The Rho family GTPases are small G proteins that act as molecular switches shuttling between active and inactive forms. Rho GTPases are regulated by two classes of regulatory proteins, guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). Rho GTPases transduce the upstream signals to downstream effectors, thus regulating diverse cellular processes, such as growth, migration, adhesion, and differentiation. In particular, Rho GTPases play essential roles in regulating neuronal morphology and function. Recent evidence suggests that dysfunction of Rho GTPase signaling contributes substantially to the pathogenesis of autism spectrum disorder (ASD). It has been found that 20 genes encoding Rho GTPase regulators and effectors are listed as ASD risk genes by Simons foundation autism research initiative (SFARI).
ASD Candidate Gene | Gene Name | Chromosome Location | Genetic Category | SFARI Gene Score | Upstream/DOWNSTREAM Rho GTPase(s) |
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Gene | Mouse/Cellular Model | Therapeutic Type | Therapeutic Strategy | Result | Reference | |||||||||||
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Rho GTPase GEF | ||||||||||||||||
TRIO | Trio deficient neurons | Pharmacological | Rp-cAMPS treatment (100 μM) | Increased dendritic spine density reversed | [81] | ARHGEF9 | Cdc42 guanine nucleotide exchange factor (GEF) 9 | Xq11.1-q11.2 | Rare Single Gene Mutation, Syndromic | Category 1 (High Confidence) | ||||||
Non-pharmacological | CDC42 | |||||||||||||||
PDE4A5 overexpression | TRIO | Trio Rho guanine nucleotide exchange factor | 5p15.2 | Rare Single Gene Mutation, Syndromic | Category 1 (High Confidence) | RHOA, RAC1 | ||||||||||
DOCK8 | Dedicator of cytokinesis 8 | 9p24.3 | Rare Single Gene Mutation | Category 2 (Strong Candidate) | CDC42 | |||||||||||
P-REX1 | Prex1-/- mice | Pharmacological | D-serine (for electrophysiology: 20 μM; for mouse: 0.8 g/kg i.p.(intraperitoneal)) | NMDAR-LTD restored; disruptive social novelty corrected | [82] | Activity ↓ Motor coordination ↓ |
Prepulse inhibition ⎻ | [81] | PREX1 | |||||||
Non-pharmacological | WT P-Rex1 or WT Rac1 overexpression (in CA1 pyramidal neurons) | NMDAR-LTD restored; disruptive social novelty and reversal learning corrected | Phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchange factor 1 | 20q13.13 | Genetic Association | NEX-Trio−/− mice Category 2 (Strong Candidate) | & | Social preference ↓ | ||||||||
DOCK4 | NT | RAC1 | ||||||||||||||
Dock4 KO mice | Nestlet shredding (M, ↑; F, ⎻) | Anxiety (M, ↑; F, ⎻) Depression ↑ |
Object recognition memory ⎻ | Activity ↑ Motor coordination ↓ |
Prepulse inhibition (M, ↓; F, ⎻) | ARHGEF10 | Rho guanine nucleotide exchange factor 10 | 8p23.3 | Rare Single Gene Mutation, Functional | Category 3 (Suggestive Evidence) | RHOA | |||||
DOCK1 | Dedicator of cytokinesis 1 | 10q26.2 | Rare Single Gene Mutation | Category 3 (Suggestive Evidence) | RAC1 | |||||||||||
DOCK4 | Dedicator of cytokinesis 4 | 7q31.1 | Rare Single Gene Mutation, Genetic Association, functional | Category 3 (Suggestive Evidence) | RAC1 | |||||||||||
Rho GTPase GAP | ||||||||||||||||
MYO9B | Myosin IXB | 19p13.11 | Rare Single Gene Mutation | Category 2 (Strong Candidate) | RHOA | |||||||||||
