Expression, animal model and pharmacological studies on the reviewed scaffolding genes
| Gene | Expression studies | Functional studies | Sources |
|---|---|---|---|
| DLG1 | Reduced expression of DLG1 mRNA in PFC of schizophrenia patients (68) Reduced expression of DLG1 protein in PFC of schizophrenia patients (175) | Administration of the NMDA receptor antagonist PCP caused an upregulation of DLG1 gene transcription in the neocortex of rats (176) | Dracheva et al. (68) Toyooka et al. (175) Hiraoka et al. (176) |
| DLG2 | Increased DLG2 mRNA and decreased protein expression in prefrontal cortex and anterior cingulate cortex of schizophrenia patients (177) | PSD-93 mutant mice exhibited deficits in LTP (178) PSD-93 mutant mice showed cognitive abnormalities (179) PSD-93 mutant mice did not show any abnormality of synaptic structure or function in cerebellum (180) | Kristiansen et al. (177) Carlisle et al. (178) Nithianantharajah et al. (179) McGee et al. (180) |
| DLG3 | Increased DLG3 mRNA and protein expression in the thalamus of schizophrenia patients (181) Decreased DLG3 protein expression in the thalamus of schizophrenia patients (182) | Mice lacking DLG3 exhibited impairments of spatial learning (183) | Clinton et al. (181) Clinton et al. (182) Cuthbert et al. (183) |
| DLG4 | Increased DLG4 mRNA and decreased protein expression in ACC of schizophrenia patients (177) Increased DLG4 mRNA and protein expression in thalamus of schizophrenia patients (182), (185) Increased DLG4 mRNA expression in the occipital cortex of schizophrenia patients (186) Decreased DLG4 mRNA expression in the PFC of schizophrenia patients (69) Decreased DLG4 mRNA and protein expression in the DLPFC of schizophrenia patients (187) Decreased DLG4 protein expression in thalamus of schizophrenia patients (182) Decreased DLG4 protein expression in hippocampus (188), (189) Decreased mRNA expression in the striatum (190) No changes in either DLG4 mRNA or protein expression in PFC of schizophrenia patients (175), (186) No changes in either DLG4 mRNA or protein expression in the hippocampus of schizophrenia patients (69), (182) | DLG4 mutant mice displayed schizophrenia and autism-spectrum disorder–like phenotypes (184) DLG4 mutant mice displayed aberrant AMPA receptor-mediated transmission (178), (191) DLG4 mutant mice exhibited enhancement in LTP and deficit in LTD (178), (192)– (194) DLG4 mutant mice exhibited disrupted synaptic plasticity and impaired learning (192) Ketamine reduced DLG4 mRNA in cortical regions of rats (195) | Ohnuma et al. (69) Toyooka et al. (175) Kristiansen et al. (177) Carlisle et al. (178) Clinton et al. (179) Clinton et al. (182) Feyder et al. (184) Clinton et al. (185) Dracheva et al. (186) Funk et al. (187) Toro et al. (188) Matosin et al. (189) Kristiansen et al. (190) Nakagawa et al. (191) Migaud et al. (192) Ehrlich et al. (193) Xu et al. (194) de Bartolomeis et al. (195) |
| DLGAP2 | — | DLGAP2 knockout mice displayed abnormal social behaviour (196) | Jiang-Xie et al. (196) |
| SHANK1 | — | SHANK1 mutant mice showed alterations in motor system and social behaviour (197)– (199) SHANK1 mutant mice showed social communication deficits (200) | Silverman et al. (197) Hung et al. (198) Wöhr et al. (199) Sungur et al. (200) |
| SHANK2 | — | SHANK2(−/−) mutant mice were hyperactive and displayed autistim-like behaviours, including social interaction and repetitive jumping (201), (202), (203) SHANK2(−/−) mutant mice exhibited fewer dendritic spines, reduced basal synaptic transmission and reduced frequency of miniature excitatory postsynaptic currents (201), (203) SHANK2(−/−) mutant mice showed a decrease in NMDA receptor function. Direct stimulation of the NMDA receptor with a partial agonist normalized its function and improved social interaction. (202) | Schmeisset et al. (201) Won et al. (202) Ha et al. (203) |
| SHANK3 | — | SHANK3 mutant mice exhibited self-injurious repetitive grooming behaviours (204), (206), (207) and social interaction, (204), (205), (207), (209), (210) learning and memory (205) deficits. They also showed anxiety and motor deficits (206), (208), (209) SHANK3 mutant mice showed deficits in glutamatergic transmission and synaptic plasticity and reduced synaptic concentrations of scaffolding proteins (e.g., DLGAP3, Homer1). (204), (208)– (210) Re-expression of the SHANK3 gene in adults led to improvements in synaptic protein composition, spine density and neural function, as well as selective rescue in autism-related phenotypes. (208) Insulin-like growth factor-1 reversed synaptic and behavioural deficits in SHANK3 mutant mice (206) and phenotypic changes in human neuronal models of Rett syndrome. (211) SHANK3B knockout mice exhibited early hyperactivation and precocious maturation of corticostriatal circuits (212) | Arons et al. (204) Wang et al. (205) Bozdagi et al. (206) Peça et al. (207) Mei et al. (208) Bozdagi et al. (209) Yang et al. (210) Marchetto et al. (211) Peixoto et al. (212) |
| HOMER1 | Increased Homer1a protein expression in hippocampal interneurons of schizophrenia patients (213) Increased Homer1a and decreased Homer1b protein expression in hippocampus of schizophrenia patients (189) | HOMER1 knockout mice displayed impaired fear memory formation (214) and impaired LTP (215) HOMER1 knockout mice showed abnormalities in motivational, emotional, cognitive and sensorimotor processing (216) HOMER1 knockout mice also showed somatic growth retardation, poor motor coordination, enhanced sensory reactivity, learning deficits and increased aggression in social interaction (218) Overexpression of HOMER1 in knockout mice reverted the cognitive and behavioural impairments (217) Exposure to novel environments upregulated HOMER1 mRNA in the hippocampus of rats (219) Methamphetamine or cocaine administration upregulated HOMER1 mRNA in the neocortex of rats (220) LSD or PCP administration upregulated HOMER1 mRNA in the PFC of rats (221), (222) 10Ketamine increased HOMER1 mRNA in the cortical regions, striatum and nucleus accumbens of rats (195), (223) Antipsychotics (haloperidol, olanzapine or clozapine) induced an increment of Homer1 protein expression in the cortex, the striatum, the caudate-putamen or nucleus accumbens of rats (107), (224)– (228) | de Bartolomeis et al. (107) Matosin et al. (189) de Bartolomeis et al. (195) Leber et al. (213) Inoue et al. (214) Gerstein et al. (215) Szumlinski et al. (216) Lominac et al. (217) Jaubert et al. (218) Vazdarjanova et al. (219) Fujiyama et al. (220) Cochran et al. (221) Nichols et al. (222) Iasevoli et al. (223) Iasevoli et al. (224) Iasevoli et al. (225) Ambesi-Impiombato et al. (226) Polese et al. (227) Tomasetti et al. (228) |
ACC = anterior cingulate cortex; AMPA = α-amino-3-hydroxy-5-methylisoxazole-4 propionic acid; LSD = lysergic acid; LTD = long-term depression; LTP = long-term potentiation; NMDA = N-methyl-d-aspartate; PCP = phencyclidine; PFC = prefrontal cortex; PSD = postsynaptic density.