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.
Abnormalities in α/β-CaMKII and related mechanisms suggest synaptic dysfunction in hippocampus of LPA1 receptor knockout mice / L. Musazzi, E. Di Daniel, P. Maycox, G.A. Racagni, M. Popoli. - In: INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY. - ISSN 1461-1457. - 14:7(2011 Aug), pp. 941-953.
|Titolo:||Abnormalities in α/β-CaMKII and related mechanisms suggest synaptic dysfunction in hippocampus of LPA1 receptor knockout mice|
MUSAZZI, LAURA (Primo)
RACAGNI, GIORGIO ANGELO (Penultimo)
POPOLI, MAURIZIO (Ultimo)
|Parole Chiave:||Animal model; CaMKII; glutamate receptor; schizophrenia; synaptic transmission|
|Settore Scientifico Disciplinare:||Settore BIO/14 - Farmacologia|
|Data di pubblicazione:||ago-2011|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1017/S1461145710001240|
|Appare nelle tipologie:||01 - Articolo su periodico|