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 patients68 Reduced expression of DLG1 protein in PFC of schizophrenia patients175 | Administration of the NMDA receptor antagonist PCP caused an upregulation of DLG1 gene transcription in the neocortex of rats176 | 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 patients177 | PSD-93 mutant mice exhibited deficits in LTP178 PSD-93 mutant mice showed cognitive abnormalities179 PSD-93 mutant mice did not show any abnormality of synaptic structure or function in cerebellum180 | 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 patients181 Decreased DLG3 protein expression in the thalamus of schizophrenia patients182 | Mice lacking DLG3 exhibited impairments of spatial learning183 | Clinton et al.181 Clinton et al.182 Cuthbert et al.183 |
| DLG4 | Increased DLG4 mRNA and decreased protein expression in ACC of schizophrenia patients177 Increased DLG4 mRNA and protein expression in thalamus of schizophrenia patients182,185 Increased DLG4 mRNA expression in the occipital cortex of schizophrenia patients186 Decreased DLG4 mRNA expression in the PFC of schizophrenia patients69 Decreased DLG4 mRNA and protein expression in the DLPFC of schizophrenia patients187 Decreased DLG4 protein expression in thalamus of schizophrenia patients182 Decreased DLG4 protein expression in hippocampus188,189 Decreased mRNA expression in the striatum190 No changes in either DLG4 mRNA or protein expression in PFC of schizophrenia patients175,186 No changes in either DLG4 mRNA or protein expression in the hippocampus of schizophrenia patients69,182 | DLG4 mutant mice displayed schizophrenia and autism-spectrum disorder–like phenotypes184 DLG4 mutant mice displayed aberrant AMPA receptor-mediated transmission178,191 DLG4 mutant mice exhibited enhancement in LTP and deficit in LTD178,192–194 DLG4 mutant mice exhibited disrupted synaptic plasticity and impaired learning192 Ketamine reduced DLG4 mRNA in cortical regions of rats195 | 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 behaviour196 | Jiang-Xie et al.196 |
| SHANK1 | — | SHANK1 mutant mice showed alterations in motor system and social behaviour197–199 SHANK1 mutant mice showed social communication deficits200 | 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 jumping201,202,203 SHANK2(−/−) mutant mice exhibited fewer dendritic spines, reduced basal synaptic transmission and reduced frequency of miniature excitatory postsynaptic currents201,203 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 behaviours204,206,207 and social interaction,204,205,207,209,210 learning and memory205 deficits. They also showed anxiety and motor deficits206,208,209 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 mice206 and phenotypic changes in human neuronal models of Rett syndrome.211 SHANK3B knockout mice exhibited early hyperactivation and precocious maturation of corticostriatal circuits212 | 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 patients213 Increased Homer1a and decreased Homer1b protein expression in hippocampus of schizophrenia patients189 | HOMER1 knockout mice displayed impaired fear memory formation214 and impaired LTP215 HOMER1 knockout mice showed abnormalities in motivational, emotional, cognitive and sensorimotor processing216 HOMER1 knockout mice also showed somatic growth retardation, poor motor coordination, enhanced sensory reactivity, learning deficits and increased aggression in social interaction218 Overexpression of HOMER1 in knockout mice reverted the cognitive and behavioural impairments217 Exposure to novel environments upregulated HOMER1 mRNA in the hippocampus of rats219 Methamphetamine or cocaine administration upregulated HOMER1 mRNA in the neocortex of rats220 LSD or PCP administration upregulated HOMER1 mRNA in the PFC of rats221,222 10Ketamine increased HOMER1 mRNA in the cortical regions, striatum and nucleus accumbens of rats195,223 Antipsychotics (haloperidol, olanzapine or clozapine) induced an increment of Homer1 protein expression in the cortex, the striatum, the caudate-putamen or nucleus accumbens of rats107,224–228 | 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.