognitive impairment and medically-refractory seizures, define these single gene disorders (Deciphering Developmental Disorders Study, 2015; Deciphering Developmental Disorders Study, 2017). Given that the list of completely penetrant NDD genes has expanded considerably over the last decade, it is critical to understand the effectiveness of adult-initiated treatments in animal models for these newly-discovered single gene disorders. Moreover, it is important to gauge to what extent emerging treatment strategies improve cognitive impairment and seizure susceptibility because these are two of the most debilitating outcomes associated with the most severe genetically-defined NDDs.

SYNGAP1 is a recently discovered NDD gene (Hoischen et al., 2014; Zhu et al., 2014; Hamdan et al., 2009), causally-linked to a range of sporadic disorders, including ID (Deciphering Developmental Disorders Study, 2015; Deciphering Developmental Disorders Study, 2017; Hamdan et al., 2009; Rauch et al., 2012), ASD (Kyle Satterstrom et al., 2018; O'Roak et al., 2014; Hamdan et al., 2011), severe epilepsy (Vlaskamp et al., 2019; Carvill et al., 2013; von Stülpnagel et al., 2015) and schizophrenia (Purcell et al., 2014). De novo nonsense variants in SYNGAP1 resulting in haploinsufficiency lead to a relatively frequent genetically-defined form of ID with epilepsy (termed MRD5; OMIM#603384). It has a reported incidence of 1-4/10,000 individuals, or 0.5–1.0% of ID cases (Deciphering Developmental Disorders Study, 2015; Deciphering Developmental Disorders Study, 2017; Kyle Satterstrom et al., 2018; Berryer et al., 2013; Parker et al., 2015), which is similar to the frequency of Fragile X syndrome. MRD5 patients express moderate-to-severe intellectual disability (IQ < 50), have severely delayed language development, and express some form of epilepsy and/or abnormal brain activity, with these manifestations appearing first in early childhood (Vlaskamp et al., 2019; Berryer et al., 2013; Parker et al., 2015; Mignot et al., 2016). SYNGAP1 has been recognized as a high-priority risk gene worthy of in-depth study. This designation was first suggested based on its causal linkage to a broad range of neuropsychiatric disorders (Hoischen et al., 2014; Zhu et al., 2014). This notion is strengthened by the known biological functions of SynGAP protein. A major function of the protein is to integrate signaling through NMDA receptors with structural and functional synapse plasticity (Kilinc et al., 2018), which is a substrate shared among nearly all neuropsychiatric disorders (Penzes et al., 2011). Therefore, biological discoveries made in Syngap1 mouse models may be broadly generalizable to idiopathic neuropsychiatric disorders.

Syngap1 heterozygous knockout mice (Hets), which have ~50% reduction in SynGAP protein levels (Clement et al., 2012), offer both construct and face validity for MRD5 (Kilinc et al., 2018). Syngap1 heterozygosity disrupts a developmental critical period, in which a normal ratio of excitatory and inhibitory synapses are formed in particular brain regions. Without this normal ratio, circuits can become overly excitable, which may contribute to pathological brain function (Clement et al., 2012; Aceti et al., 2015; Clement et al., 2013; Ozkan et al., 2014). Prior studies have shown that reduced Syngap1 expression during this developmental critical period prevents the normal emergence of certain behavioral responses and cognitive functions because altered measures of working memory, locomotor activity, and anxiety are sensitive to neonatal reversal of Syngap1 pathogenicity (Aceti et al., 2015) but resistant to similar approaches performed in adulthood (Clement et al., 2012). However, knocking out SynGAP protein in the adult hippocampus causes memory impairments (Muhia et al., 2012) and increases seizure susceptibility (Ozkan et al., 2014), suggesting that Syngap1 may also have unique, non-developmental functions in the adult brain that promotes cognitive function and suppresses neural excitability. Syngap1 mice have an extensive endophenotype (Clement et al., 2012; Ozkan et al., 2014; Guo et al., 2009; Muhia et al., 2010). However, only a small subset of individual phenotypes have been tested for sensitivity to adult reversal of genetic pathogenicity in this line of mice (Clement et al., 2012). Based on these past results, we determined if robust disease-associated phenotypes in Syngap1 mice, such as long-term memory and seizure susceptibility, are sensitive to a method of adult gene restoration that boosts pathologically low levels of SynGAP protein. Moreover, we also searched for neurophysiological correlates of behavioral alterations in Syngap1 animals to gain insight into how protein re-expression in mature animals may improve brain function related to cognitive ability and seizure.

