Sustained Extracellular Signal-Regulated Kinase 1/2 Phosphorylation in Neonate 6-Hydroxydopamine-Lesioned Rats after Repeated D1-Dopamine Receptor Agonist Administration: Implications for NMDA Receptor Involvement

Extracellular signal-regulated kinase (ERK) 1/2, a well known regulator of gene expression, is likely to contribute to signaling events underlying enduring neural adaptations. Phosphorylated (phospho)-ERK was examined immunohistochemically after both single and repeated (i.e., sensitizing) doses of the partial D1-dopamine (DA) receptor agonist SKF-38393 (2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benazepine HCl) to adult rats lesioned as neonates (neonate lesioned) with 6-hydroxydopamine. Remarkably, prolonged phospho-ERK accumulated primarily in layers II–III of medial prefrontal cortex (MPC), where it declined gradually yet remained significantly elevated for at least 36 d after repeated doses of SKF-38393. Sustained (≥7 d) phospho-ERK was observed for shorter periods in various other cortical regions but was not detectable in striatum or nucleus accumbens. At 36 d, an additional injection of SKF-38393 to sensitized rats restored phospho-ERK to maximal levels only in MPC when examined 7 d later. Phosphorylated cAMP response element-binding protein (CREB), examined 7 d after the sensitizing regimen, was observed exclusively in MPC, where it was abundant throughout all layers. Systemic injections of SL327 (α-[amino[(4-aminophenyl)thio]methylene]-2-(trifluoromethyl)benzeneacetonitrile), an inhibitor of the upstream ERK activator mitogen ERK kinase, attenuated both ERK and CREB phosphorylation in layers II–III of MPC. Pretreatment with the D1 antagonist SCH-23390 ((R)-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine-7-OL maleate) inhibited the prolonged increase in MPC phospho-ERK, whereas the 5-HT2 receptor antagonist ketanserin (3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2,4(1H,3H)-quinazolinedione tartrate) was ineffective. Competitive and noncompetitive NMDA receptor antagonists also blocked sustained ERK phosphorylation. Collectively, the present results demonstrate coupling of D1 and NMDA receptor function reflected in sustained activation of the ERK signaling pathway in MPC of SKF-38393-sensitized neonate-lesioned rats. Ultimately, long-lasting phosphorylation of ERK and CREB in MPC may play a pivotal role in any permanent adaptive change(s) in these animals

NMDA and Dopamine Converge on the NMDA-Receptor to Induce ERK Activation and Synaptic Depression in Mature Hippocampus

The formation of enduring internal representation of sensory information demands, in many cases, convergence in time and space of two different stimuli. The first conveys the sensory input, mediated via fast neurotransmission. The second conveys the meaning of the input, hypothesized to be mediated via slow neurotransmission. We tested the biochemical conditions and feasibility for fast (NMDA) and slow (dopamine) neurotransmission to converge on the Mitogen Activated Protein Kinase signaling pathways, crucial in several forms of synaptic plasticity, and recorded its effects upon synaptic transmission. We detected differing kinetics of ERK2 activation and synaptic strength changes in the CA1 for low and high doses of neurotransmitters in hippocampal slices. Moreover, when weak fast and slow inputs are given together, they converge on ERK2, but not on p38 or JNK, and induce strong short-term synaptic depression. Surprisingly, pharmacological analysis revealed that a probable site of such convergence is the NMDA receptor itself, suggesting it serves as a detector and integrator of fast and slow neurotransmission in the mature mammalian brain, as revealed by ERK2 activation and synaptic function

The effect of treatment with vincristine on transient evoked and distortion product otoacoustic emissions

Objective: Vincristine chemotherapy is mainly associated with neurotoxic effects. The ototoxicity of vincristine has been related to high dosage, while low and moderate doses do not seem to induce significant hearing impairment when measured by pure tone or speech audiometry. Otoacoustic emissions have been reported to be more sensitive in early detection of ototoxicity than conventional pure tone audiometry. The present study was directed at determining whether vincristine treatment interferes with outer hair cell function in the absence of measurable changes in pure tone audiometry. Methods: We studied prospectively a cohort of ten children suffering from Leukemia. ALL children were subjected to tympanogram, stapedial. muscle reflex, pure tone audiometry, transient evoked (TEOAEs) and distortion product (DPOAEs) otoacoustic emissions on day 1 and on day 22 of treatment with vincristine. TEOAEs were analyzed in terms of emission level and reproducibility as a function of frequency. DPOAEs were obtained as DP-grams and were analyzed in terms of amplitude. Results: The analyzed parameters of TEOAEs and DPOAEs revealed a declining tendency, a(though changes did not reach statistical significance. Pure tone audiometry and stapedial. reflex thresholds were not altered. Conclusion: For the population of this study, vincristine did not seem to cause significant alterations of otoacoustic emissions’ recordings and consequently significant outer hair cell damage. (C) 2005 Elsevier Ireland Ltd. All rights reserved

