Abstract
In the striatum, the input nucleus of the basal ganglia, the extracellular-signal-regulated kinase (ERK) pathway, necessary for various forms of behavioral plasticity, is triggered by the combined engagement of dopamine D1 and ionotropic glutamate receptors. In this study, we investigated the potential crosstalk between glutamatergic, dopaminergic, and brain-derived neurotrophic factor (BDNF)-TrkB inputs to ERK cascade by using an ex vivo model of mouse striatal slices. Our results confirmed that the concomitant stimulation of D1 and glutamate receptors is necessary to activate ERK in striatal medium spiny neurons (MSNs). Moreover, we found that ERK activation is significantly enhanced when BDNF is co-applied either with glutamate or the D1 agonist SKF38393, supporting the idea of possible integration between BDNF, glutamate, and D1R-mediated signaling. Interestingly, ERK activation via BDNF-TrkB is upregulated upon blockade of either AMPAR/NMDAR or D1 receptors, suggesting a negative regulatory action of these two neurotransmitter systems on BDNF-mediated signaling. However, the observed enhancement of ERK1/2 phosphorylation does not result in corresponding downstream signaling changes at the nuclear level. Conversely, the TrkB antagonist cyclotraxin B partially prevents glutamate- and D1-mediated ERK activation. Altogether, these results suggest a complex and unexpected interaction among dopaminergic, glutamatergic, and BDNF receptor systems to modulate the ERK pathway in striatal neurons.
Highlights
The extracellular-signal regulated kinase (ERK) cascade belongs to the mitogen-activated protein kinase (MAPK) superfamily, a class of highly conserved serine/threonine kinases, originally implicated in cell proliferation, survival, and apoptosis (Mebratu and Tesfaigzi, 2009; Roskoski, 2012)
Previous work has shown that ERK activation in the striatal network is a central integration point for ionotropic glutamate receptors (AMPARs and NMDARs) and dopamine D1 receptors signaling (Cahill et al, 2014b; Pascoli et al, 2014)
We preliminarily investigated the potential crosstalk between glutamatergic, dopaminergic, and brain-derived neurotrophic factor (BDNF) inputs to ERK cascade in mouse striatal slices obtained from mature mouse brains
Summary
The extracellular-signal regulated kinase (ERK) cascade belongs to the mitogen-activated protein kinase (MAPK) superfamily, a class of highly conserved serine/threonine kinases, originally implicated in cell proliferation, survival, and apoptosis (Mebratu and Tesfaigzi, 2009; Roskoski, 2012). Glutamateinduced ERK activation is amplified by D1 receptors stimulation via cAMP, PKA, and cAMP-regulated phosphoprotein (DARPP32) pathway, which maintains ERK1/2 in their active forms via the concerted inhibitory action of striatal-enriched tyrosine phosphatase (STEP) and protein phosphatase 1 (PP1; Valjent et al, 2005; Pascoli et al, 2011). This ERK regulation occurs in the medium spiny neurons of the direct striatal pathway (dMSNs), where D1Rs are primarily expressed. Very little is known of the role of ERK signaling modulation in the medium spiny neuron’s indirect striatal pathway (iMSNs)
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