Suppression of PKR Promotes Network Excitability and Enhanced Cognition by Interferon-γ-Mediated Disinhibition

Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA.
Cell (Impact Factor: 32.24). 12/2011; 147(6):1384-96. DOI: 10.1016/j.cell.2011.11.029
Source: PubMed


The double-stranded RNA-activated protein kinase (PKR) was originally identified as a sensor of virus infection, but its function in the brain remains unknown. Here, we report that the lack of PKR enhances learning and memory in several behavioral tasks while increasing network excitability. In addition, loss of PKR increases the late phase of long-lasting synaptic potentiation (L-LTP) in hippocampal slices. These effects are caused by an interferon-γ (IFN-γ)-mediated selective reduction in GABAergic synaptic action. Together, our results reveal that PKR finely tunes the network activity that must be maintained while storing a given episode during learning. Because PKR activity is altered in several neurological disorders, this kinase presents a promising new target for the treatment of cognitive dysfunction. As a first step in this direction, we show that a selective PKR inhibitor replicates the Pkr(-/-) phenotype in WT mice, enhancing long-term memory storage and L-LTP.

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    • "Additionally, it was also seen that C 16 is able to cross the blood brain barrier (BBB) in new born rats [15]. Pharmacological inhibition of PKR in WT mice or PKR knockout mice showed hyperexcitability in cortical and hippocampal networks [16]. It was also demonstrated that PKR-inhibitor significantly prevented the increase in pT451-PKR and pS194-FADD levels in SH-SY5Y nuclei and completely inhibited activities of caspase −3 and −8 [17]. "
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    ABSTRACT: MAP/microtubule affinity-regulating kinase 4 (MARK4) plays a central role in the cellular physiology, and it is inseparably linked with many human diseases including cancer, diet induced obesity, type2 diabetes and neurodegenerative disorders. Here, we studied the interaction of PKR-inhibitor with two variants of human MARK4. One variant is named as MARK4-F1 which has 59 N-terminal residues along with kinase domain while another variant is MARK4-F2 which has kinase domain only. Molecular-docking, molecular dynamics (MD) simulation and fluorescence-binding studies were undertaken to understand the role of Nterminal 59-residues in the binding of substrate/inhibitors. Molecular docking studies revealed that the PKR-inhibitor binds in the large hydrophobic cavity of the kinase domain of MARK4 through several hydrophobic and hydrogen-bonded interactions. Furthermore, MD simulation showed a stable parameters for the complexes of both MARK4-F1 and MARK4-F2 to PKRinhibitor with marginal difference in their binding affinities. A significant decrease in the fluorescence intensity of MARK4 was observed on successive addition of the PKR-inhibitor. Using fluorescence data we have calculated the binding-affinity and the number of binding site of PKR-inhibitor to the MARK4. A significantly high binding affinity was observed for the PKR-inhibitor to the MARK4 variants. However, there is no any significant difference in the binding affinity of PKR-inhibitor to the MARK4 variants was observed, indicating that 59 Nterminal residues of MARK4-F1 are not playing a crucial role in the binding of ligand. The present study will provide insights into designing of a new PKR-inhibitor derivative as potent and selective therapeutic agent against many life threatening diseases which are associated with MARK4.
    Full-text · Article · Oct 2015 · Journal of Molecular Graphics and Modelling
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    • "IL-1β, IL-6, and TNF-a, which have been associated with cognitive decline, inhibited synaptic plasticity and caused hippocampal LTP impairment in previous studies (Balosso et al., 2008; Viviani et al., 2003; Viviani et al., 2006). It has also been demonstrated that both IL-4 and IFN-γ contribute to hippocampal LTP and neurogenesis (Nolan et al., 2005; Zhu et al., 2011). In line with previous reports, our results showed that the levels of IL-4 and IFN-γ were significantly Fig. 5. Neonatal BCG, HBV, and BH vaccination alters the levels of cytokines and neurotrophins in the hippocampus and serum. "
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    ABSTRACT: Immune activation can exert multiple effects on synaptic transmission. Our study demonstrates the influence of neonatal vaccination on hippocampal synaptic plasticity in rats under normal physiological conditions. The results revealed that neonatal BCG vaccination enhanced synaptic plasticity. In contrast, HBV hampered it. Furthermore, we found that the cytokine balance shifted in favour of the T helper type 1/T helper type 2 immune response in BCG/HBV-vaccinated rats in the periphery. The peripheral IFN-γ:IL-4 ratio was positively correlated with BDNF and IGF-1 in the hippocampus. BCG raised IFN-γ, IL-4, BDNF and IGF-1 and reduced IL-1β, IL-6, and TNF-α in the hippocampus, whereas, HBV triggered the opposite effects.
    Full-text · Article · Sep 2015 · Journal of Neuroimmunology
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    • "Ro 31-8220 is known as a PKC inhibitor and previous studies showed that the compound affects the hyperphosphorylation of CUGBP1 [8] and ameliorates the cardiac phenotype in DM1 mouse model [10]. C16 has been applied in a number of in vitro and in vivo studies to inhibit PKR [52] [53] [54]. However, its selectivity against other kinases is also shown [51]. "
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    DESCRIPTION: Contribution for a book entitled: Myotonic Dystrophies: Epidemiology, Diagnosis and Therapeutic Challenges.
    Full-text · Research · May 2015
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