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. 2018 Aug 29;11:294. doi: 10.3389/fnmol.2018.00294

Table 1.

Zebrafish models of autism spectrum disorders (ASD)-associated genes and genetic syndromes.

Human Gene(s) Zebrafish Gene(s) Disorder* Method** Phenotype(s) Rescue Reference
CHD7 chd7 CHARGE MO

  • Abnormal somite segmentation (13 somite)

  • Small eyes, pericardial edema, abnormal otoliths (48 hpf)

  • Abnormal vascular patterning (48 hpf), cranial neural crest (34 –36 hpf), cranial neuron (48 hpf), and retinal (72 hpf) development; decreased bone mineralization (8 dpf, 14 dpf)

 Zebrafish mRNA rescues eye, heart, and otolith abnormalities Patten et al. (2012)
MO

  • Developmental defects as in Patten et al. (2012)

  • Decreased cell proliferation (25 hpf)

  • Abnormal craniofacial cartilage (4 dpf)

 fbxl10 MO reduced developmental defects, cell proliferation deficit Balow et al. (2013)
MO
CRISPR Mutant
  • chd7 −/− mutants and chd7 MO:
    • -
      Pericardial edema, cardiomegaly (3 dpf); abnormal pigmentation (4 dpf)
    • -
      Reduction of vagal innervation of GI tract in foregut more than hindgut (5 dpf)
    • -
      Decreased GI emptying (5 dpf)
 Prokinetic drugs do not rescue GI emptying Cloney et al. (2018)
CHD8 chd8 ASD MO;
F0
CRISPR

  • Macrocephaly (increased interorbital/intertectal distance (4.3 dpf) in MO; increased interorbital distance in F0 CRISPR)

  • Developmental marker expression changes: expansion of chordin (shield stage); increased mid/forebrain neuronal progenitor marker otx2 (tail bud) and dlx2 in prethalamus (24 hpf; MO)

  • Decreased GI motility (MO) and # of enteric neurons (6 dpf; MO and F0 CRISPR)

 − Bernier et al. (2014)
MO

  • Ectopic HuC/D expression in anterior forebrain (2 dpf)

  • Increased cell proliferation in brain (2 dpf)

 − Sugathan et al. (2014)
CNTNAP2 cntnap2a/b ASD
EP
CDFE		 ZFN
Mutant

  • Decreased forebrain GABAergic neurons (4 dpf)

  • Increased sensitivity to drug-induced seizures; nighttime hyperactivity (4–6 dpf)

  • GABA-modifying drugs induce differential behavioral responses

  • Increased sensitivity to behavioral activation by NMDA antagonists

 Estrogenic compounds identified in drug screen rescue nighttime hyperactivity Hoffman et al. (2016)
DYRK1A dyrk1aa ASD TALEN
Mutant

  • Normal development, morphology (24–48 hpf); normal larval locomotor activity (5–7 dpf)

  • No difference in brain size (2 weeks old); increased apoptosis in brain (3 weeks old)

  • Adult Phenotypes: Microcephaly; decreased anxiety, social behavior impairments, decreased c-fos, crh expression in hypothalamic regions after social interaction, social isolation, respectively

 − Kim et al. (2017)
FMR1 fmr1 FXS MO
OE
  • fmr1 MO:
    • -
      Abnormal mid-hindbrain boundary, altered dlx2a expression (24 hpf)
    • -
      Increased branching of trigeminal and Rohon-Beard neurites (24 hpf)
    • -
      Axon defasciculation of lateral longitudinal fasciculus (5 dpf)
    • -
      Fewer trigeminal neurons; craniofacial abnormalities (5 dpf)
 fmr1 mRNA rescues dlx2a expression; MPEP rescues neurite branching, number of trigeminal neurons Tucker et al. (2006)
  • OE fmr1 mRNA:
    • -
      Decreased branching of trigeminal and Rohon-Beard neurites (24 hpf)
    • -
      Increased trigeminal neurons
TILLING
Mutant

  • No gross morphological abnormalities; no differences in dlx2a expression

  • No craniofacial abnormalities (5 dpf); no defects in Rohon-Beard neurite branching

 − den Broeder et al. (2009)
MECP2 mecp2 RTT TILLING
Mutant

  • Increased contractions during coiling events (25 hpf)

  • Increased C-bend duration during escape response (51 hpf)

  • Decreased locomotor activity and thigmotaxis (6 dpf)

 − Pietri et al. (2013)
MECP2 mecp2 RTT MO;
F0
CRISPR;
OE
  • mecp2 MO:
    • -
      Increased neural, glial proliferation; decreased differentiation (48 hpf) (MO and F0 CRISPR)
    • -
      Upregulation of Notch signaling genes; increased brain her2, id1 expression (48 hpf)
  • mecp2 OE:
    • -
      Decreased cell proliferation, increased neuronal differentiation (48 hpf)
    • -
      Decreased id1 expression (48 hpf)
 mecp2 mRNA, her2 MO, id1 MO rescue proliferation, differentiation phenotypes in mecp2 MO; id1 MO rescues her2 levels in mecp2 MO Gao et al. (2015)
MO;
TILLING
Mutant
  • mecp2−/− mutant and mecp2 MO:
    • -
      Decreased trigeminal neurite length (24 hpf); less severe in mutant
    • -
      Downregulation of sema3f, sema5b and robo2 (24 hpf); less severe in mutant
    • -
      MO + mutant does not worsen mutant phenotypes
  • mecp2 MO:
    • -
      Increased apoptosis (16 hpf, 24 hpf); delayed response to tactile stimuli (48 hpf)
 Zebrafish mecp2 mRNA rescues neurite length; HuC-mecp2, sema5b, robo2 mRNA rescue neurite length and tactile response phenotypes Leong et al. (2015)
MO

