INIBIOLP   05426
INSTITUTO DE INVESTIGACIONES BIOQUIMICAS DE LA PLATA "PROF. DR. RODOLFO R. BRENNER"
Unidad Ejecutora - UE
artículos
Título:
A Putative Mechanism of Age-Related Synaptic Dysfunction Based on the Impact of IGF-1 Receptor Signaling on Synaptic CaMKIIa Phosphorylation
Autor/es:
PARDO J; LEE CC; FRANCIS J; FRANCIS J; OGUNDELE, OLALEKAN M.; GOYA RG; OGUNDELE, OLALEKAN M.; GOYA RG; PARDO J; LEE CC
Revista:
Frontiers in Neuroanatomy
Editorial:
Frontiers
Referencias:
Lugar: Lausana; Año: 2018
ISSN:
1662-5129
Resumen:
Insulin-like growth factor 1 receptor (IGF-1R) signaling regulates the activity andphosphorylation of downstream kinases linked to inflammation, neurodevelopment,aging and synaptic function. In addition to the control of Ca2C currents, IGF-1Rsignaling modulates the activity of calcium-calmodulin-dependent kinase 2 alpha(CaMKIIa) and mitogen activated protein kinase (MAPK/ErK) through multiple signalingpathways. These proteins (CaMKIIa and MAPK) regulate Ca2C movement and long-termpotentiation (LTP). Since IGF-1R controls the synaptic activity of Ca2C, CaMKIIaand MAPK signaling, the possible mechanism through which an age-dependentchange in IGF-1R can alter the synaptic expression and phosphorylation of theseproteins in aging needs to be investigated. In this study, we evaluated therelationship between an age-dependent change in brain IGF-1R and phosphorylationof CaMKIIa/MAPK. Furthermore, we elucidated possible mechanisms through whichdysregulated CaMKIIa/MAPK interaction may be linked to a change in neurotransmitterprocessing and synaptic function. Male C57BL/6 VGAT-Venus mice at postnatal days80 (P80), 365 and 730 were used to study age-related neural changes in two brainregions associated with cognitive function: hippocampus and prefrontal cortex (PFC).By means of high throughput confocal imaging and quantitative immunoblotting, weevaluated the distribution and expression of IGF-1, IGF-1R, CaMKIIa, p-CaMKIIa,MAPK and p-MAPK in whole brain lysate, hippocampus and cortex. Furthermore,we compared protein expression patterns and regional changes at P80, P365 andP730. Ultimately, we determined the relative phosphorylation pattern of CaMKIIa andMAPK through quantification of neural p-CaMKIIa and p-MAPK/ErK, and IGF-1Rexpression for P80, P365 and P730 brain samples. In addition to a change in synapticfunction, our results show a decrease in neural IGF-1/IGF-1R expression in wholebrain, hippocampus and cortex of aged mice. This was associated with a significantupregulation of phosphorylated neural MAPK (p-MAPK) and decrease in total brain CaMKIIa (i.e., CaMKIIa and p-CaMKIIa) in the aged brain. Taken together, we showedthat brain aging is associated with a change in neural IGF-1/IGF-1R expression and maybe linked to a change in phosphorylation of synaptic kinases (CaMKIIa and MAPK) thatare involved in the modulation of LTP.