Postnatal NMDA receptor ablation in corticolimbic interneurons confers schizophrenia-like phenotypes.
Cortical GABAergic dysfunction may underlie the pathophysiology of psychiatric disorders, including schizophrenia. Here, we characterized a mouse strain in which the essential NR1 subunit of the NMDA receptor (NMDAR) was selectively eliminated in 40-50% of cortical and hippocampal interneurons in early postnatal development. Consistent with the NMDAR hypofunction theory of schizophrenia, distinct schizophrenia-related symptoms emerged after adolescence, including novelty-induced hyperlocomotion, mating and nest-building deficits, as well as anhedonia-like and anxiety-like behaviors. Many of these behaviors were exacerbated by social isolation stress. Social memory, spatial working memory and prepulse inhibition were also impaired. Reduced expression of glutamic acid decarboxylase 67 and parvalbumin was accompanied by disinhibition of cortical excitatory neurons and reduced neuronal synchrony. Postadolescent deletion of NR1 did not result in such abnormalities. These findings suggest that early postnatal inhibition of NMDAR activity in corticolimbic GABAergic interneurons contributes to the pathophysiology of schizophrenia-related disorders.
Belforte
Juan E
JE
Unit on Genetics of Cognition and Behavior, Mood and Anxiety Disorders Program, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, USA.
Zsiros
Veronika
V
Sklar
Elyse R
ER
Jiang
Zhihong
Z
Yu
Gu
G
Li
Yuqing
Y
Quinlan
Elizabeth M
EM
Nakazawa
Kazu
K
D000200:Action Potentials / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D002540:Cerebral Cortex / Q000473:pathology*; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000502:physiology; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D005968:Glutamate Decarboxylase / Q000235:genetics / Q000378:metabolism; D006948:Hyperkinesis / Q000209:etiology / Q000235:genetics; D007395:Interneurons / Q000502:physiology*; D008032:Limbic System / Q000473:pathology*; D008569:Memory Disorders / Q000209:etiology / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009434:Neural Pathways / Q000473:pathology; D010320:Parvalbumins / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000172:deficiency*; D021641:Recognition, Psychology / Q000502:physiology; D012559:Schizophrenia / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D012934:Social Isolation / Q000523:psychology; D018709:Statistics, Nonparametric; D005680:gamma-Aminobutyric Acid / Q000378:metabolism; D000097847:Protein Phosphatase Inhibitory Proteins
D005968:Glutamate Decarboxylase; D010320:Parvalbumins; D011506:Proteins; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; D005680:gamma-Aminobutyric Acid; C409466:NR1 NMDA receptor; C024833:protein phosphatase inhibitor-2; D000097847:Protein Phosphatase Inhibitory Proteins; C402565:glutamate decarboxylase 1