Epileptic encephalopathy (EE) is one outcome of pathogenic SYNGAP1 variation (Carvill et al., 2013). EE is a childhood neurological condition where epileptiform activity is believed to cause progressive worsening of brain function. Consistent with an EE designation, a substantial portion of MRD5 patients exhibit regressive phenotypes and are medically refractory to anti-epileptic drugs (Vlaskamp et al., 2019). Syngap1 mice also express electrographic and behavioral seizures (Mignot et al., 2016; Ozkan et al., 2014; Weldon et al., 2018). Therefore, these animals can be used as a model for understanding how seizure-related phenotypes associated with MRD5 are modified by adult-initiated therapies. To do this, we used a Syngap1 heterozygous (Het) animal model that enables whole-body SynGAP protein re-expression at different stages of life (Clement et al., 2012; Ozkan et al., 2014). This model is created by crossing Syngap1 Lox-stop Het mice (Syngap1^+/ls) to hemizygous mice expressing a tamoxifen (TMX)-inducible form of Cre recombinase. Upon Cre activation, an artificial exon containing a premature stop codon is excised from the Syngap1 gene, leading to re-activation of the targeted allele and restoration of SynGAP protein levels. To test for seizure susceptibility, we used the flurothyl seizure induction paradigm, which has been used previously to uncover phenotypes in constitutive Syngap1 Het knockout mice (Clement et al., 2012). In this paradigm, flurothyl exposure leads to gradually progressing seizure types, and seizure susceptibility is quantified by recording the latency to reach each distinct seizure stage. In TMX(-) mice, there was a main effect of Syngap1 genotype (i.e. the presence of the Lox-Stop allele), but not with the presence of Cre-ER, in the first two stages of seizure (Figure 1A; Figure 1—source data 1). There was no interaction detected between these two factors during any of the stages. The pairwise comparisons indicated that both Cre(-) and Cre(+) Syngap1 Lox-Stop Hets reached the first two stages of seizure significantly faster than the corresponding Syngap1 WT mice (Figure 1A; Supplementary file 1), which is indicative of a reduced seizure threshold and replicates our previous findings in adult constitutive Syngap1 Het knockout mice (Ozkan et al., 2014). Importantly, there was no statistical difference between Cre(-) and Cre(+) Syngap1 Lox-Stop Hets, indicating that Cre remained largely inactive in Cre(+)TMX(-) mice (Figure 1A; Supplementary file 1).

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In TMX-treated mice, for the first two seizure stages, there was again an effect of the Lox-Stop allele, but not for Cre-ER (Figure 1B). However, we detected an interaction between Lox-Stop and Cre-ER in this study (Figure 1B). This suggested that restoration of SynGAP protein in adulthood influenced seizure threshold measurements. Pairwise comparisons of all four genotypes demonstrated that TMX improved the seizure threshold in Cre(+) Lox-Stop mice. For example, Cre(+) Syngap1 Lox-Stop Het mice, or mice with Syngap1 pathogenicity reversed starting at PND60 (Figure 1—figure supplement 1; Supplementary file 2; Figure 1—figure supplement 1—source data 1), were not statistically different from Cre(+) WT Syngap1 mice in the second seizure stage (Figure 1B; Supplementary file 1; Figure 1—source data 2). This demonstrates that TMX increased the latency to tonic-clonic seizure induction in Lox-Stop mice to WT levels. Consistent with this, the same comparison during the first seizure stage uncovered a large difference in effect size between Cre(+) WT and Cre(+) Lox-Stop mice. Furthermore, the latency to seizure induction in Cre(+) Syngap1 Lox-Stop mice was significantly increased compared to Cre(-) Syngap1 Hets in the first two stages of the test (Figure 1B; Supplementary file 1; Figure 1—source data 2). Together, these data demonstrate that SynGAP re-expression in adulthood improves seizure threshold in Syngap1 haploinsufficient mice.

