Comprehensive behavioral analysis of heterozygous Syngap1 knockout mice

Abstract

Aims Synaptic Ras GTPase‐activating protein 1 (SYNGAP1) regulates synaptic plasticity through AMPA receptor trafficking. SYNGAP1 mutations have been found in human patients with intellectual disability (ID) and autism spectrum disorder (ASD). Almost every individual with SYNGAP1‐related ID develops epilepsy, and approximately 50% have ASD. SYNGAP1‐related ID is estimated to account for at least 1% of ID cases. In mouse models with Syngap1 mutations, strong cognitive and affective dysfunctions have been reported, yet some findings are inconsistent across studies. To further understand the behavioral significance of the SYNGAP1 gene, we assessed various domains of behavior in Syngap1 heterozygous mutant mice using a behavioral test battery. Methods Male mice with a heterozygous mutation in the Syngap1 gene (Syngap1−/+ mice) created by Seth Grant's group were subjected to a battery of comprehensive behavioral tests, which examined general health, and neurological screens, rotarod, hot plate, open field, light/dark transition, elevated plus maze, social interaction, prepulse inhibition, Porsolt forced swim, tail suspension, gait analysis, T‐maze, Y‐maze, Barnes maze, contextual and cued fear conditioning, and home cage locomotor activity. To control for type I errors due to multiple‐hypothesis testing, P‐values below the false discovery rate calculated by the Benjamini‐Hochberg method were considered as study‐wide statistically significant. Results Syngap1−/+ mice showed increased locomotor activity, decreased prepulse inhibition, and impaired working and reference spatial memory, consistent with preceding studies. Impairment of context fear memory and increased startle reflex in Syngap1 mutant mice could not be reproduced. Significant decreases in sensitivity to painful stimuli and impaired motor function were observed in Syngap1−/+ mice. Decreased anxiety‐like behavior and depression‐like behavior were noted, although increased locomotor activity is a potential confounding factor of these phenotypes. Increased home cage locomotor activity indicated hyperlocomotor activity not only in specific behavioral test conditions but also in familiar environments. Conclusion In Syngap1−/+ mice, we could reproduce most of the previously reported cognitive and emotional deficits. The decreased sensitivity to painful stimuli and impaired motor function that we found in Syngap1−/+ mice are consistent with the common characteristics of patients with SYNGAP‐related ID. We further confirmed that the Syngap1 heterozygote mouse recapitulates the symptoms of ID and ASD patients.

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

“…P120 1/2 mice spent more time asleep but were hyperactive when awake, as they traveled twice the distance of WT 1/1 mice. These results are consistent with recent reports of home-cage hyperactivity in male Syngap1 1/2 mice (34,35).…”

Effects of repetitive gentle handling of male C57BL/6NCrl mice on comparative behavioural test results

“…tests that have been performed since a long time and are widely used worldwide [13][14][15][16] . In particular, conducting a behavioural test battery is extremely important for detecting abnormal behaviour in mice [17][18][19] . In many behavioural tests, the experimenter frequently needs to come into contact with the mouse.…”

Heterozygous deletion of SYNGAP enzymatic domains in rats causes selective learning, social and seizure phenotypes

“…Several reports indicate that mouse models of SYNGAP1 haploinsufficiency exhibit hyperactivity and abnormal measures of anxiety (Berryer et al, 2016;Guo et al, 2009;Muhia et al, 2009;Nakajima et al, 2019;Ozkan et al, 2014) which can affect performance in, and confound the analysis of, tasks designed to study animal cognition (Crawley et al, 1997).…”

“…SYNGAP1 encodes multiple isoforms of a multifunctional, synaptically enriched protein, SYNGAP, that is essential for development and survival (Chen et al, 1998;Kim et al, 2003;Kim et al, 1998;Knuesel et al, 2005;Komiyama et al, 2002). Syngap heterozygosity (Syngap +/-) in mice is associated with behavioural and neurological phenotypes including deficits in learning and memory, pronounced hyperactivity, as well as reduced threshold for induced seizures and spontaneous epileptiform activity (Berryer et al, 2016;Clement et al, 2013;Creson et al, 2019;Guo et al, 2009;Muhia et al, 2009;Nakajima et al, 2019;Ozkan et al, 2014;Sullivan et al, 2020). SYNGAP isoform identity regulates its function and subcellular distribution (Araki et al, 2020;Gou et al, 2020;Li et al, 2001;McMahon et al, 2012).…”