Table 1 Mouse models of ASD
From: Signalling pathways in autism spectrum disorder: mechanisms and therapeutic implications
Target | Mice | Behaviour phenotypes | Molecular, cellular and circuit phenotypes | Mechanism | Ref. |
|---|---|---|---|---|---|
Nlgn | Nlgn-3 KO | Reduced ultrasound vocalization Impaired social novelty preference Olfactory deficit Increased repetitive behaviour | Selective synapse impairment | Nlgn-3 mutations specifically impede synaptic inhibition on D1-dopamine receptor-expressing neurons | |
Nlgn-3 R451C | Impaired social interactions Enhanced spatial learning abilities | Altered inhibitory synaptic transmission Altered excitatory synaptic transmission Enhanced the complexity of dendritic branching | Neuroligin dysfunction altered the E/I balance and synaptic transmission | ||
Nlgn-4 KO | Impaired social interactions and social memory Reduced ultrasound vocalization | Reduced brain volume | Loss of Nlgn-4 selectively impaired glycinergic synaptic transmission | ||
Nrxn | Nrxn-1α KO | Increased repetitive grooming Deficient social behaviours Elevated anxiety Reduced nest building | Deficient excitatory synaptic strength Impaired PPI | Nrxn-1α deficiency reduced excitatory synaptic transmission and resulted in an E/I imbalance | |
Nrxn-2α KO | Deficient social interaction Increased anxiety-like behaviour | Reduced spontaneous transmitter release at excitatory synapses in the neocortex Impaired NMDAR function | E/I imbalance | ||
MeCP2 | MeCP2+/− | Impaired motor coordination Increased anxiety Abnormal social behaviour Deficient contextual fear memory Breathing abnormalities | Reduced brain volume Enhanced PPI | Absence of MeCP2 | |
MeCP2-TG1 | Motor defects Stereotypies and seizures Impaired social behaviour Anxiety-like behaviour | Increased Crh and Oprm1 in the amygdala | Social approach deficits may be due to increased Oprm1 levels | ||
Shank3 | Shank3 e4–9 KO | Repetitive grooming Deficits in learning and memory Abnormal ultrasound vocalizations | Decreased levels of Homer1b/c, GKAP and GluA1 at the PSD Decreased NMDA/AMPA ratio at excitatory synapses Deficits in LTP | Homozygous deletion of exons 4-9 induce loss of isoforms of Shank3 | |
Shank3B-/- | Repetitive grooming Deficient social interaction | Altered PSD composition in the striatum Morphological defects of medium spiny neurons Reduced cortico-striatal synaptic transmission | Dysfunction of Nrxn/Nlgn/PSD95/SAPA-P/Shank complex | ||
Shank3 HET | Impaired social behaviour Reduced ultrasound vocalization | Reduced basal neurotransmission | Shank3 deficiency influence AMPA receptor recruitment and synaptic development | ||
Shank3+/ΔC | Social deficits Repetitive behaviours | Diminished NMDAR synaptic function and synaptic distribution | Shank3 deficiency leads to the reduced expression of βPIX (GEF for Rac1), and Rac1/PAK/LIMK signalling | ||
InsG3680 | Impaired social interaction Repetitive self-grooming Increased levels of anxiety Impaired motor coordination | Severe striatal synaptic defects Altered PSD composition Much minor molecular defects at cortical synapses at P14 | Impaired synaptic transmission induced long-lasting alterations in striatal connectivity | ||
Shank2 | Shank2−/− | Repetitive grooming Abnormal vocal and social behaviours | Reduced dendritic spines basal synaptic transmission Decreased frequency of miniature excitatory postsynaptic currents enhanced NMDAR-mediated excitatory currents at the physiological level | Altered glutamatergic neurotransmission can lead to the core symptoms of ASD | |
L7-Shank2−/− | Impaired motor learning Abnormal social and repetitive behaviour | Decreased AMPAR in cerebellar synaptosomes Increased sIPSCs and spiking irregularity Impaired synaptic and intrinsic plasticity in PC | Shank2 deficiency impairs PC intrinsic plasticity and induction of LTP at the parallel fibre to PC synapse | ||
Fmr1 | Fmr1 KO | Deficient social behaviour | Elevated basal protein synthesis LTD is exaggerated downstream of an mGluR5 signalling pathway | The absence of FMRP leads to enhanced activity of mGluR5 signal transduction pathways | |
Tsc | Tsc1+/−, Tsc2+/− | Deficient social interaction | Hyperactivation of mTOR | Uninhibited mTOR signalling pathways | |
L7Cre; Tsc1+/+ | Abnormal social interaction and vocalizations Increased repetitive behaviour | Decreased PC excitability | Overactivity of the mTOR signalling pathway | ||
Tsc2+/− | Deficient social interaction | Deficient spine pruning and cortical projection neurons Deficient autophagy | Tsc2 mutations caused unregulated mTOR activity | ||
Ube3a | Ube3a 1× and 2× transgenic | Defective social interaction Impaired communication Increased repetitive stereotypic behaviour | Suppressed glutamatergic synaptic transmission | Increased E3A ubiquitin ligase gene dosage results in reduced excitatory synaptic transmission | |
Chd8 | Chd8+/− | Deficient social behaviour Communication difficulties Repetitive behaviour | Synaptic dysfunction within MSNs in the NAc Delayed neurodevelopment | Reduced expression of CHD8 is associated with abnormal activation of REST | |