Given the behavioral improvements in response to SynGAP re-expression in adult Cre(+)/Lox-Stop Het mice, we explored how this approach impacts neurophysiological correlates of seizure susceptibility. Prior studies have shown through EEG recordings that constitutive Syngap1 heterozygous knockout mice display frequent high-amplitude interictal spiking (IIS) events in addition to occasional electrographic seizure events (Ozkan et al., 2014). Interictal spikes (IIS) are pathological electrical events that reflect seizure susceptibility in patients and may share common mechanisms with ictal events (Karoly et al., 2016). We reasoned that because behavioral seizure susceptibility was reversed after SynGAP re-expression in Cre(+)/Lox-Stop Hets, IIS events may also be ameliorated by this therapeutic approach. However, neurophysiological studies have not been performed in Syngap1 Lox-Stop mice. Therefore, it is unknown if IIS events are present in this line. We performed in vivo neurophysiological recordings in both Cre(+) WT and Cre(+) Lox-Stop Het mice. In addition to left and right sub-cranial EEG electrodes, a depth electrode was lowered into CA1 to acquire a hippocampal local field potential (hLFP). A study utilizing chronic recordings in these animals consisted of two phases. Phase one was geared toward identifying putative genotype-dependent differences in neurophysiological signals between Cre(+) WT and Cre(+) Lox-Stop mice. Phase II, in which all animals in Phase I underwent a procedure to induce Cre recombinase immediately following Phase I studies, was geared toward determining how putative neurophysiological abnormalities in each animal were impacted by restoration of SynGAP levels in Cre(+) Lox-Stop Het mice. In Phase I recordings, we observed frequent high amplitude IIS events that generalized across the three recording channels in Lox-Stop mice (Figure 2A; Figure 2—figure supplement 1). This finding demonstrates that IIS is a reproducible phenotype across different strains of mice with Syngap1 haploinsufficiency. We quantified the frequency of IIS events during wakefulness in each genotype and found that spiking events were ~50 fold more frequent in mutants compared to WT controls (Figure 2B; Figure 2—source data 1). We also observed that high-amplitude IIS events in Lox-Stop animals exhibited state-dependence during Phase one recordings, with an ~18 fold higher frequency of these events observed during sleep compared to wakefulness (Figure 2A,C; Figure 2—source data 2). We took advantage of the ability to re-express SynGAP protein in Lox-Stop mice to investigate how this strategy impacted IIS events. Remarkably, recordings during Phase II revealed that SynGAP re-expression in adult Lox-Stop mice eliminated IIS activity during wakefulness and sleep (Figure 2A–B). These data demonstrate that SynGAP protein dynamically regulates cellular mechanisms that govern systems-level excitability in the mature mouse forebrain.

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EEG waveforms are emerging as potential endpoints in clinical research studies for quantifying the efficacy of novel treatments for brain disorders (Jeste et al., 2015b; Modi and Sahin, 2017). We were therefore interested in determining if EEG-recorded IIS events in Syngap1 mice have parallels in humans expressing pathogenic SYNGAP1 variants. While IIS events are commonly observed in both humans and animal models expressing genetic risk variants linked to epilepsy, worsening of these events during sleep is uncommon and is a symptom of a distinct cluster of epilepsy syndromes, such as electrical status epilepticus in sleep (ESES)/continuous spikes and waves during slow sleep (CSWS) (Gencpinar et al., 2016). Therefore, because sleep-dependent worsening of IIS events was observed in Syngap1 mice, we searched for evidence of sleep-dependent worsening of paroxysmal spiking events in MRD5 patients. To do this, we mined data from a SYNGAP1 patient registry, which has been used to uncover previously unreported phenotypes in this NDD population (Michaelson et al., 2018). In this database, we found 11 entries that included a relatively complete medical history, including an EEG report from a neurologist and a detailed genetic report defining the SYNGAP1 variant. Each of the selected patients was confirmed to have a severe SYNGAP1 variant expected to cause genetic haploinsufficiency (i.e. heterozygous knockout caused by either a nonsense variant or a frameshift caused by an InDel). In each of these unique patient entries, there were clear references to IIS activity (Supplementary file 3). However, there were six unique entries where the neurologist noted that spike-related events worsened during sleep. In one patient (#5569), the neurologist noted that epileptiform activity was nearly constant during light sleep. In another (#1029), IIS was observed in 30% of recorded sleep. Moreover, we obtained EEG recordings from two additional patients, S3-060 and S3-080, confirmed to express variants consistent with SYNGAP1 haploinsufficiency. In these cases, we also observed evidence of sleep-dependent worsening of pathological EEG signals (Figure 3A–D). These clinical observations indicate that some patients with SYNGAP1 haploinsufficiency have worsening EEG profiles during sleep, which strengthens the validity of sleep-dependent worsening of IIS in Syngap1 mouse models.