OPHN1 | Oligophrenin 1 | Xq12 | Rare Single Gene Mutation, Syndromic | Category 2 (Strong Candidate) | RHOA, RAC1, CDC42 | |||||||||||
ARHGAP5 | Rho GTPase activating protein 5 | |||||||||||||||
Pharmacological | D-cycloserine (DCS, 20 mg/kg i.p.) | Social novelty restored | [84] | PREX1 | Prex1−/− mice * | Social preference ↓ Social learning and memory ↓ Olfactory function ⎻ |
Ultrasonic vocalizations (pup) ↓ | Grooming ↑ | Anxiety ⎻ | Reversal learning ↓ Fear memory ↓ Object recognition memory ⎻ |
Activity ⎻ Motor coordination ⎻ |
Prepulse inhibition ⎻ | ||||
Non-pharmacological | [ | 82 | ] | |||||||||||||
WT Rac1 overexpression (in CA1 region) | Social novelty and synapatic transmission (mEPSC and LTP) restored | ARHGEF10 | Arhgef10 KO mice * | |||||||||||||
Dock4 knockdown neurons | Sociability and social novelty preference ↓ | NT | NT | Anxiety ↓ Depression ↓ |
Spatial learning and memory ⎻ | Activity ↑ | Non-pharmacological | WT Rac1 overexpression | Decreased dendritic spine density reversed | Prepulse inhibition ⎻ | [102[83] | |||||
] | DOCK4 | Dock4 KO mice & | Social novelty preference ↓ | Ultrasonic vocalizations (pup) ↓ | ||||||||||||
OPHN1 | Ophn1-/y mice | Stereotyped circling (~9% F; M, ⎻) |
Pharmacological | Marble burying (M, ⎻; F, NT) Grooming (M, ⎻; F, NT) |
Rp-cAMPS (bilaterally infused into PFC; 10 μg/μL; 300–400 nl) | Anxiety ↑ | Object recognition memory (F, ↓; M, ⎻) Spatial memory (M, ↓; F, ⎻) Working memory (M, ↓; F, ⎻) |
Activity (~9% F, ↑; M, ⎻) | NT | Cognitive dysfunction in Y-maze ameliorated | [ | [89]84] | 14q12 | Rare Single Gene Mutation | Category 3 (Suggestive Evidence) | RHOA, RAC1, CDC42 |
ARHGAP11B | ||||||||||||||||
Dock4 HET mice & | Social novelty preference (F,↓; M, ⎻) |
Ultrasonic vocalizations (pup) ⎻ | Stereotyped circling (~1.7% F; M, ⎻) Marble burying (M, ⎻; F, NT) Grooming (M, ⎻; F, NT) |
Anxiety ⎻ | ||||||||||||
Fasudil (dissolved in daily drinking water at 0.65 mg/mL for 3 weeks) | Spine morphology in olfactory bulbs, frequency and amplitude of mIPSC in olfactory neurons, and olfactory behaviors rescued | [87]Object recognition memory ⎻ Spatial memory (F, ↓; M, ⎻) Working memory ⎻ |
Activity (~1.7% F,↑; M, ⎻) | NT | ||||||||||||
Summary of ASD-related behavior tests in Rho GAP mouse models | ||||||||||||||||
OPHN1 | ||||||||||||||||
Fear memory extinction restored | [88 | Ophn1-/y mice * | Aggressivity ↓ Social memory ⎻ Olfactory function ↓ |
NT | NT | Anxiety ⎻ | Working, object recognition, and spatial learning and memory ↓ Fear memory extinction ↓ Vicarious trial and error (VTE) behavior ↓ |
Activity ↑ Motor coordination ⎻ Behavioral lateralization ↓ |
NT | [85][86][87][88][89] | ||||||
ARHGAP32 | PX-RICS−/− mice (M were used in most behavior tests unless otherwise stated) | Social novelty preference ↓ social interaction ↓ |
Ultrasonic vocalizations (M and F,↓) | Grooming ↑ Marble burying ↑ |
NT | Reversal learning ↓ Fear memory ↓ |
Motor coordination ↓ | Epilepsy (Severe progressive seizures) | [90][91] | Rho GTPase activating protein 11B | 15q13.2 | Rare Single Gene Mutation | Category 3 (Suggestive Evidence) | Unknown | ||
