DECREASED CAMKII AND PKC ACTIVITIES IN SPECIFIC BRAIN REGIONS ARE ASSOCIATED WITH COGNITIVE IMPAIRMENT IN NEONATAL VENTRAL HIPPOCAMPUS-LESIONED RATS

作者：Yabuki Y; Nakagawasai O; Moriguchi S; Shioda N; Onogi H; Tan No K; Tadano T; Fukunaga K^*

来源：Neuroscience, 2013, 234: 103-115.

DOI：10.1016/j.neuroscience.2012.12.048

• Ca2+/calmodulin-dependent protein kinase II
• cognitive dysfunction
• dopamine- and cAMP-regulated phospho-protein-32
• NMDA receptor
• NVH-lesioned rats
• schizophrenia

Neonatal ventral hippocampus (NVH)-lesioned rats represent a neurodevelopmental impairment model of schizophrenia. Previous observations indicate that postpubertal NVH-lesioned rats exhibit impairments in prepulse inhibition (PPI), spontaneous locomotion and social interaction behavior. Here, we document the neurochemical basis of those defects. PPI impairment but not cognitive impairment was improved by acute risperidone treatment (0.30 mg/ kg i.p.). Immunohistochemical analyses using anti-autophosphorylated Ca2+/calmodulin-dependent protein kinase II (CaMKII) antibody indicated significantly reduced CaMKII autophosphorylation, especially in the medial prefrontal cortex (mPFC), striatum and hippocampal CA1 region, of NVH-lesioned rats relative to control animals. We also confirmed that reduced CaMKII autophoshorylation in the mPFC, striatum and hippocampal CA1 region causes decreased phosphorylation of alpha-amino-3-hydroxy-5-methyl-4-isoxazol-propionic acid-type glutamate receptor subunit 1 (GluR1) (Ser 831), a CaMKII substrate. Like CaMKII, PKC alpha (Ser 657) autophosphorylation and NR1 (Ser 896) phosphorylation were decreased both in the mPFC and CA1 region. Interestingly, phosphorylation of DARPP-32 (Thr 34) was decreased in the mPFC but increased in the striatum and CA1 region of NVH-lesioned rats compared to controls. Risperidone treatment restored increased DARPP-32 phosphorylation in the striatum and CA1 regions of NVH-lesioned rats but did not rescue CaMKII and PKC alpha autophosphorylation. Taken together, we find that impaired cognition observed in NVH-lesioned rats is associated with decreased CaMKII and PKC alpha activities in memory-related brain regions, changes not rescued by risperidone treatment.

• 出版日期2013-3-27