Table 2. Genetic animal models targeting classical ASD risk genes.

Genes		Neuronal function		Clinical relevancea													Rescue agentc				References
				Typical symptoms						Animal performancesb
				①	②	③	④	⑤			①	②	③	④	⑤		Genetic		Pharmaceutical
a: M: Monkey; R: Rodents; F: Fish; I: Invertebrates. b: ①: Social communication disorders; ②: Repetitive/stereotyped behaviors; ③: Narrow interests; ④: Impaired linguistics; ⑤: Intellectual disability. +: Positive, –: Negative. c: Based on the public data from SFARI GENE: https://gene.sfari.org/database/animal-models/rescue-animal-models.
Syndromic
MECP2		Starts or inhibits transcription; neuron maturation; regulated by development		+	+	+	+	+		M	+	+	+	–	+		One copy knocked out of Crh, or Crhr1, or Oprm; Reducing Mecp2 expression from a transgene, MECP2-dNIC; Reinstatement of Mecp2		7,8-Dihydroxyflavone; Acetyl-L-carnitine; D-Cycloserine; CX546; Antalarmin; Cysteamine; RU-486; Isoguvacine; Midazolam; Fenobam; SCH-23390; SCH-39166		Achilly et al., 2021; Zhan et al., 2021
										R	+	+	+	+	+
										F	+	+	+	–	+
										I	+	+	+	–	+
FMR1		Involves in translation; affects neuronal proliferation and migration		+	+	+	+	+		R	+	+	+	+	+		Inactivation of one allele of App gene; inactivation of one copy of S6K1; inactivation of S6K1 gene		Cyclosporine-A; Dexpramipexole; Isoguvacine; CTEP; Bryostatin1; MPEP; BW-723C86; MDL-11,939; JQ1; Sulpiride; CX-4945, Recombinant IL-17a, Lithium; Minocycline; Lipopolysaccharide; Bumetanide; FRAX486		Dockendorff et al., 2002; Kim et al., 2014b; Reynolds et al., 2021; Schiavi et al., 2020
										F	+	+	+	–	+
										I	+	+	+	–	+
SHANK3		Promotes formation, maturation, and stability of dendritic spines		+	+	+	+	+		M	+	+	+	–	+		Reinstatement of Shank3; beta-catenin shRNA; constitutively active Rac1		CDPPB; MPEP; Insulin-like growth factor 1 and its peptide derivative; CX-546; Lipopolysaccharide; Cocaine; Isoguvacine; D-Cycloserine; 7,8-Dihydroxyflavone; TG003; Valproic acid; Aripiprazole; Clozapine; Romidepsin; Fluoxetine; Phospho-cofilin peptide; Oxytocin; Risperidone; Trichostatin A		Han et al., 2013; Kozol et al., 2015; Liu et al., 2018; Matas et al., 2021; Mossa et al., 2021
										R	+	+	+	+	+
										F	+	+	+	–	+
										I	+	+	+	–	+
TSC1/2		Regulates mTORC1 pathway, neuronal differentiation, and Purkinje cell excitability		+	+	+	+	+		R	+	+	+	+	+		–		D-Cycloserine, Fenobam, SCH-23390, SCH-39166, Rapamycin		Normand et al., 2013; Tsai et al., 2012
UBE3A		Regulates neuronal homeostatic synaptic plasticity		+	+	+	+	+		R	+	+	+	–	+		Reinstatement of Ube3a in GABAergic neurons		Cbln1 expression; THIP; Pamin		Krishnan et al, 2017; Xu et al, 2018
Non-syndromic
NLGNs		Regulates the formation of hippocampal neurons and post-glutamatergic synapse proteins		+	+	+	+	+		R	+	+	+	+	+		Nlgn3，shRNAs against Nlgn1，shRNAs against Nlgn2，DIO-NL3 transgene in nucleus accumbens，Optogenetic activation of Pvalb interneurons， Nlgn3 reexpression		ETC-168, ACEA, HU-210, Quinpirole, URB597		Camacho et al., 2014; Kolozsi et al., 2009; Sledziowska et al., 2020
NRXNs		Encodes neuronal transmembrane protein; interacts glial cells		+	+	+	+	+		R	+	+	+	+	+		–		–		Etherton et al., 2009; Tromp et al., 2021
CHD8		Controls epigenetic and transcript regulation; affects brain phenotype		+	+	+	+	+		R	+	+	+	–	+		Human CHD8; stabilized Ctnnb1(S37A)		CPI-455; Oxytocin		Kunkel et al, 2018; Platt et al, 2017; Sugathan et al, 2014
										F	–	–	–	–	–
POGZ		Regulates neuronal development		+	+	+	+	+		R	+	+	+	–	–		–		NBQX; Oxytocin; Perampanel		Matsumura et al, 2020; Suliman-Lavie et al, 2020; White et al, 2016
ANK2		Affects axonal branching; regulates postnatal development of excitatory synapses		+	+	+	–	–		R	+	+	+	–	–		–		–		Iossifov et al, 2014; Sztainberg et al, 2016
MIR137		Regulates neuronal gene expression and neurogenesis		+	+	+	+	+		R	+	+	+	–	–		Ablation of Pde10a		Papaverine		Cheng et al., 2018
16p11.2		Controls prefrontal connectivity; endothelium-dependent structural and functional neurovascular		+	+	+	+	+		R	+	+	+	+	+		–		–		Portmann et al, 2014; Yin et al, 2021
										F	–	–	–	–	–