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We next explored other measures of cognitive function impacted by SynGAP re-expression in adulthood. To date, only spontaneous alternation has been used to determine the impact of adult reversal of Syngap1 pathogenicity on changes to cognitive function (Clement et al., 2012). This measure of working memory was not improved after protein restoration in adult Syngap1 Het mice. To expand cognitive-based testing of adult gene-restoration, we employed contextual fear conditioning, which requires animals to associate a novel context (e.g. the training environment) with an adverse event (e.g. mild foot-shock). Memory is inferred from a behavior change, such as freezing and/or immobility, when the animal is placed back in the training environment hours or days later. We, and others, have previously reported that Syngap1 Het mice have normal expression of contextual fear 1 day (1d) after training (Guo et al., 2009; Muhia et al., 2010). However, Syngap1 Het mice display disrupted remote contextual memory because they have increased immobility when tested one month after training (Ozkan et al., 2014). Thus, we focused on remote memory in this study. For these experiments, we used activity suppression ratios (ASR) to quantify behavioral performance rather than freezing. We did this because ASR is a well-validated measure of context fear and is reported to be a more reliable measure of context memory in mice with suspected differences in basal levels of detectable freezing (Anagnostaras et al., 2000). Indeed, we have observed that the inclusion of the Cre-ER allele can cause intermittent, subtle twitching in mice during obvious bouts of freezing. This twitching behavior confounds automated measures of freezing. Here, we report that two different Syngap1 Het strains (i.e. constitutive Syngap1 Het mice and Syngap1 Lox-Stop mice) exhibit a deficit in contextual memory deficit when tested 26-30d after training (Figure 4A; Figure 4—source data 1; Figure 4B; Figure 4—source data 2). The first few days after contextual fear conditioning is marked by remote memory consolidation (Frankland et al., 2004), a systems-level process that involves communication between the hippocampus and the cortex and is believed to convert memory traces into a more permanent form of storage or maintenance. A selective deficit at remote time points is indicative of a systems memory consolidation deficit in Syngap1 mice.

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Upon further testing, we discovered that retrieval 1d after training prevented 26-30d remote memory deficits in Syngap1 Hets (Figure 4C; Figure 4—source data 3). The retrieval-induced protection of remote memory in adult Syngap1 animals suggested that the biological processes that promote systems consolidation may not be permanently damaged by heterozygosity of this gene during development. Therefore, we hypothesized that adult re-expression of SynGAP protein would improve the function of brain circuits that support remote memory. To do this, we again used the Syngap1 Lox-Stop Het animal model that enables whole-body SynGAP protein re-expression beginning in adulthood. We trained adult offspring resulting from this cross in contextual fear conditioning and tested memory ~1 month after treatments with or without TMX (Figure 4D). In TMX(-) mice, we observed a strong main effect on genotype (i.e. the presence of Lox-Stop cassette; p=9.28E-10), but not with the presence of Cre-ER (p=0.864), which further supports the idea that Syngap1 heterozygosity impacts remote memory (Figure 4E; Figure 4—source data 4). We observed a relatively weak statistical interaction between Cre-ER and Lox-Stop (p=0.011). Importantly, pairwise comparisons among all four groups indicated that both Cre(-) and Cre(+) Syngap1 Hets performed significantly differently compared to corresponding Syngap1 WT controls (Figure 4E; Supplementary file 4; Figure 4—source data 5). There was also no difference in performance between Cre(-) and Cre(+) Syngap1 Hets (Figure 4E; Supplementary file 4), indicating that Cre remained sufficiently inactive in the absence of TMX in these mice.

