Activity‐dependent expression of ELAV/Hu RBPs and neuronal mRNAs in seizure and cocaine brain

Abstract

Growing evidence indicates that both seizure (glutamate) and cocaine (dopamine) treatment modulate synaptic plasticity within the mesolimbic region of the CNS. Activation of glutamatergic neurons depends on the localized translation of neuronal mRNA products involved in modulating synaptic plasticity. In this study, we demonstrate the dendritic localization of HuR and HuD RNA‐binding proteins (RBPs) and their association with neuronal mRNAs following these two paradigms of seizure and cocaine treatment. Both the ubiquitously expressed HuR and neuronal HuD RBPs were detected in different regions as well as within dendrites of the brain and in dissociated neurons. Quantitative analysis revealed an increase in HuR, HuD and p‐glycogen synthase kinase 3β (GSK3β) protein levels as well as neuronal mRNAs encoding Homer, CaMKIIα, vascular early response gene, GAP‐43, neuritin, and neuroligin protein products following either seizure or cocaine treatment. Inhibition of the Akt/GSK3β signaling pathway by acute or chronic LiCl treatment revealed changes in HuR, HuD, pGSK3β, p‐Akt, and β‐catenin protein levels. In addition, a genetically engineered hyperdopaminergic mouse model (dopamine transporter knockout) revealed decreased expression of HuR protein levels, but no significant change was observed in HuD or fragile‐X mental retardation protein RBPs. Finally, our data suggest that HuR and HuD RBPs potentially interact directly with neuronal mRNAs important for differentiation and synaptic plasticity.

Neuroprotection requires the functions of the RNA-binding protein HuR

“…Despite the extensive regional variability in the expression of Elavl/Hu proteins 6 in the CNS (Supplementary Figure 1), both HuR and nElavls are present in the hippocampus formation as indicated by the signals detected with anti-HuR and anti-HuD antisera ( Figure 1a); we selected to focus primarily on HuD as a representative of nElavls given prior indications on its involvement in the activity-dependent responses of pyramidal neurons. 7,13 HuR's expression is strong in the CA1 and DG regions, but lower in the CA2/CA3 regions. In contrast, the expression of HuD is strong in the CA2/CA3 regions, but low in the CA1 and DG regions.…”

“…A considerable body of literature demonstrates the importance of nElavls in neuronal differentiation and the PTR of mRNAs involved in neuronal excitation and synaptic plasticity. [7][8][9][10] On the contrary, HuR was considered as a redundant factor in neurons; recent evidence contradicts this supposition. Genetic ablation and molecular experiments demonstrated that HuR can promote the renewal of neuronal progenitors, whereas in differentiated cells it is silenced by nElavls via the alternative polyadenylation of its mRNA.…”

“…4,6,7 Consistently, three members of this family (HuB/Hel-N1/Elavl2, HuC/Elavl3 and HuD/Elavl4) are mostly expressed in neurons (nElavls); the fourth memberElavl1/HuR -is expressed in both neuronal and non-neuronal tissues. Elavl/Hu proteins share similarities in their structures, which include RNA-recognition motifs for specific U-rich RNA structures.…”

“…11,12 In adult neuron dendrites exposed to dopaminergic or glutamatergic activators, HuR and nElavls recognize overlapping and also distinct RNA targets, suggesting a functional disparity in activity-dependent responses. 7 In non-neuronal tissues, HuR has a proven involvement in a multitude of cellular programs (e.g. cell cycle control, inflammation, genotoxic stress, cell death) by altering the PTR of its target mRNAs -as such it could also be engaged in neurophysiologic or neurodegenerative settings.…”

Embryonic lethal abnormal vision proteins and adenine and uridine-rich element mRNAs after global cerebral ischemia and reperfusion in the rat

“…18,19 HuR has ubiquitous tissue expression, but HuB, HuC, and HuD are neuron specific. [20][21][22] HuR stabilizes ARE-mRNAs, such as cfos, 23 against degradation. HuB and HuC function in neuronal differentiation.…”