Long-term effects of neonatal exposure to MK-801 on recognition memory and excitatory-inhibitory balance in rat hippocampus.
Blockade of the N-methyl-d-aspartate receptors (NMDARs) during the neonatal period has been reported to induce long-term behavioral and neurochemical alterations that are relevant to schizophrenia. In this study, we examined the effects of such treatment on recognition memory and hippocampal excitatory and inhibitory (E/I) balance in both adolescence and adulthood. After exposure to the NMDAR antagonist, MK-801, at postnatal days (PND) 5-14, male Sprague-Dawley rats were tested for object and object-in-context recognition memory during adolescence (PND 35) and adulthood (PND 63). The parvalbumin-positive (PV+) γ-aminobutyric acid (GABA)-ergic interneurons and presynaptic markers for excitatory and inhibitory neurons, vesicular glutamate transporter-1 (VGLUT1) and vesicular GABA transporter (VGAT) were examined in the hippocampus to reflect the E/I balance. We found that rats receiving MK-801 treatment showed deficits of recognition memory, reduction in PV+ cell counts and upregulation of the VGLUT1/VGAT ratio in both adolescence and adulthood. Notably, the changes of the VGLUT1/VGAT ratio at the two time points exhibited distinct mechanisms. These results parallel findings of hippocampal abnormalities in schizophrenia and lend support to the usefulness of neonatal NMDAR blockade as a potential neurodevelopmental model for the disease.
National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital/Institute of Mental Health) and the Key Laboratory of Mental Health, Ministry of Health (Peking University), Beijing 100191, China.
J-T
JT
Li
Depression Treatment Center, Beijing Anding Hospital of Capital Medical University, Beijing 100088, China.
Y-Y
YY
Zhao
National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital/Institute of Mental Health) and the Key Laboratory of Mental Health, Ministry of Health (Peking University), Beijing 100191, China.
H-L
HL
Wang
Department of Neurobiology, Key Laboratory of Medical Neurobiology of Ministry of Health of China, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University School of Medicine, 310058 Hangzhou, China.
X-D
XD
Wang
National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital/Institute of Mental Health) and the Key Laboratory of Mental Health, Ministry of Health (Peking University), Beijing 100191, China. Electronic address: suyunai@163.com.
Y-A
YA
Su
National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital/Institute of Mental Health) and the Key Laboratory of Mental Health, Ministry of Health (Peking University), Beijing 100191, China. Electronic address: si.tian-mei@163.com.
T-M
TM
Si
D000818:Animals; D000831:Animals, Newborn; D002452:Cell Count; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000633:toxicity*; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects* / Q000254:growth & development* / Q000503:physiopathology; D007150:Immunohistochemistry; D008297:Male; D008569:Memory Disorders / Q000473:pathology / Q000503:physiopathology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010320:Parvalbumins / Q000378:metabolism; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D021641:Recognition, Psychology / Q000187:drug effects / Q000502:physiology; D050598:Vesicular Glutamate Transport Protein 1 / Q000378:metabolism; D050495:Vesicular Inhibitory Amino Acid Transport Proteins / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D010320:Parvalbumins; C493466:Slc17a7 protein, rat; C118623:Slc32a1 protein, rat; D050598:Vesicular Glutamate Transport Protein 1; D050495:Vesicular Inhibitory Amino Acid Transport Proteins; D005680:gamma-Aminobutyric Acid; D016291:Dizocilpine Maleate
VGAT; VGLUT1; cognition; parvalbumin; schizophrenia