Erbb4 deletion from fast-spiking interneurons causes schizophrenia-like phenotypes.
Genetic variation in neuregulin and its ErbB4 receptor has been linked to schizophrenia, although little is known about how they contribute to the disease process. Here, we have examined conditional Erbb4 mouse mutants to study how disruption of specific inhibitory circuits in the cerebral cortex may cause large-scale functional deficits. We found that deletion of ErbB4 from the two main classes of fast-spiking interneurons, chandelier and basket cells, causes relatively subtle but consistent synaptic defects. Surprisingly, these relatively small wiring abnormalities boost cortical excitability, increase oscillatory activity, and disrupt synchrony across cortical regions. These functional deficits are associated with increased locomotor activity, abnormal emotional responses, and impaired social behavior and cognitive function. Our results reinforce the view that dysfunction of cortical fast-spiking interneurons might be central to the pathophysiology of schizophrenia.
Instituto de Neurociencias, Consejo Superior de Investigaciones Científicas and Universidad Miguel Hernández, Sant Joan d'Alacant 03550, Spain.
Isabel
I
Del Pino
Cristina
C
García-Frigola
Nathalie
N
Dehorter
Jorge R
JR
Brotons-Mas
Efrén
E
Alvarez-Salvado
María
M
Martínez de Lagrán
Gabriele
G
Ciceri
María Victoria
MV
Gabaldón
David
D
Moratal
Mara
M
Dierssen
Santiago
S
Canals
Oscar
O
Marín
Beatriz
B
Rico
D000200:Action Potentials / Q000235:genetics* / Q000502:physiology; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000473:pathology* / Q000503:physiopathology; D003072:Cognition Disorders / Q000209:etiology / Q000235:genetics; D004195:Disease Models, Animal; D018274:Electroporation; D066246:ErbB Receptors / Q000172:deficiency* / Q000235:genetics; D005968:Glutamate Decarboxylase / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics; D066298:In Vitro Techniques; D007395:Interneurons / Q000502:physiology*; D060850:LIM-Homeodomain Proteins / Q000235:genetics; D008297:Male; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000235:genetics; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D010320:Parvalbumins / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010641:Phenotype; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D022661:RNA, Untranslated; D066247:Receptor, ErbB-4; D011963:Receptors, GABA-A / Q000378:metabolism; D012559:Schizophrenia / Q000150:complications / Q000235:genetics / Q000473:pathology; D012919:Social Behavior; D013223:Statistics as Topic; D009435:Synaptic Transmission / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics
C110853:Gt(ROSA)26Sor non-coding RNA, mouse; C498504:LHX6 protein, mouse; D060850:LIM-Homeodomain Proteins; D009419:Nerve Tissue Proteins; D010320:Parvalbumins; D011506:Proteins; D022661:RNA, Untranslated; D011963:Receptors, GABA-A; D014157:Transcription Factors; D049452:Green Fluorescent Proteins; D066246:ErbB Receptors; C587690:Erbb4 protein, mouse; D066247:Receptor, ErbB-4; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2