科研之友
微信
新浪微博
Facebook
分享链接
摘要
Lysophosphatidic acid (LPA) is a natural lysophospholipid that regulates neuronal maturation. In mice, the deletion of the LPA(1) receptor causes some phenotypic defects partly overlapping with those found in schizophrenia. In this study, we identified molecular abnormalities in hippocampal synaptic mechanisms involved in glutamatergic neurotransmission, which allow further characterization of synaptic aberrations in LPA(1) knockout (KO) mice. At the synaptic level, we found dysregulation of Ca2+/calmodulin (CaM)-dependent kinase II (CaMKII) activity and phosphorylation, with markedly higher Ca2+-dependent kinase activity, probably related to increased expression levels of the beta isoform of CaMKII. Conversely, although the synaptic Ca2+-independent activity of the enzyme was unchanged, autophosphorylation levels of both alpha and beta isoforms were significantly increased in LPA(1) KO mice. Moreover, in LPA(1) KO mice the alpha/beta isoform ratio of CaMKII, which plays a key role in neuronal maturation during development, was markedly decreased, as found previously in schizophrenia patients. At post-synaptic level, LPA(1) KO mice showed changes in expression, phosphorylation and interactions of NMDA and AMPA receptor subunits that are consistent with basal strengthening of glutamatergic synapses. However, we measured a reduction of nuclear cAMP responsive element-binding protein phosphorylation, suggesting that activation of the NMDA receptor does not occur at the intracellular signalling level. At the presynaptic level, in line with previous evidence from schizophrenia patients and animal models of pathology, LPA(1) KO mice showed accumulation of SNARE protein complexes. This study shows that CaMKII and related synaptic mechanisms at glutamatergic synapses are strongly dysregulated in LPA(1) KO mice.
- 出版日期2011-8
