Model
Approach
Function
Construct
Expression pattern
Gross anatomy
Cellular abnormalities
Behavior
Significance
Kamiya
In utero E14.5
KD function of endogenous Disc1
Disc1 RNAi or express
C-terminally truncated DISC1
Pyramidal cortical neurons
n/d
P2: Inhibition of neuronal migration.
P14: Shorter, misoriented dendrites
n/d
KD of Disc1 either with RNAi or with mDISC1 leads to abnormal development of the cortex
Duan
Oncoretrovirus injected into the adult dentate gyrus
KD endogenous Disc1
Disc1 RNAi
Hippocampus
n/d
Soma hypertrophy, multiple primary dendrites, overextended migration, and accelerated synaptogenesis
n/d
DISC1 is involved in embryonic and adult neuronal migration
Mao
In utero E13, BrdU 2 h before sacrificing at E16
KD endogenous Disc1
Disc1 shRNA
Hippocampus
n/d
Reduced BrdU positive cells, rescued by degradation of resistant β-catenin or GSK3-β inhibitor
n/d
DISC1 regulates neuronal progenitor proliferation by inhibiting GSK3-β
Lentivirus injected into the adult dentate gyrus,
BrdU 5 weeks later
KD endogenous Disc1
Disc1 shRNA
Hippocampus
n/d
Reduced BrdU positive cells,
rescued by GSK3-β inhibitor
Locomotor hyperactivity increased immobility in forced swim test
Clapcote
ENU mutagenesis, screening of DISC1 exon 2
Missense point mutations:
Q31L, L100P
n/a
Endogenous
Reduced brain volume
Reduced binding to PDE4B
Q31L: greater immobility in the forced swim test, reduced sociability, reduced sucrose consumption.
L100P: novelty-induced activity, deficits in PPI, latent inhibition, and working memory
A point mutation in Disc1 produced various abnormalities.
The two point mutants had different behavioral phenotypes (Q31L depression-like, L100P schizophrenia-like)
Koike
Kvajo
Spontaneous mutation in 129S6/SvEv, transferred to C57BL/6
Some Disc1 isoforms are missing
25 bp deletion in exon 6, results in premature stop codon in exon 7
Endogenous
Reduced prefrontal cortex volume
Altered organization of the dentate gyrus,
No difference in parvalbumin+ or calbindin+ staining in medial prefrontal cortex
Impaired working memory
Loss of some isoforms altered hippocampal morphology and memory performance. Note that all 129 substrains have the mentioned mutation which may affect the phenotypes of the models generated in them.
Hikida
Transgenic
Express C-terminally truncated human DISC1, dominant negative
Constitutive under CaMKII promoter
Olfactory bulbs, frontal cortex, hippocampus, basal ganglia postnatally
Enlarged lateral ventricles
Decreased parvalbumin+ immunoreactivity in the medial prefrontal cortex
Increased immobility in forced swim test, mild hyperactive in the open field,
PPI deficit
First DISC1 model based on a human mutation
Pletnikov
Transgenic
Express C-terminally truncated human DISC1, dominant negative
Bi-transgenic regulatory plasmid expresses tTA under CAMKII promoter
Hippocampus, cortex, striatum and olfactory bulb. Expression is highest at embryonic life, and decreases with age
Enlarged lateral ventricles
Decreased neurite outgrowth in primary neurons
Altered spatial memory in females; decreased social interaction and increased aggression in males
First inducible DISC1 model
Li
Transgenic
Express the C-terminus of DISC1, which competes on binding to NDEL1 and LIS1
Transgenic under CaMKII promoter, inducible by tamoxifen for <2 days
Cortex, hippocampus, striatum, cerebellum.
Activated at P7
n/d
Reduced hippocampal dendritic complexity
Impaired working memory, greater immobility in the forced swim test, reduced sociability
Short induction at P7 is sufficient to elicit significant abnormalities in adulthood
Shen
BAC (bacterial artificial chromosome) transgenic
Express C-terminally truncated mouse DISC1
Fused GFP in-frame to the end of exon 8
Endogenous
Smaller cortex, enlarged lateral ventricles, corpus callosum agenesis
Thinning of layers II/III due to reduced neuronal proliferation
Impaired latent inhibition, greater immobility in the forced swim test
Mouse transgene regulated by endogenous promoter
New models of DISC1 will advance our knowledge of the gene. One approach can include generating models with cell type-specific expression. For example, as DISC1 is proposed to be expressed in glial cells (58), mouse models with changes in expression of DISC1 in astrocytes or oligodendrocytes would provide new information on the function of DISC1 in those glial cells. Glia–neuron interaction is necessary for effective synaptic transmission and altered interaction might be associated with mental disorders (53, 59, 60). Abnormalities in glial expression of DISC1 might cause dysfunction in glial cellular operations and eventually disrupt glia–neuron interaction.
DISC1 is not the only susceptibility gene in schizophrenia in particular and for other major mental disorders. Distinct roles of NRG1, NRGIII, RGS4, DAO, AKT1, and PICK1 have been also demonstrated (61–65) and corresponding animal models have been generated (66–69). These mouse models may provide in vivo working models of how these genes interact (70–73), how the common pathways are affected by a mutation in any of these genes, and what outcomes those interactions have at cellular, circuitry, systems, and behavioral levels. Evaluation of interactions between susceptibility genes may provide identification of pathways that may be targeted for preventive measures or treatment approaches.
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