Comprehensive Review of Emergence and Virology of Tickborne Bourbon Virus in the United States

The emergence of SARS-CoV-2 and the worldwide COVID-19 pandemic triggered considerable attention to the emergence and evolution of novel human pathogens. Bourbon virus (BRBV) was first discovered in 2014 in Bourbon County, Kansas, USA. Since its initial discovery, several cases of BRBV infection in humans have been identified in Kansas, Oklahoma, and Missouri. BRBV is classified within the Thogotovirus genus; these negative-strand RNA viruses appear to be transmitted by ticks, and much of their biology remains unknown. In this review, we describe the emergence, virology, geographic range and ecology, and human disease caused by BRBV and discuss potential treatments for active BRBV infections. This virus and other emerging viral pathogens remain key public health concerns and require continued surveillance and study to mitigate human exposure and disease

Ethanol Regulation of Synaptic GABAA 4 Receptors Is Prevented by Protein Kinase A Activation

Ethanol alters GABAA receptor trafficking and function through activation of protein kinases, and these changes may underlie ethanol dependence and withdrawal. In this study, we used subsynaptic fraction techniques and patch-clamp electrophysiology to investigate the biochemical and functional effects of protein kinase A (PKA) and protein kinase C (PKC) activation by ethanol on synaptic GABAAα4 receptors, a key target of ethanol-induced changes. Rat cerebral cortical neurons were grown for 18 days in vitro and exposed to ethanol and/or kinase modulators for 4 hours, a paradigm that recapitulates GABAergic changes found after chronic ethanol exposure in vivo. PKA activation by forskolin or rolipram during ethanol exposure prevented increases in P2 fraction α4 subunit abundance, whereas inhibiting PKA had no effect. Similarly, in the synaptic fraction, activation of PKA by rolipram in the presence of ethanol prevented the increase in synaptic α4 subunit abundance, whereas inhibiting PKA in the presence of ethanol was ineffective. Conversely, PKC inhibition in the presence of ethanol prevented the ethanol-induced increases in synaptic α4 subunit abundance. Finally, we found that either activating PKA or inhibiting PKC in the presence of ethanol prevented the ethanol-induced decrease in GABA miniature inhibitory postsynaptic current decay τ1, whereas inhibiting PKA had no effect. We conclude that PKA and PKC have opposing effects in the regulation of synaptic α4 receptors, with PKA activation negatively modulating, and PKC activation positively modulating, synaptic α4 subunit abundance and function. These results suggest potential targets for restoring normal GABAergic functioning in the treatment of alcohol use disorders

Astrocytes carrying the superoxide dismutase 1 (SOD1G93A) mutation induce wild-type motor neuron degeneration in vivo

Recent studies highlight astrocytes as key drivers of motor neuron (MN) degeneration and disease propagation in mutant human superoxide dismutase 1 (mSOD1)-mediated amyotrophic lateral sclerosis. However, in vivo analysis of specific astrocytic influence in amyotrophic lateral sclerosis has proven difficult because mSOD1 is ubiquitously expressed throughout the CNS of rodent models studied. Here, we transplanted SOD1G93A glial-restricted precursor cells—glial progenitors capable of differentiating into astrocytes—into the cervical spinal cord of WT rats to reveal how mutant astrocytes influence WT MNs and other cells types (microglia and astrocytes) in an in vivo setting. Transplanted SOD1G93A glial-restricted precursor cells survived and differentiated efficiently into astrocytes. Graft-derived SOD1G93A astrocytes induced host MN ubiquitination and death, forelimb motor and respiratory dysfunction, reactive astrocytosis, and reduced GLT-1 transporter expression in WT animals. The SOD1G93A astrocyte-induced MN death seemed in part mediated by host microglial activation. These findings show that mSOD1 astrocytes alone can induce WT MN death and associated pathological changes in vivo