In TMX(+) studies (Figure 4F), we again observed a strong main effect on genotype (p=1.48E-6), but not with the presence of Cre-ER (p=0.891). In contrast to TMX(-) studies, here we observed a highly significant interaction between Cre-ER and Lox-Stop (p=2.59E-4), which suggested that SynGAP re-expression altered activity suppression levels. Pairwise comparisons of all four genotypes indicated that elevated ASR levels normally found in Syngap1 haploinsufficient mice were reversed back to WT levels by TMX injections. For example, TMX-treated Cre(+) Syngap1 Het mice were no different from corresponding Cre(+) WT Syngap1 mice (Figure 4F; Supplementary file 4). Moreover, the ASR in these mice was significantly reduced compared to Cre(-) Syngap1 Lox-Stop Hets [i.e. mice with preserved Syngap1 pathogenicity), consistent with adult reversal of the remote memory deficit (Figure 4F; Supplementary file 4). It is important to note that while we did not observe any main effects of Cre-ER in either TMX(-) or TMX(+) studies, there is a trend for Cre-ER to increase ASR in WT mice (i.e. mice without the Lox-Stop allele) across both experiments. However, we conclude that this trend did not confound the interpretation of how gene restoration impacted behavioral performance in this experiment. To the contrary, the trend for Cre-ER to increase ASR in WT mice was actually reversed when comparing Cre(-) and Cre(+) Lox-Stop mice (Figure 4F). We interpreted this as further evidence that SynGAP re-expression improved performance in the memory task. Taken together, these data support the interpretation that SynGAP re-expression in adulthood rescues remote contextual memory deficits in Syngap1 haploinsufficient mice.

Next, we directly tested the idea that Syngap1 gene restoration improves the function of neural circuits that promote systems-memory consolidation. Hippocampal oscillations are linked to a range of cognitive functions, including various mnemonic processes associated with systems memory consolidation (Colgin, 2016). Therefore, we recorded hippocampal oscillations through an LFP electrode implanted in CA1. We recorded these signals in mice both before and after Syngap1 gene restoration, which enabled us to assess how this therapeutic strategy impacted hippocampal function in each animal. Theta rhythms were clearly observable in WT mice during both recording phases (Figure 5A). However, in recordings from Lox-Stop mice during Phase I, theta rhythms often appeared less robust during periods of free exploration compared to WT littermates (Figure 5B; Figure 5—figure supplement 1). After SynGAP re-expression, theta oscillations in these animals increased compared to pre-injection baseline recordings (Figure 5B). Across the entire Lox-Stop population, we found that theta-range signal amplitude was significantly enhanced by raising SynGAP protein levels in this population of adult Lox-Stop mice (Figure 5C), which is a finding consistent with improved performance in memory tasks considering that increased theta rhythm expression has been shown to correlate with better memory performance.

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Theta rhythms in mice are modulated by running speed (Gereke et al., 2018) and it has been reported that Syngap1 Het mice are hyperactive in some, but not all, contexts (Kilinc et al., 2018). Therefore, we tracked locomotor activity in all recorded mice across both sessions to determine if phase-specific changes in activity levels may have contributed to changes in theta amplitude (Figure 5—figure supplement 2; Figure 5—figure supplement 2—source data 1). Similar to past studies, Cre(+) Lox-Stop Het mice were hyperactive compared Cre(+)WT controls as evidenced by a significant main effect of genotype (i.e. group) on distance traveled (p=0.002). However, we did not observe an effect of phase (p=0.692), or an interaction between phase and genotype in this analysis (p=0.085). Therefore, the phase-independent increases in locomotor activity in Het mice are unlikely to explain the phase-specific changes to theta rhythms in these animals.