Scn1 | Scn1a+/− | Stereotyped behaviour Deficient social interaction Impaired context-dependent spatial memory | Decreased NMDAR synaptic function and synaptic distribution Decreased cortical actin filaments Insufficient NMDAR | Scn1a haploinsufficiency impaired GABAergic neurotransmission and NaV1.1 dysfunction induce behavioural and cognitive impairments | |
Syngap | Syngap1 HET | Deficient social memory Tendency to social isolation | Dendritic spine synapses develop prematurely Premature spine maturation enhanced excitability | SYNGAP1 deficiency impaired NMDAR-CAMKII-SynGAP-GluR1 pathway SYNGAP1 haploinsufficiency altered E/I balance | |
Arid1b | Arid1b+/− | Abnormal cognitive and social behaviour | Decreased number of cortical GABAergic interneurons Reduced proliferation of interneuron progenitors in the ganglionic eminence Imbalance between excitatory and inhibitory synapses | Arid1b haploinsufficiency suppressed H3K9Ac overall, and reduced H3K9Ac of the Pvalb promoter, resulting in decreased transcription | |
Tbr1 | Tbr1+/− | Impairment of social interaction, ultrasound vocalization, associative memory and cognitive flexibility | Defective axonal projections of amygdala neurons | Tbr1 gene altered the expression of Ntng1, Cntn2 and Cdh8 and reduced both inter- and intra-amygdala connections | |
Pten | Pten+/– | Deficient social behaviour Repetitive behaviour Lower circadian activity Impaired emotional learning | Brain overgrowth Abnormal immune system Altered cytoarchitecture and synaptic | Desynchronized growth in key cell types | |
Nse-cre; Ptenf/f | Abnormal social interaction Heightened anxiety Decreased motor activity | Macrocephaly Neuronal hypertrophy Loss of neuronal polarity | Abnormal activation of the PI3K/AKT pathway in specific neuronal populations | ||
NS-Pten KO | Repetitive behaviour Deficient social behaviour | Decreased mGluR Increased phosphorylated fragile X mental retardation protein Decreased dendritic potassium channel Kv4.2 Decreased PSD-95 and SAP102 | Hyperactivation of the PI3K/AKT/mTOR pathway | ||
Nestin-cre; Ptenf/f | Impaired social interactions Increased seizure activity | Increased differentiation to the astrocytic lineage Stem/progenitor cells develop into hypertrophied neurons with abnormal polarity | Altered AKT/mTOR/GSK3β signalling pathway | ||
En2 | En2-/- | Deficient social behaviour Deficient novel object recognition memory and spatial learning Increased depression-like behaviour | Deficient PPI | En2 deficiency influence SynI mRNA and protein levels | |
Cntnap2 | Cntnap2−/− | Abnormal vocal communication Repetitive and restrictive behaviours Abnormal social interactions | Neuronal migration abnormalities Reduced number of interneurons Abnormal neuronal network activity Reduced cortical neuronal synchrony | Cntnap2 deficiency may induce overactivation of direct pathway which promotes motor behaviour | |
15q11-13 | patDp/+ | Deficient social interaction Behavioural inflexibility Abnormal ultrasound vocalizations Correlates of anxiety | Increased [Ca2+]i response to 5-HT2cR signalling | Increased MBII52 snoRNA within the duplicated region, affecting 5-HT2cR | |
15q13.3 | Df (h15q13)/+ | Impairment in social interactions Restricted-repetitive behaviours Deficient communication | Enlarged brains and lateral ventricles Altered gamma-band EEG and ERPs | 15q13.3 microdeletion impair expression of Fan1, Mtmr10, Chrna7, Trpm1, Klf13, or Otud7a | |
16p11.2 | df/+ dp/+ | Stereotypic motor behaviour | Increased numbers of Drd2 MSNs in the striatum Downregulation of DA signalling | 16p11.2 deletion induce ENK dysregulation | |
22q11 | Df (16)1/+ | Deficient hippocampus-dependent spatial memory | Enhanced short- and long-term synaptic plasticity at hippocampal CA3–CA1 synapses Altered calcium kinetics in CA3 presynaptic terminals upregulated SERCA2 | Presynaptic SERCA2 upregulation | |
_ | (COX)-2− | Decreased motor activity Increased anxiety-linked behaviours Increased repetitive behaviours Deficient social behaviour | Altered expression of Wnt2, Glo1, Grm5 and Mmp9 Decreased glyoxalase 1 expression | Altered COX2/PGE2 pathway change neuronal cell behaviour and differential expression of genes and proteins related to ASD | |
_ | mice treated with VPA | Decreased social interaction | Chronic activation of glial in the hippocampus and the cerebellum Increased expression of TNF-α and IL-6 in the cerebellum Increased microglia density in the hippocampus | VPA-treatment led to decreased expression of PTEN and increased levels of p-AKT protein | |
_ | BTBR T+ltpr3tf/J | Increased self-grooming Impaired social behaviour | Increased IgG and IgE in serum and IgG anti-brain antibodies Increased expression of cytokines in the brain Increased proportion of MHC-II-expressing microglia | Different autoimmune profile of BTBR mice is implicated in their aberrant behaviours | |
_ | MIA | Deficient sociability Increased repetitive/stereotyped behaviour | Deficits in dendritic spine density, levels of synaptic proteins, synaptic transmission, LTP, and cortical malformations | Immune activation within the maternal compartment likely influences the developing fetal CNS through inflammatory mediators found in the blood and amniotic fluid of mothers |
