Table 1 Mouse models of ASD-associated genetic mutations and their phenotypes.
From: Sensory abnormalities in autism spectrum disorder and their in vitro modeling
Gene | Models | Features | Sensory-related phenotypes | Reference |
|---|---|---|---|---|
Synapse formation and function-related genes | ||||
Shank1 | Knockout mice | Loss of Shank1 in parvalbumin(PV)-positive interneurons disrupted E/I balance, reducing both excitatory inputs and inhibitory outputs to pyramidal neurons in the hippocampus. | Not tested | Mao et al., (2015) [91] |
Knock-in mice (p.R882H) | In SHANK1(R882H) knock-in mice, reduced mGluR1-IP3R1 calcium signaling was observed, which corresponded with the manifestation of social deficits and repetitive behaviors. | Not tested | Qin et al., (2022) [92] | |
Shank2 | Knockout mice | Shank2 deficiency led to impaired NMDA receptor function, which may contribute to ASD-like behaviors. Restoring NMDAR function alleviated social impairments. Indirectly enhancing NMDAR activity through mGluR5 modulation presents a promising therapeutic approach. | Not tested | Won et al., (2012) [93] |
Knockout mice | In female Shank2 knockout mice, deficits in signaling were observed within social attachment circuits, including the medial preoptic area, which resulted in reduced maternal bonding with their pups. | Not tested | Grabrucker et al., (2021) [94] | |
Shank3 | Knockout mice | In Shank3B knockout mice, excitatory pyramidal neurons in the somatosensory cortex exhibited enhanced activity, whereas inhibitory interneurons showed diminished responsiveness. | Hypersensitivity to mild tactile stimuli | Chen et al., (2020) [68] |
Knock-in mice (e21-InsG) | SHANK3(e21-InsG) knock-in mice displayed ASD-like behaviors and impairments in hippocampal excitatory transmission, marked by altered NMDA receptor responses. These changes suggest that an imbalance between excitatory and inhibitory signaling underlies the observed phenotype. | Not tested | Speed et al., (2015) [95] | |
Heterozygous knockout mice | Shank3 haploinsufficiency caused aberrant actin cytoskeleton regulation and impaired NMDA receptor trafficking in excitatory neurons of the prefrontal cortex, contributing to an imbalance between excitatory and inhibitory signaling. | Not tested | Duffney et al., (2015) [96] | |
Knockout mice | Shank3Δe4-9 in mice induced neuronal hyperactivity by altering dendritic spine morphology and disrupting the excitatory/inhibitory balance within the PFC–BLA circuit, ultimately leading to impaired social behavior. | Not tested | Kim et al., (2022) [97] | |
Nlgn1 | Knockout mice | In Nlgn1 knockout mice, impaired spatial memory and increased repetitive grooming behavior were observed. These phenotypes was linked to a reduced NMDA/AMPA ratio and deficits in hippocampal long-term potentiation, which contribute to an excitatory/inhibitory imbalance relevant to ASD. | Not tested | Blundell et al., (2010) [98] |
Knockout mice | Nlgn1 deficiency in the striatum resulted in hyperactivity of dopamine receptor D2-expressing medium spiny neurons, which was correlated with excessive restricted and repetitive behaviors. | Not tested | Lv et al., (2025) [99] | |
Nlgn3 | Knockout mice | Nlgn3 knockout mice exhibited disrupted synaptic plasticity and heterosynaptic competition defects reminiscent of those seen in Fragile X syndrome, suggesting a shared synaptic pathophysiology. | Not tested | Baudouin et al., (2012) [100] |
Knock-in mice (p.R451C) | In NLGN3(R451C) knock-in mice, an increased inhibition-to-excitation ratio onto Purkinje cells and reduced climbing fiber activity were observed. These findings indicate that NLGN3 plays a critical role in cerebellar development and may contribute to ASD-like behaviors. | Not tested | Lai et al., (2021) [101] | |
Syngap1 | Heterozygous knockout mice | Syngap1 haploinsufficiency selectively affected excitatory neurons in the forebrain, resulting in increased excitatory synaptic activity and cognitive deficits. This disruption caused a secondary imbalance between excitatory and inhibitory signaling, leading to persistent brain dysfunction into adulthood. | Not tested | Ozkan et al., (2014) [102] |
Heterozygous knockout mice | Haploinsufficiency of Syngap1 in mice led to alterations in spine size and synaptic strength of indirect pathway striatal projection neurons, along with increased excitatory synaptic activity. Consistently, behavioral assessments revealed impaired rotarod motor performance and deficits in goal-directed behavior. | Not tested | Haetzel et al., (2024) [103] | |
Scn1a | Heterozygous knockout mice | Scn1a haploinsufficiency impaired GABAergic neurotransmission by reducing the excitability of forebrain interneurons, which led to an imbalance between inhibitory and excitatory signaling. This disruption contributed to ASD-like behaviors in mice, including deficits in social interactions, increased stereotyped behaviors, and impaired spatial memory. | Aversion to novel food odors / social odors | Han et al., (2012) [104] |
Heterozygous knockout mice | In Scn1a haploinsufficient mice, a delay in the GABA switch was observed, which has been identified as a cause of cognitive and social alterations resembling ASD-like features. | Not tested | Pizzamiglio et al., (2025) [105] | |
Neuronal development-related genes | ||||
Cntnap2 | Knockout mice | Real-time modulation of the excitatory/inhibitory balance in the prefrontal cortex of this mouse model rescued ASD-associated social deficits and hyperactivity, underscoring the critical role of E/I imbalance in ASD-like phenotypes. | Not tested | Selimbeyoglu et al., (2017) [67] |
