TABLE 1.
Summary of DA neuron phenotypes in mouse models of syndromic autism spectrum disorders.
| Syndrome | Human gene | Mouse model | Gene manipulation | Type of mutation | Age at manipulation | Age at experiment | DA neuron number | DA neuron cell body morphology | DA neuron intrinsic excitability | DA neuron axonal morphology | DA release | TH expression | DA tissue content | DAT expression and function | References |
| Angelman | UBE3A | Ube3a m-/p+ and Ube3a flox/p+ x TH-Cre | deletion | constitutive and conditional | embryonic | P60-P90 | – | – | Unchanged in VTA neurons | – | Unchanged evoked release in NAc (FCV, optogenetic stim) | – | – | – | Berrios et al., 2016 |
| Ube3a m-/p+ | deletion | constitutive | embryonic | P210-240 | Decreased SNc neuron number (IHC) | – | – | – | – | – | – | Increased striatal DAT expression (IHC) | Mulherkar and Jana, 2010 | ||
| Ube3a m-/p+ | constitutive | deletion | embryonic | adult | – | – | – | – | – | – | – | Decreased DAT function (synaptosomal efflux) | Steinkellner et al., 2012 | ||
| Ube3a m-/p+ | deletion | constitutive | embryonic | P90-120 | No changes in SNc or VTA (IHC) | – | – | – | Decreased evoked release in dorsal striatum and increased in ventral striatum (in vivo FCV, MFB electrical stim) | No change in dorsal or ventral striatum (WB) | No change in dorsal or ventral striatum (HPLC) | – | Riday et al., 2012 | ||
| Ube3a m-/p+ | constitutive | deletion | embryonic | P84-105 | – | – | – | – | – | – | Increased in striatum and unchanged in midbrain (HPLC) | – | Farook et al., 2012 | ||
| ASD | 15q11-q13 | 7p duplication | duplication | constitutive | embryonic | P84-105 | – | – | – | – | – | – | Increased in striatum and midbrain (HPLC) | – | Farook et al., 2012 |
| Fragile X | FMR1 | Fmr1 KO | deletion | constitutive | embryonic | adult | – | – | – | – | Increased evoked release in PFC and decreased in striatum (in vivo microdialysis, amphetamine stim) | – | – | – | Ventura et al., 2004 |
| deletion | Fmr1 KO | embryonic | constitutive | P28-42; P63-77 | – | – | – | – | – | – | No change in young mice, increased striatal content in older mice (HPLC) | – | Sørensen et al., 2015 | ||
| Fmr1 KO | deletion | constitutive | embryonic | P28-31; P209-221 | – | – | – | – | – | – | No change in striatum in young or old mice (HPLC) | – | Gruss and Braun, 2001, 2004 | ||
| Fmr1 KO | deletion | constitutive | embryonic | P70; P105-140 | – | – | – | – | No change in evoked release in dorsal striatum in younger animals but decreased in older mice (FCV, electrical stim) | – | No change in striatum in young or old mice (HPLC) | No change in DAT function in young animals and reduced DAT function in older mice (FCV) | Fulks et al., 2010 | ||
| Fmr1 KO | deletion | constitutive | embryonic | P81-166 | Decreased SNc and unchanged VTA neuron number (stereology) | – | – | – | – | No change in dorsal or ventral striatum (WB) | – | – | Fish et al., 2013 | ||
| Fmr1 KO | deletion | constitutive | embryonic | P56-112 | – | – | – | Increased axonal complexity in striatum (IHC) | – | No change in midbrain (IHC), dorsal or ventral striatum (IHC, WB) | – | Decreased striatal DAT expression (WB) | Chao et al., 2020 | ||
| Rett | MECP2 | Mecp2-/y | deletion | constitutive | embryonic | P21; P56 | – | – | – | – | – | – | No change in striatum or midbrain in juveniles or adults (HPLC) | – | Santos et al., 2010 |
| Mecp2-/y | constitutive | deletion | embryonic | P24; P35; P55 | Decreased SNc cell number in adults (IHC) | Decreased SNc soma size in adults (IHC) | – | – | – | Decreased midbrain and striatal expression in adults (IHC) | No change in midbrain and decreased in striatum in adults (HPLC) | – | Panayotis et al., 2011a, b | ||