PX-RICS+/− mice (M were used in most behavior tests unless otherwise stated) | Social novelty preference ↓ social interaction ↓ |
Ultrasonic vocalizations (M and F, ⎻) | Grooming ⎻ Marble burying ↑ |
NT | Reversal learning ⎻ | Motor coordination ⎻ | NT | [90] | ||||||||
SRGAP3 | WRP−/− mice & | NT | NT | NT | Anxiety ⎻ | Object recognition and long-term memory ↓ Spatial and reversal learning ↓ Working memory ⎻ |
Activity ⎻ Motor coordination ⎻ |
NT | [92] | |||||||
] | ||||||||||||||||
Fasudil (orally a daily dose of 3 mg for 3 months) | Locomotor activity and object recognition memory restored; abnormal brain morphology ameliorated | [86] | ||||||||||||||
ARHGAP32 | PX-RICS-/- mice | Pharmacological | Clonazepam (CZP, 0.03 mg/kg i.p.) | Deficits of social preference, reversal learning, and cued fear learning memory reversed | [90][91] | ARHGAP32 | Rho GTPase activating protein 32 | 11q24.3 | Rare Single Gene Mutation, Functional | Category 3 (Suggestive Evidence) | RHOA, RAC1, CDC42 | |||||
SRGAP3 | SLIT-ROBO Rho GTPase activating protein 3 | 3p25.3 | Rare Single Gene Mutation | WRP+/− mice &Category 3 (Suggestive Evidence) | CDC42, RAC1 | |||||||||||
NT | NT | NT | Anxiety ⎻ | Object recognition and long-term memory ↓ Spatial and reversal learning ↓ Working memory ⎻ |
Activity ⎻ Motor coordination ⎻ |
NT | OCRL | Oculocerebrorenal syndrome of Lowe | Xq26.1 | Rare Single Gene Mutation, Syndromic | ||||||
SrGAP3-/- mice | Syndromic | & | Social interaction ↓CDC42, RAC1 | |||||||||||||
NT | Marble burying (M, ⎻; F, NT) | Anxiety ⎻ | Working memory ↓ Spatial and object recognition memory ⎻ Fear memory ↑ |
Activity (M,↓; F, ⎻) | Prepulse inhibition (F,↓; M, ⎻) | [93][94] | ||||||||||
OCRL | Ocrl1−/y mice * | NT | NT | NT | NT | Passive avoidance preference ⎻ | Activity ⎻ Motor coordination ↓ |
NT | [95] | |||||||
Ocrl1−/y mice * (Inpp5b deleted but human INPP5B overexpressed) | Social preference ⎻ Social novelty ⎻ |
NT | NT | NT | Spatial learning and memory ⎻ | Activity ↓ | NT | [96] | ||||||||
Summary of ASD-related behavior tests in Rho effector mouse models | ||||||||||||||||
CYFIP1 | Cyfip1 HET mice * | |||||||||||||||
CYFIP1 | Cyfip1 HET mice hippocampal slices | Pharmacological | LY367385 (100 μM) and MPEP (2-Methyl-6-phenylethynyl pyridine), (10 μM) (Incubated in slices) | mGluR-LTD normalized to control levels | [70] | |||||||||||
Cyfip1HET mice | Non-pharmacological | Motor training (at postnatal days 40, 50, and 51) | Motor deficits alleviated | [73] | ||||||||||||
PAK2 | Pak2+/- mice | Non-pharmacological | p-cofilin peptide (15 pmol/g i.v. (intravenous)) | Social behaviors moderately improved | [97] | |||||||||||
ITPR1 | Wnt1-Cre;Itpr1flox/flox mice | Pharmacological | CNQX (5 mM; infused into the cerebellum; 0.5 μL/min for 20 min) | Dyskinesia ameliorated | [100] | Rho GTPase Effector | ||||||||||
NCKAP1 | NCK-associated protein 1 | 2q32.1 | Rare Single Gene Mutation | Category 1 (High Confidence) | RAC1 | |||||||||||
CYFIP1 | Cytoplasmic FMR1 interacting protein 1 | 15q11.2 | Rare Single Gene Mutation, Genetic Association, Functional | Category 2 (Strong Candidate) | RAC1 | |||||||||||
PAK2 | p21 (RAC1) activated kinase 2 | 3q29 | Rare Single Gene Mutation | Category 2 (Strong Candidate) | CDC42, RAC1 | |||||||||||