Knockout mice | In Cntnap2 knockout mice, selective impairment of inhibitory synaptic transmission onto hippocampal CA1 pyramidal neurons resulted in an excitatory/inhibitory imbalance. | Not tested | Jurgensen et al., (2015) [106] | |
Knockout mice | Ectopic neuronal connectivity of perineuronal nets and PV-positive interneurons was formed across various sensory cortical regions and developmental stages in this mouse model, which may contribute to E/I balance disruptions associated with ASD. | Aberrant corticothalamic connectivity in primary sensory cortices | Gandhi et al., (2023) [107] | |
Knockout mice | In the Cntnap2 mouse model of autism, hyperexcitability within the reticular thalamic nucleus was identified, potentially disrupting thalamocortical inhibitory control and thereby contributing to ASD-associated behavioral phenotypes. | Not tested | Jang et al., (2025) [108] | |
Cntnap4 | Knockout mice | Cntnap4 knockout mice exhibited reduced inhibitory output from GABAergic basket cells and enhanced dopamine release in the nucleus accumbens. They also displayed abnormal sensory-motor gating and excessive grooming behaviors. | Auditory hypersensitivity | Karayannis et al., (2014) [109] |
Knockout mice | In male Cntnap4 knockout mice, GABAergic transmission and receptor expression in the basolateral amygdala were reduced, accompanied by a decrease in gut Lactobacillus abundance. | Not tested | Zhang et al., (2022) [110] | |
Tbr1 | Heterozygous knockout mice | Tbr1 haploinsufficient mice displayed ASD-like social behavior and impaired amygdala axonal projection, linked to E/I imbalance, fewer c-fos-positive neurons and lack of Grin2b induction. | Not tested | Huang et al., (2014) [111] |
Heterozygous knockout mice | In Tbr1 haploinsufficient mice, basolateral amygdala neurons exhibited aberrant axonal projections and mistargeting. These mice also displayed disrupted default-mode-network connectivity and reduced social interaction, hallmarks of ASD-like phenotypes, which were alleviated by deep-brain stimulation of the basolateral amygdala. | Not tested | Hsu et al., (2024) [112] | |
Foxp1 | Conditional knockout mice | Brain-specific Foxp1 deletion in mice disrupted striatal development and produces subtle hippocampal alterations including abnormal neuronal morphology and an E/I imbalance in the CA1 region. | Not tested | Bacon et al. (2015) [113] |
Conditional knockout mice | Cortex-specific Foxp1 deletion disrupted barrel formation in the primary somatosensory cortex, impaired growth of layer IV neurons, and led to abnormal thalamocortical synapse formation. Mutant mice consequently showed delayed tactile responses and heightened sensitivity to tactile stimuli. | Barrel formation defects, abnormal tactile response | Li et al., (2023) [114] | |
Gene expression or Protein synthesis-related genes | ||||
Eif4ebp2 | Knockout mice | Deletion of Eif4ebp2 enhanced translation of neuroligin, postsynaptic proteins implicated in ASD, and elevated the excitatory-to-inhibitory synaptic input ratio in mice, thereby eliciting ASD-like behaviors. | Barrel formation defects, abnormal tactile response | Gkogkas et al., (2013) [115] |
Conditional knockout mice | In mice with cerebellar Eif4ebp2 deficiency, Purkinje cells were reduced in number and fired action potentials with greater regularity. While these animals showed impairments in spatial memory and motor learning, they did not exhibit ASD-like behaviors. | Net tested | Hooshmandi et al., (2021) [116] | |
Mecp2 | Conditional knockout mice | In Mecp2 knockout mice, tactile-sensory processing abnormalities were linked to reduced GABA A receptor expression, resulting in deficient presynaptic inhibition at low-threshold mechanoreceptor terminals. | Tactile hypersensitivity, tactile avoidance | Orefice et al., (2016) [69] |
Transgenic duplicated mice | In MECP2-duplication mice, layer II/III neurons in the primary visual cortex displayed unusually high trial-to-trial reliability of visually evoked responses, coupled with reduced response amplitudes and dampened intrinsic activity fluctuations. | Abnormalities in visual processing | Ash et al., (2022) [117] | |
Fmr1, Tsc2 | Fmr1 hemizygote, Tsc2 heterozygote knockout mice | In both the tuberous sclerosis complex (TSC) and fragile X syndrome (FXS) mouse models, excessive protein synthesis triggered by mTOR hyperactivation in TSC or loss of FMRP in FXS disrupted the E/I balance, resulting in synaptic dysfunction and behavioral impairments. | Not tested | Auerbach et al., (2011) [118] |
Fmr1 hemizygote, Tsc2 heterozygote knockout mice | In both mouse models, sensory deprivation disrupted PV homeostatic plasticity in the primary somatosensory cortex. Moreover, the expected increase in PV-neuron excitability following sensory enrichment was absent in heterozygous Tsc2 mice, indicating a breakdown in the bidirectional homeostatic regulation of PV circuits. | Not tested | Monday et al., (2025) [119] | |
Pten | Conditional knockout mice | Loss of Pten in interneurons depleted somatostatin (SST)-positive interneurons, raising the PV/SST ratio, driving ectopic PV-cell projections into cortical layer I, and altering inhibition onto glutamatergic neurons. This E/I imbalance led to social deficits and abnormal EEG power. | Not tested | Vogt et al., (2015) [120] |
Conditional knockout mice | Selective Pten deletion in PV- and SST-expressing interneurons elicited ASD-like phenotypes in mice, including social deficits, impaired motor coordination and learning, and heightened repetitive behaviors. | Not tested | Shin et al., (2021) [121] | |