| Mecp2-/y | deletion | constitutive | embryonic | adult | – | – | – | – | – | Decreased in midbrain (WB) | Decreased in striatum (HPLC) | – | Samaco et al., 2009 | ||
| Mecp2-/y | deletion | constitutive | embryonic | P28-35 | – | – | – | – | – | – | Decreased in dorsal striatum, more in rostral than caudal striatum (HPLC) | – | Kao et al., 2013 | ||
| Mecp2fl/y x Dlx5/6-Cre | deletion | conditonal KO | embryonic | P28-35 | – | – | – | – | – | No change in rostral striatum and midbrain, increased in caudal striatum (WB) | Decreased in rostral dorsal striatum, increased in caudal dorsal stratum, no change in middle striatum or midbrain (HPLC) | – | Su et al., 2015 | ||
| Mecp2-/y | deletion | constitutive | embryonic | P30-57; P101-105 | – | – | Decreased membrane capacitance in SNc | – | – | – | – | – | Gantz et al., 2011 | ||
| Mecp2+/- | deletion | constitutive | embryonic | P16-30; P169-519 | – | Decreased soma size and dendritic complexity in SNc (IHC) | Decreased membrane capacitance and increased resistance in SNc | – | Decreased evoked release in striatum of adult mice (FCV, electrical stim) | – | – | – | Gantz et al., 2011 | ||
| PHTS | PTEN | Pten+/– | deletion | constitutive | embryonic | P56 | – | – | – | – | – | Increased in striatum and PFC (IHC,WB) | – | – | He et al., 2015 |
| Ptenfl/fl x DAT-Cre | deletion | conditional KO | embryonic | adult | Increased SNc and VTA cell number (IHC) | Increased soma size in SNc (IHC) | – | Increased axon terminal size (IHC) | – | – | – | – | Inoue et al., 2013 | ||
| Ptenfl/fl x DAT-Cre | deletion | conditional KO | embryonic | P84-112 | Increased SNc and VTA cell number (stereology) | Increased soma size in SNc and VTA and increased dendrites in SNc (IHC) | – | Increased axonal size in caudal striatum (IHC) | No changes in basal or evoked release in dorsal striatum (in vivo microdialysis) | Increased in midbrain and unchanged in striatum (IHC) | Increased in striatum and midbrain (HPLC) | No change in DA clearance rate (microdialysis) | Diaz-Ruiz et al., 2009 | ||
| Ptenfl/fl x DAT-Cre-ERT | deletion | conditional KO | 8-10 weeks | P98-112 | No changes in SNc (IHC) | Increased soma size in SNc and VTA (IHC) | – | Increased axon terminal density in striatum (IHC) | – | Increased in midbrain and striatum (WB) | Increased in striatum (HPLC) | Increased striatal DAT expression (IHC) | Domanskyi et al., 2011 | ||
| TSC | TSC1, TSC2 | Tsc1fl/fl x DAT-Cre | deletion | conditional KO | embryonic | P60-P112 | No changes in SNc or VTA (IHC) | Increased soma size and dendritic branching in SNc and VTA (IHC) | Decreased excitability in SNc and VTA neurons | Hypertrohic axon terminals, greater enlargement in dorsal than ventral striatum (EM) | Strongly decreased evoked release, more pronouced in dorsal than ventral sitratum (FCV, electrical stim) | Increased in midbrain and striatum (IHC, WB) | Increased in dorsal and ventral striatum (HPLC) | Increased DAT function (FCV) | Kosillo et al., 2019 |
Cre-ERT, tamoxifen-dependent Cre-recombinase; DA, dopamine; DAT, dopamine active transporter; EM, electron microscopy; FCV, fast-scan cyclic voltammetry; HPLC, high performance liquid chromatography; KO, knock-out; MFB, medial forebrain bundle; NAc, nucleus accumbens; PFC, prefrontal cortex; SNc, substantia nigra pars compacta; TH, tyrosine hydroxylase; VTA, ventral tegmental Area; WB, western blot; IHC, immunohistochemistry.