Insulin can induce the expression of a memory-related synaptic protein through facilitating AMPA receptor endocytosis in rat cortical neurons

Abstract

Learning and memory depend on long-term synaptic plasticity including long-term potentiation (LTP) and depression (LTD). Activity-regulated cytoskeleton-associated protein (Arc) plays versatile roles in synaptic plasticity mainly through inducing F-actin formation, underlying consolidation of LTP, and promoting AMPA receptor (AMPAR) endocytosis, underlying LTD. Insulin can also induce LTD by facilitating the internalization of AMPARs. In neuroblastoma cells, insulin induced a dramatic increase in Arc mRNA and Arc protein levels, which may underlie the memory-enhancing action of insulin. Thus, a hypothesis was made that, in response to insulin, increased AMPAR endocytosis leads to enhanced Arc expression, and vice versa. Primary cultures of neonatal Sprague-Dawley rat cortical neurons were used. Using Western-blot analysis and immunofluorescent staining, our results reveal that inhibiting AMPAR-mediated responses with AMPAR antagonists significantly enhanced whereas blocking AMPAR endocytosis with various reagents significantly prevented insulin (200 nM, 2 h)-induced Arc expression. Furthermore, via surface biotinylation assay, we demonstrate that acute blockade of new Arc synthesis after insulin stimulation using Arc antisense oligodeoxynucleotide prevented insulin-stimulated AMPAR endocytosis. These findings suggest for the first time that an interaction exists between insulin-stimulated AMPAR endocytosis and insulin-induced Arc expression.

A novel form of synaptic plasticity in field CA3 of hippocampus requires GPER1 activation and BDNF release

“…Arc has been implicated in AMPA receptor endocytosis during synaptic plasticity ( Rial Verde et al, 2006 ; Waung et al, 2008 ; Peebles et al, 2010 ; Liu et al, 2012 ) and after hormone stimulation ( Chen et al, 2014 ). Therefore, we tested the effects of GPER1 activation on the levels of several AMPA receptor subunits in membrane and cytosolic fractions from hippocampal slices.…”

Brain insulin resistance impairs hippocampal synaptic plasticity and memory by increasing GluA1 palmitoylation through FoxO3a

“…The transcriptional regulation of zDHHC3 by FoxO3a and its post-translational activation add novel elements to the complex modulation of synaptic function by insulin 38 . Insulin may directly stimulate AMPA receptor phosphorylation 39 and endocytosis 40 . Additionally, phosphotidylinositide-3-kinase, which is the main arm of insulin signaling, increases cell surface expression of AMPARs along with LTP 41 .…”

Dicholine succinate, the neuronal insulin sensitizer, normalizes behavior, REM sleep, hippocampal pGSK3 beta and mRNAs of NMDA receptor subunits in mouse models of depression

“…These functions are well established for most of them, such as for immediate early gene Arc, whose activity is regulated by stimulation of insulin receptor in neurons (Kremerskothen et al, 2002; Chen et al, 2014), suppressed by chronic stress (Elizalde et al, 2008, 2010) and increased by antidepressants (Alme et al, 2007; Molteni et al, 2008), immediate-early gene Nptx2 encoding neuronal activity-regulated pentraxin (Narp) that modulates AMPA-receptor functions (O'Brien et al, 1999; Chang et al, 2010), SGK1, which regulates hippocampal postsynaptic density-95 and dendritic growth (Ma et al, 2006; Yang et al, 2006). Also, TAF15 was shown to be implicated in the trafficking of NMDA glutamate receptor (Ibrahim et al, 2013).…”