The principal finding in this study is that genetic reversal of Syngap1 pathogenicity in adult mice reverses deficits in remote memory, lowers seizure threshold, re-balances neural excitability, and improves hippocampal/cortical function. On the surface, these exciting results are somewhat paradoxical given that we have previously found that Syngap1 pathogenicity causes hardwired impairments in the development of forebrain circuits that mediate a subset of previously tested cognitive functions (Clement et al., 2012; Aceti et al., 2015; Ozkan et al., 2015). These previous studies indicated that impaired assembly of forebrain circuits contribute to life-long impairments in brain function because a set of behaviors were shown to be resistant to adult re-activation of SynGAP protein expression. How then can these current findings be reconciled with past findings demonstrating that certain behavioral paradigms are not sensitive to adult re-expression of SynGAP protein? The most parsimonious explanation is that not all behavioral impairments common to the Syngap1 endophenotype are governed by hardwired circuit changes, which in turn reflect altered neurodevelopmental processes. Some behavioral impairments may be caused by altered ‘real-time’ neuronal signaling that is not restricted to defined periods of neurodevelopment (Zoghbi and Bear, 2012). Elegant work in Shank3 mouse models directly supports this interpretation (Mei et al., 2016). Feng and colleagues demonstrated that adult reversal of Shank3 pathogenicity improved some non-cognitive and non-seizure-related behavioral phenotypes, while other independent phenotypes remained completely impaired even though protein levels were restored to WT levels. Restoring Shank3 protein levels early in development prevented the emergence of adult reversal-resistant behavioral impairments, indicating that low expression of germline Shank3 protein disrupts both developmental and non-developmental cellular processes.

Evidence in the literature indicates that Syngap1 may have unique functions during both development and adulthood, which supports an evolving interpretation of SynGAP function in the brain. For instance, Syngap1 heterozygosity causes a transient increase in baseline postsynaptic function in CA1 Schaffer collateral synapses during postnatal development (Clement et al., 2012). This is a true developmental impact of Syngap1 pathogenicity because inducing pathogenicity in adulthood does not induce a change in baseline excitatory synapse function in hippocampal synapses. Interestingly, baseline excitatory function of this pathway normalizes by adolescence, as evidenced by several groups (Kim et al., 2003; Komiyama et al., 2002), including our own (Clement et al., 2012), reporting normal postsynaptic baseline function in this synapse in mature animals. However, there is a dramatic impairment in LTP stability at these synapses in adult Syngap1 mice (Kim et al., 2003; Komiyama et al., 2002). This function of Syngap1 appears unrelated to neurodevelopment because LTP can be completely rescued after adult re-expression of low SynGAP protein levels (Ozkan et al., 2014). Thus, Syngap1 exhibits both developmental and non-developmental functions within the same synapses in the hippocampus. As a consequence, not all deficits related to neuronal function in the adult Syngap1 Het mouse brain can be attributed to hardwired circuit damage caused by impaired neurodevelopment.

The real-world impact of our current findings is two-fold. First, therapies that improve the expression and/or function of SynGAP protein may be beneficial to MRD5 patients of all ages. Adult re-expression of SynGAP appears to correct neurophysiological imbalances within circuits that predispose the brain to seizure generation and certain forms of cognitive impairment. Therefore, the impact of therapies related to elevated SynGAP levels in adult patients could be significant. It remains unclear if adult re-expression of SynGAP corrects seizure susceptibility and memory impairments through a common mechanism. Future studies will be necessary to determine the molecular and cellular mechanisms that are recovered in the forebrain after SynGAP re-expression. Moreover, it will be critical to link these recovered molecular and cellular processes to circuit-level processes that directly contribute to behavioral memory and seizure. This type of experimental strategy may help to elucidate novel neural circuit correlates of behavioral alterations and excitability impairments associated with NDDs. However, early therapeutic intervention should remain the primary NDD treatment strategy. Treatments during development would protect the brain from both hardwired circuit damage caused by disruptions to critical neurodevelopmental processes (Clement et al., 2012; Aceti et al., 2015; Clement et al., 2013) and ‘real-time’ age-independent neurophysiological imbalances described in this study.

The second real-world implication of this study is that it may have identified a candidate translatable biomarker that can serve as an endpoint for efficacy testing of novel treatments for MRD5 patients. Our data indicate that IIS events appear to worsen during sleep in both humans and mice with SYNGAP1/Syngap1 haploinsufficiency. Sleep-linked worsening of IIS is a hallmark of epilepsy syndromes with significant cognitive impairment (Gencpinar et al., 2016). Similar to what we report here, a recent, comprehensive analysis of a cohort of SYNGAP1 patients observed a sleep-dependent increase in pathological EEG waveforms in approximately half of the children (Vlaskamp et al., 2019). We found that SynGAP re-expression in adult mutant mice eliminated these pathological events, which are also detected by EEG electrodes, during both wakefulness and sleep. Considering that this treatment strategy also improved measures of behavioral seizure and memory, the severity of IIS during sleep may be a predictor of generalized cortical impairment associated with SYNGAP1 pathogenicity. If a relationship between the severity of state-dependent IIS and cognitive impairment is observed in patients, then these signals may be useful as biomarkers for improved cortical function in translational studies aimed at identifying effective therapeutic strategies for SYNGAP1 patients.

