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. Author manuscript; available in PMC: 2019 Feb 1.
Published in final edited form as: Curr Opin Neurobiol. 2017 Aug 30;48:17–29. doi: 10.1016/j.conb.2017.08.003

Table 1.

Diverse behavioral, synaptic, and cellular phenotypes are observed in nigrostriatal and mesocorticolimbic pathways in mouse models of neurodevelopmental syndromes and ASD candidate genes.

Neurodevelopmental Syndromes
Syndrome Mouse Model Major Findings Citation
15q11–13 Duplication Syndrome Ube3a-2× Triplication of Ube3a synergizes with seizures to reduce expression of the glutamatergic synapse organizer Cbln1, impairs glutamatergic transmission in VTA neurons, and leads to loss of sociability. [99]
16p11.2 Deletion Syndrome 16p11.2+/− Mice carrying a homologous chromosomal deletion to 16p11.2 (7F3) exhibit abnormal synaptic signaling and increased numbers of dopamine D2 receptor (D2R)-expressing medium spiny neurons (MSNs) in the striatum, fewer D1 receptor (D1R)-expressing neurons in the cortex, locomotor hyperactivity, and deficits in motor control. [157]
Angelman Syndrome Ube3am−/p+ Ube3am−/p+ mice display enhanced electrically evoked dopamine release in the NAc and reward seeking but decreased sensitivity to drugs that increase dopamine overflow. [100]
TH-Cre∷Ube3am−/p+, TH-Cre∷Ube3aFLOX/p+ Loss of maternal Ube3a in tyrosine hydroxylase (TH)-expressing neurons enhanced optical self-stimulation via increased GABA release from dopaminergic terminals in the NAc. [101]
Fragile X Syndrome Fmr1−/y Fmr1−/y mice are more sensitive to the rewarding effects but less sensitive to the motor effects of cocaine compared to wildtype; the number of TH-expressing neurons in reduced in the SNc but not VTA of these mice. [158]
Fmr1−/y Locomotor sensitization, conditioned place preference, and synaptic changes in the NAc following repeated cocaine is reduced in Fmr1−/y mice. [159]
Neurofibromatosis Type 1 Nf1+/−:Nf1FLOX∷GFAP-Cre:Nf1FLOX/FLOX Mice with one non-functional Nf1 allele in all somatic cells and complete Nf1 knockout in glial fibrillary acid protein (GFAP)-expressing cells display reduced striatal dopamine and TH expression in vivo and reduced dopaminergic neurite outgrowth in vitro. [47]
Nf1+/−, TH-Cre∷Nf1FLOX/FLOX, GFAP-Cre∷GFAPFLOX/FLOX Knockout of Nf1 in TH or GFAP-expressing cells is associated with reduced dopamine content in the hippocampus and deficits in spatial working memory. [46]
Rett Syndrome Mecp2+/−, Mecp2−/y SNc neurons exhibit decreased somal size, dendrite count, and striatal dopamine release in Mecp2+/− mice and symptomatic Mecp2−/y males. [52]
Mecp2+/− Mecp2+/− display aberrant motor coordination and motor skill learning secondary to reduced striatal dopamine content, down-regulation of tyrosine hydroxylase expression, and dopamine D2 receptor (D2R) up-regulation. [102]
Mecp2S421A Loss of MeCP2 phosphorylation at position 421 results in accelerated amphetamine sensitization and changes in MSN excitability in the NAc. [160]
Dlx5/6-Cre∷DMecp2FLOX/y Conditional knockout of Mecp2 in the striatum phenocopies Mecp2+/− mice in dopamine deregulation and motor dysfunction. [161]
Non-Syndromic ASD Genes
Gene (Product) Mouse Model Major Findings Citation
Cntnap4 (CNTNAP4) Cntnap4−/− Loss of Cntnap2 results in enhanced dopamine release in the NAc and dorsal striatum through a presynaptic mechanism and results in excessive grooming. [53]
Nlgn1 (Neuroligin-1) Nlgn1−/− Nlgn1−/− display reduced GluN2A-containing NMDA receptor currents and glutmatergic inputs in dopamine D1 receptor (D1R) and D2R-expressing striatal medium spiny neurons (MSNs), respectively. [162]
Nlgn2 (Neuroligin-2) Nlgn2 miR knockdown Striatal knockdown of Nlgn2 results in downregulation of dopaminergic synapses and upregulation of GABAergic synapses. [163]
Nlgn3 (Neuroligin-3) Nlgn3−/−, Nlgn3R451C Both Nlgn3 knockout mice and mice modeling the R451C polymorphism demonstrate enhanced repetitive motor routines by impairing inhibitory transmission onto D1R-expressing MSNs in the NAc. [164]
Shank3 (SHANK3) (Note: loss of SHANK3 is also seen in Phelan McDermid Syndrome) Shank3 shRNA knockdown Shank3 knockdown via short hairpin RNA (shRNA) in the VTA impairs excitatory synapse maturation, reduces dopaminergic neuron excitability via increased inhibitory tone, reduces social preference, and can be rescued an mGluR1 agonist or optogenetic stimulation of dopaminergic neurons [98]
Shank3b−/− Loss of Shank3b alters the development of excitatory inputs to medium spiny neurons of the dorsomedial striatum, which can be rescued by chemogenetic inhibition of corticostriatal inputs. [165]
Shank3bfx/fx Loss of Shank3b in a conditional knock-in model results in abnormal motor, social and exploratory behaviors; repetitive grooming; and synaptic changes in the striatum. These deficits are rescued with germline re-activation of Shank3 expression. [166]