SYNGAP1 heterozygosity disrupts sensory processing by reducing touch-related activity within somatosensory cortex circuits


In addition to cognitive impairments, neurodevelopmental disorders often result in sensory processing deficits. However, the biological mechanisms that underlie impaired sensory processing associated with neurodevelopmental disorders are generally understudied and poorly understood. We found that SYNGAP1 haploinsufficiency in humans, which causes a sporadic neurodevelopmental disorder defined by cognitive impairment, autistic features, and epilepsy, also leads to deficits in tactile-related sensory processing. In vivo neurophysiological analysis in Syngap1 mouse models revealed that upper-lamina neurons in somatosensory cortex weakly encode information related to touch. This was caused by reduced synaptic connectivity and impaired intrinsic excitability within upper-lamina somatosensory cortex neurons. These results were unexpected, given that Syngap1 heterozygosity is known to cause circuit hyperexcitability in brain areas more directly linked to cognitive functions. Thus, Syngap1 heterozygosity causes a range of circuit-specific pathologies, including reduced activity within cortical neurons required for touch processing, which may contribute to sensory phenotypes observed in patients.

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Fig. 1: Reduced sensory-evoked brain activity in Syngap1 SSC.
Fig. 2: Reduced ongoing and whisker-generated activity in SSC L2/3 neurons from awake Syngap1 mice.
Fig. 3: Reduced whisker responsiveness of SSC neurons in behaving Syngap1 mice.
Fig. 4: Reduced sensory responsiveness of L2/3 SSC neurons in Syngap1 mice is cortex-specific.
Fig. 5: Reduced sensory responsiveness in both excitatory and inhibitory neuronal populations in L2/3 SSC of Syngap1 mutants.
Fig. 6: In vivo patch clamp reveals that L2/3 SSC neurons in Syngap1 mutants have reduced sensory-evoked synaptic input.
Fig. 7: Syngap1 heterozygosity degrades synaptic connectivity and reduces intrinsic excitability of upper layer SSC neurons.
Fig. 8: Impaired texture discrimination and whisker-dependent go/no-go task performance in Syngap1 mice.

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.


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This work was supported in part by NIH grants from the National Institute of Mental Health (MH096847 and MH108408 to G.R. and MH105400 to C.A.M.), the National Institute for Neurological Disorders and Stroke (NS064079 to G.R. and NS083894 to J.M.C.), and the National Institute for Drug Abuse (DA034116 and DA036376 to C.A.M.). J.L.H. is supported by a National Institute for Neurological Disorders and Stroke Mentored Clinical Scientist Research Career Development Award (NS091381). The SYNGAP1 Natural History Study and Patient Registry is supported by a grant to M.W., J.L.H., and G.R. from The National Organization of Rare Disorders (NORD).

Author information




S.D.M. performed experiments, designed experiments, analyzed data, co-wrote the manuscript, and edited the manuscript. E.D.O. performed experiments, designed experiments, analyzed data, and edited the manuscript. M.A. performed experiments, designed experiments and analyzed data. S.M. performed experiments, designed experiments, and analyzed data. E.M. performed experiments, designed experiments, and analyzed data. M.W. performed experiments, designed experiments, and analyzed data. N.L. performed experiments and analyzed data. T.V. performed experiments and analyzed data. M.A.G. designed experiments and interpreted data. J.M.C. designed experiments and interpreted data. J.L.H. performed experiments, designed experiments, analyzed data, interpreted data, and edited the manuscript. C.A.M. designed experiments, interpreted data, and edited the manuscript. G.R. conceived the study, designed experiments, interpreted data, co-wrote the manuscript, and edited the manuscript.

Corresponding author

Correspondence to Gavin Rumbaugh.

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The authors declare no competing financial interests. M.W. is a paid employee of Bridge-the-GAP Educational Research Foundation. G.R. and J.L.H. are unpaid scientific advisors to Bridge-the-GAP Educational Research Foundation.

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Integrated supplementary information

Supplementary Figure 1 Impaired sensory-evoked GCaMP6s dynamics in SSC of Syngap1 mice.

(a) Example wide-field ΔF/F images superimposed over craniotomy pictures of WT and Het mice. (b-d) Traces of individual (b) and averaged (c) GCaMP6s responses, as well as a scatter plot showing the integrated ΔF/F signal amplitude (d) in response to 5 pulses at 5 Hz (Student’s t-test t(12)=4.09 p=0.0015). (e-g) Average time courses of GCaMP6s dynamics in response to a single whisker stimulation (e), 5 pulses at 5 Hz (f) and 5 pulses at 1 Hz (g) stimulation protocols. (h) Scatter plot showing ratio of fourth pulse to first pulse in 5 pulse at 1 Hz paradigm (Student’s t-test t(12)=4.16 p=0.0013). Peak (i, j) and integrated (k, l) ΔF/F responses for increasing number of pulses at 10 Hz (j, l) and increasing frequency of pulses at 5 pulses (i, k) (2-way RM-ANOVA : (i) F(1,12)=3.90 p=0.07 for genotype and F(2,24)=7.44 p=0.003 for genotype and frequency interaction; (j) F(1,12)=2.27 p=0.16 for genotype and F(4,48)=2.92 p=0.031 for genotype and frequency interaction; (k) F(1,12)=7.11 p=0.02 for genotype and F(2,24)=4.92 p=0.01 for genotype and frequency interaction; (l) F(1,12)=4.22 p=0.06 for genotype and F(4,48)=5.96 p=0.001 for genotype and frequency interaction). Open circles represent animal means, black lines or closed circles indicate population means and error bars or shaded areas indicate SEMs. Data were obtained n= 6 WT and n=8 Het mice from two cohorts of animals. All statistical tests were two-sided.

