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Lysophosphatidic acid (LPA) is a natural lysophospholipid that regulates neuronal maturation. In mice, the deletion of the LPA1 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 LPA1 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 β isoform of CaMKII. Conversely, although the synaptic Ca2+-independent activity of the enzyme was unchanged, autophosphorylation levels of both α and β isoforms were significantly increased in LPA1 KO mice. Moreover, in LPA1 KO mice the α/β 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, LPA1 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, LPA1 KO mice showed accumulation of SNARE protein complexes. This study shows that CaMKII and related synaptic mechanisms at glutamatergic synapses are strongly dysregulated in LPA1 KO mice.

Original publication

DOI

10.1017/S1461145710001240

Type

Journal article

Journal

Int J Neuropsychopharmacol

Publication Date

08/2011

Volume

14

Pages

941 - 953

Keywords

Actins, Animals, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Cyclic AMP Response Element-Binding Protein, Hippocampus, Isoenzymes, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Neurons, Phosphorylation, Receptors, AMPA, Receptors, Lysophosphatidic Acid, Receptors, N-Methyl-D-Aspartate, SNARE Proteins, Signal Transduction, Synapses, Synaptic Transmission, Synaptosomes