ITPR1 | Inositol 1,4,5-trisphosphate receptor type 1 | 3p26.1 | Rare Single Gene Mutation | Category 3 (Suggestive Evidence) | RHOA | |||||||||||
PRKCA | Protein kinase C alpha | 17q24.2 | Rare Single Gene Mutation | Category 3 (Suggestive Evidence) | RHOA, RAC1, CDC42 | |||||||||||
WASF1 | WAS protein family member 1 | 6q21 | Syndromic | Syndromic | RAC1 |
Gene | Mouse Model | Core Symptoms | Comorbidities | Reference | |||||
---|---|---|---|---|---|---|---|---|---|
Social Related Behavior | Language Communication | Repetitive Behavior | Anxiety and Depression | Learning and Memory | Basic locomotion and Motor Coordination | Schizophrenia and Epilepsy | |||
Summary of ASD-related behavior tests in Rho GEF mouse models | |||||||||
ARHGEF9 | Arhgef9 KO mice * | NT 1 | NT | NT | Anxiety ↑ | Spatial learning and memory ↓ | Activity ⎻ | NT | [79] |
TRIO | Emx1-Trio−/− mice # | NT | NT | NT | NT | Spatial learning and memory ↓ Fear memory ↓ |
NT | NT | [80] |
NEX-Trio+/− mice & | Social preference ↓ | NT | Nestlet shredding (M2, ↑; F3, ⎻) | Anxiety ↑ Depression ⎻ |
Object recognition memory ⎻ | ||||
Non-pharmacological | |||||||||
Mating with | |||||||||
Lurcher | |||||||||
mice ( | |||||||||
GluD2 | |||||||||
LC/+ | ) | Dystonic movements eliminated | |||||||
Social interaction ⎻ | |||||||||
NT | NT | Anxiety ⎻ | Hippocampus-dependent memory ↓ Working, spatial, and fearing memory ⎻ |
Activity ⎻ | Prepulse inhibition ⎻ | [70] | |||
Cyfip1HET mice # | Social interest ↓ | Ultrasonic vocalizations ⎻ | Marble burying ⎻ | NT | NT | Activity ⎻ Motor coordination ↓ |
NT | [73] | |
Cyfip1 m+/p− (Paternal origin) and Cyfip1 m−/p+ (maternal origin) mice # | NT | NT | NT | Anxiety-like behavior | Fear memory (m+/p−, ↑; m−/p+, ⎻) | Activity (m+/p−, ⎻; m−/p+, ↓) | NT | [74] | |
Cyfip1+/− mice * | NT | NT | Self-grooming ⎻ Marble burying ⎻ |
NT | Spatial memory and flexibility ⎻ Object recognition memory ↓ Working memory ⎻ |
Activity ⎻ Motor coordination ↓ |
Prepulse inhibition ↓ | [75] | |
Cyfip1+/− rat * | NT | NT | NT | NT | Behavioral flexibility ↓ | NT | NT | [77] | |
Human CYFIP1 overexpressing mice (Tg line 1 and Tg line 2) & | Social preference ⎻ | Ultrasonic vocalizations ⎻ | Grooming ⎻ Digging ⎻ |
Anxiety ⎻ | Fear memory (Line 1 and line 2, ↑) Spatial learning memory (Line 2, ↓; line 1, ⎻) Working memory (M and F of both lines, ⎻) |
Activity ⎻ | Prepulse inhibition ⎻ | [78] | |
PAK2 | PAK2+/− mice * | Social preference ↓ Social memory ↓ |
Ultrasonic vocalizations ⎻ | Marble burying ↑ Grooming ↑ |
Anxiety ⎻ | Spatial learning and memory ⎻ | Activity ⎻ | Prepulse inhibition ⎻ Acoustic startle response ⎻ |
[97] |
ITPR1 | IP3R1+/− mice& | NT | NT | NT | NT | NT | Activity ⎻ Motor coordination ↓ |
NT | [98] |
L7-Cre; Itpr1flox/flox mice # | NT | NT | NT | NT | NT | Motor coordination ↓ | NT | [99] | |
Wnt1-Cre; Itpr1flox/flox mice # | NT | NT | NT | NT | NT | Motor coordination ↓ | NT | [100] | |
WASF1 | WAVE-1 KO mice # | NT | NT | NT | Anxiety ↓ | Spatial learning and memory ↓ Object recognition memory ↓ Passive avoidance ⎻ |
Activity ↓ Motor coordination ↓ |
NT | [101] |
WAVE-1 HET mice # | NT | NT | NT | Anxiety ⎻ | Learning and memory ⎻ | Activity ↓ Motor coordination ↓ |
NT |