Data used for generating figures are included in the manuscript and supporting files.

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Author details

1. Thomas K Creson

   1. Department of Neuroscience, The Scripps Research Institute, Jupiter, United States
   2. Department of Molecular Medicine, The Scripps Research Institute, Jupiter, United States

   Contribution

   Formal analysis, Investigation, Methodology, Writing—review and editing

   Contributed equally with

   Camilo Rojas

   Competing interests

   No competing interests declared

2. Camilo Rojas

   1. Department of Neuroscience, The Scripps Research Institute, Jupiter, United States
   2. Department of Molecular Medicine, The Scripps Research Institute, Jupiter, United States

   Contribution

   Formal analysis, Investigation, Writing—review and editing

   Contributed equally with

   Thomas K Creson

   Competing interests

   No competing interests declared

3. Ernie Hwaun

   Department of Neuroscience, Institute for Neuroscience, Center for Learning and Memory, University of Texas at Austin, Austin, United States

   Contribution

   Formal analysis, Writing—review and editing

   Competing interests

   No competing interests declared

4. Thomas Vaissiere

   1. Department of Neuroscience, The Scripps Research Institute, Jupiter, United States
   2. Department of Molecular Medicine, The Scripps Research Institute, Jupiter, United States

   Contribution

   Investigation, Visualization, Methodology, Writing—review and editing

   Competing interests

   No competing interests declared

5. Murat Kilinc

   1. Department of Neuroscience, The Scripps Research Institute, Jupiter, United States
   2. Department of Molecular Medicine, The Scripps Research Institute, Jupiter, United States

   Contribution

   Formal analysis, Investigation, Writing—review and editing

   Competing interests

   No competing interests declared

6. Andres Jimenez-Gomez

   1. Jan and Dan Duncan Neurological Research Institute, Baylor College of Medicine, Houston, United States
   2. Department of Pediatrics, Baylor College of Medicine, Houston, United States

   Contribution

   Formal analysis, Investigation, Writing—review and editing

   Competing interests

   No competing interests declared

7. Jimmy Lloyd Holder Jr

   1. Jan and Dan Duncan Neurological Research Institute, Baylor College of Medicine, Houston, United States
   2. Department of Pediatrics, Baylor College of Medicine, Houston, United States

   Contribution

   Investigation, Methodology, Writing—review and editing

   Competing interests

   No competing interests declared

8. Jianrong Tang

   1. Jan and Dan Duncan Neurological Research Institute, Baylor College of Medicine, Houston, United States
   2. Department of Pediatrics, Baylor College of Medicine, Houston, United States

   Contribution

   Investigation, Methodology, Writing—review and editing

   Competing interests

   No competing interests declared

9. Laura L Colgin

   Department of Neuroscience, Institute for Neuroscience, Center for Learning and Memory, University of Texas at Austin, Austin, United States

   Contribution

   Investigation, Methodology, Writing—review and editing

   Competing interests

   Reviewing editor, eLife

10. Courtney A Miller

    1. Department of Neuroscience, The Scripps Research Institute, Jupiter, United States
    2. Department of Molecular Medicine, The Scripps Research Institute, Jupiter, United States

    Contribution

    Investigation, Methodology, Writing—review and editing

    Competing interests

    No competing interests declared

11. Gavin Rumbaugh

    1. Department of Neuroscience, The Scripps Research Institute, Jupiter, United States
    2. Department of Molecular Medicine, The Scripps Research Institute, Jupiter, United States

    Contribution

    Conceptualization, Data curation, Formal analysis, Supervision, Funding acquisition, Investigation, Methodology, Writing—original draft

    For correspondence

    grumbaug@scripps.edu

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0001-6360-3894

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