Supplementary Figure 2 Cluster analysis of ongoing and whisker-generated spike counts in SSC L2/3 neurons from awake Syngap1 mice.

(a) Relating to Fig. 2, graph showing the fraction of neurons clustered into low- (white), medium- (gray), and high-spiking (black) activity clusters. Mean spike count for each cluster is noted in the graph legend. Number of neurons in each cluster is denoted on the bar graph for each group. (b) Results of Chi-square analysis showing overall effect on how the neurons clustered across the four groups. (c) Results of Chi-square analyses demonstrating differences in each of the three activity clusters when comparing the four experimental groups. (d) Results of Chi-square analyses comparing the four groups to each other for all three activity clusters.

Supplementary Figure 3 Cell-type-specific recombination in Cux2-CreERT2 and Rbp4-Cre lines.

(a) Representative coronal brain sections of a Cux2-Cre+/-;Ai9+/- mouse, where Cre activity is reported by red fluorescence (black) from the TdTomato expression at PND60 (TMX injection at PND2). (b) Representative coronal brain section from a Cux2-Cre+/-;Ai9+/- mouse, where Cre activity is reported by TdTomato expression in the somatosensory cortex (red) at PND60 (TMX injection at PND2). (c) Representative coronal brain sections of a Rbp4Cre+/-;Ai6+/- mouse, where Cre activity is reported by green fluorescence (black) from the zsGreen expression at PND60. (d) Representative coronal brain section from a Rbp4Cre+/-;Ai9+/- mouse where Cre activity is reported by TdTomato expression in the somatosensory cortex (red) at PND60. Validation of the Cre driver lines were repeated in 2-3 mice per genotype.

Supplementary Figure 4 Additional performance metrics of Syngap1 mice in the go–no-go task.

Representative learning curves during Step 2 training for a WT (a, b) and a Het (c, d) mouse depicting probability of licking on Go (black) and NoGo (blue) trials (a, c) and discrimination index (b, d). Learning curves were similar for 6/7 WT and 7/7 Het mice. (e) Normalized bodyweights of mice from one day before water restriction to the completion of the experiment (2-way RM-ANOVA with Bonferroni’s multiple comparison, Genotype: F(1,12)=1.29, p=0.28; Day: F(45,540)=6.64, p= 1.19E-29; Genotype*Day interaction: F(45,540)=0.49, p=0.99). (f, g) Scatter plots of licking behavior during lick-port training depicting mean number of water licks (f, Unpaired t-test: t(12)=0.17, p=0.87) and total reward licks (g, Unpaired t-test t(12)=0.88, p=0.40). (h, i) Averaged response times across sessions during Go (h, 2-way RM-ANOVA with Bonferroni’s multiple comparison, Genotype: F(1,12)=0.33, p=0.58; Session: F(15,180)=16.84, p= 5.965E-27; Genotype*Session interaction: F(15,180)=0.89, p=0.57) and NoGo (i, 2-way RM-ANOVA with Bonferroni’s multiple comparison, Genotype: F(1,12)=0.0059, p=0.94; Session: F(15,180)=13.94, p= 4.88E-23; Genotype*Session interaction: F(15,180)=0.95, p=0.51) trials. (j-l) For Step 2 training, mean number of trials plotted against session (j, 2-way RM-ANOVA with Bonferroni’s multiple comparison, Genotype: F(1,12)=0.88 p=0.37; Session: F(15,180)=1.88 p=0.028; Genotype*Session interaction: F(15,180)=1.56 p=0.088), scatter plots of mean trials per session (k: Unpaired t-test t(12)=1.29, p=0.22) and total trials performed (l: Unpaired t-test t(12)=0.59, p=0.56). (m) Mean number of total licks for each session in Step 2 training (2-way RM-ANOVA with Bonferroni’s multiple comparison, Genotype: F(1,12)=2.08 p=0.18; Session: F(15,180)=3.51 p= 2.73E-5; Genotype*Session interaction: F(15,180)=2.58 p=0.0016). (n) Scatter plot of mean licks per trial in Step 2 training (Mann-Whitney test, U=11, p= 0.097). (o) Scatter plot of total number of licks in Step 2 training (Unpaired t-test t(12)=1.44, p=0.18). (e-o) Open circles represent individual animals, closed circles or solid black lines indicate population means and error bars or shaded area represent the SEMs. (a,c) Solid black and blue dashed lines indicate performance criteria for hits and FAs, respectively. (b,d) Solid black line indicates performance criteria for d’. All data obtained from n=7 WT and n=7 Het mice, from two cohorts of animals. All statistical tests were two-sided.

Supplementary information

Supplementary Figures 1–4

Reporting Summary

Supplementary Table 1

Registry entries with a completed sensory profile

Supplementary Table 2

Genotype of registry entries denoting touch-related sensory abnormalities

Supplementary Table 3

Up/down state properties of L2/3 barrel cortex neurons

Supplementary Video 1

Head-fixed wild-type mouse without a Botox injection

Supplementary Video 2

Head-fixed wild-type mouse after a Botox injection

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Michaelson, S.D., Ozkan, E.D., Aceti, M. et al. SYNGAP1 heterozygosity disrupts sensory processing by reducing touch-related activity within somatosensory cortex circuits. Nat Neurosci 21, 1–13 (2018).

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