  • Decreased Rohon-Beard axon length/branching (28 hpf)

  • Motor neuron axon abnormalities: caudal primary (28 hpf), caudal secondary (72 hpf)

  • Decreased touch response (28 hpf, 72 hpf)

  • Increased bdnf expression (24 hpf)

  • Increased presynaptic SV2-stained area, abnormal formation of neuromuscular junction (72 hpf; also in bdnf OE); bdnf MO decreases presynaptic area in mecp2 MO

 Human MECP2 mRNA rescues motor axon, touch response phenotypes; MECP2 lacking MBD domain does not rescue Nozawa et al. (2017)
TILLING
Mutant

  • Body length: decreased at 2 dpf; normal at 7 dpf

  • GI tract discoloration, abnormal droplets (4 dpf, 7 dpf)

  • Expression of inflammatory marker crp: normal at 3 dpf; increased at 4–5 dpf

 mecp2 OE partially rescues tnfa expression (24 hpf); tnfa OE does not rescue body length, GI-associated neutrophil number (2–3 dpf) van der Vaart et al. (2017)

  • Neutrophil number: normal at 3 dpf, increased at 4–5 dpf; increased in GI tract (2–5 dpf)

  • Dysregulated cytokine expression; decreased tnfa expression (6 hpf, 24 hpf–7 dpf)

  • No tnfa activation during acute inflammation (3 dpf)
SHANK3 shank3a ASD
PMS		 MO

  • Abnormal mid-hindbrain boundary, ventricle size (28–30 hpf)

  • Increased apoptosis in CNS (reversed by p53 MO) (24–28 hpf)

  • Decreased GABAergic neurons (mid/hindbrain), glutamatergic neurons (hindbrain; 48 hpf)

  • Abnormal escape responses and seizure-like behaviors (72 hpf)

 Human SHANK3 mRNA partially rescues apoptosis Kozol et al. (2015)
shank3b CRISPR
Mutant

  • Transient developmental delay (24 hpf)

  • Decreased HuC:RFP levels (24–72 hpf), though difference decreases over time

  • Decreased locomotor activity (7 dpf)

  • Adult Phenotypes: Increased brain size, decreased locomotor activity/thigmotaxis, social behavior impairments, repetitive behaviors, decreased brain homer1, synaptophysin levels

 − Liu et al. (2018)
SYNGAP1 syngap1b ASD MO

  • Abnormal mid-hindbrain boundary, ventricle size (28–30 hpf)

  • Increased apoptosis in CNS (not reversed by p53 MO) (24–28 hpf)

  • Microcephaly, developmental delay (48–72 hpf)

  • Decreased GABAergic neurons in midbrain, glutamatergic neurons in hindbrain (48 hpf)

  • Abnormal escape responses and seizure-like behaviors (72 hpf)

 Human SYNGAP1 mRNA partially rescues apoptosis Kozol et al. (2015)
TSC1 tsc1a TSC MO

  • Body curvature, cysts in tubular/glomerular regions of pronephros

  • Decreased left-right asymmetry; increased TOR activity (24 hpf), ciliary length (20–24 hpf)

 − DiBella et al. (2009)
TSC2 tsc2 TSC TILLING
Mutant;
OE;
Cell
transplantation
  • tsc2−/−:
    • -
      Deflated swim bladder, enlarged liver, increased TORC1 activity (7 dpf); death by 11 dpf
    • -
      Increased size of hepatocytes (9 dpf), brain and spinal cord neurons (7.5 dpf)
    • -
      Forebrain gray and white matter disorganization, ectopic neurons in white matter (7.5 dpf)
  • Mutant tsc2 mRNA OE:
    • -
      Increased TORC1 activity (10–11 hpf); dorsal expansion of hindbrain (27 hpf)
  • Cell transplantation of tsc2−/− cells into wild-type at 4 hpf:
    • -
      Increased TORC1 activity in mutant, not wild-type, cells (7.5 dpf; adult)
    • -
      Disrupted gray-white matter boundaries (7.5 dpf; adult)
    • -
      Ectopic wild-type cells in white matter in some chimeric embryos (7.5 dpf)
    • -
      Mutant cell clusters found in gray-white matter boundary, gray matter (adult)
 Zebrafish mRNA rescues elevated TORC1 activity (partial rescue by human mRNA); rapamycin reverses elevated TORC1 activity Kim et al. (2011)

Key: hpf, hours post fertilization; dpf, days post fertilization; *Disorder: ASD, autism spectrum disorder; CDFE, cortical dysplasia focal epilepsy; CHARGE, CHARGE Syndrome; EP, epilepsy; FXS, Fragile X syndrome; PMS, Phelan-McDermid Syndrome; RTT, Rett syndrome; TSC, tuberous sclerosis complex; **Methods of Risk Gene Disruption: CRISPR, clustered regularly interspaced short palindromic repeats; CRISPR F0, Mosaic CRISPR-injected embryo; MO, Morpholino; OE, overexpression; TALEN, transcription activator-like effector nuclease; TILLING, targeted induced local lesions in genomes; ZFN, zinc finger nuclease.