Class I histone deacetylase-mediated repression of the proximal promoter of the activity-regulated cytoskeleton-associated protein gene regulates its response to brain-derived neurotrophic factor.

We examined the transcriptional regulation of the activity-regulated cytoskeleton-associated protein gene (Arc), focusing on BDNF-induced Arc expression in cultured rat cortical cells. Although the synaptic activity-responsive element (SARE), located -7 kbp upstream of the Arc transcription start site, responded to NMDA, BDNF, or FGF2, the proximal region of the promoter (Arc/-1679) was activated by BDNF or FGF2, but not by NMDA, suggesting the presence of at least two distinct Arc promoter regions, distal and proximal, that respond to extracellular stimuli. Specificity protein 4 (SP4) and early growth response 1 (EGR1) controlled Arc/-1679 transcriptional activity via the region encompassing -169 to -37 of the Arc promoter. We found that trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor, significantly enhanced the inductive effects of BDNF or FGF2, but not those of NMDA on Arc expression. Inhibitors of class I/IIb HDACs, SAHA, and class I HDACs, MS-275, but not of class II HDACs, MC1568, enhanced BDNF-induced Arc expression. The enhancing effect of TSA was mediated by the region from -1027 to -1000 bp, to which serum response factor (SRF) and HDAC1 bound. The binding of HDAC1 to this region was reduced by TSA. Thus, Arc expression was suppressed by class I HDAC-mediated mechanisms via chromatin modification of the proximal promoter whereas the inhibition of HDAC allowed Arc expression to be markedly enhanced in response to BDNF or FGF2. These results contribute to our understanding of the physiological role of Arc expression in neuronal functions such as memory consolidation.

Isolated bilateral hypoglossal nerve paralysis following an atlanto-occipital dislocation: A case report.

The present report highlights a case of successful treatment of an 11-year-old male patient who presented with an atlanto-occipital dislocation and multiple fractures of the forearm, pelvis, and lower leg because of a fall. The patient experienced dysarthria and paralysis of the tongue, which became completely immobile and could not be moved from side to side, impeding speech. The patient also experienced dysphagia due to the inability to propel food toward the pharynx and chewing attempts resulted in scattering of food residue throughout the oral cavity. The lack of tongue mobility led to saliva accumulation, forcing the patient to swallow frequently, which was possible as larynx movement was unaffected. The other cranial and motor sensory nerves appeared normal. Our diagnostic examinations confirmed the presence of isolated bilateral paralysis of the hypoglossal nerve secondary to traction at the base of the skull. The patient was still unable to protrude his tongue and tongue gradually atrophied two weeks after admission. Electromyography revealed denervation of the tongue and minimal active contraction of the single motor units. Immobilization therapy and rehabilitation therapy were initiated to improve tongue movement, but this was unsuccessful and one month after the accident, the patient's tongue was still atrophied. The patient was placed on a soft food diet and experienced no difficulty in swallowing either saliva or food three months after admission. Tongue mobility was deemed normal. Electromyography six months after the initial episode revealed normal motor unit potentials during contractions. We postulate that compression and stretching of the bilateral hypoglossal nerves against the greater horn of the hyoid bone was a probable cause of the hypoglossal palsy. The use of immobilization and rehabilitation therapy likely supported the recovery of functionality and resulted in a good prognosis.

Treatment of transient prosopagnosia with a tyrosine kinase inhibitor in a case of brain metastasis from EGFR-mutated lung adenocarcinoma.

Background: Prosopagnosia is a rare form of apraxia, in which a person has normal memory and vision, but has impaired cognition of human faces that are manifested through symptoms such as not being able to recognize the face of a familiar person, one has known or not being able to remember the face of a person. Here, we report the case of a patient with transient prosopagnosia associated with brain metastasis from epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma who was treated with tyrosine kinase inhibitors (TKIs). Case Description: A 52-year-old right-handed man with lung adenocarcinoma was introduced to our department because brain metastasis. On admission, he complained that he could not recognize his wife's face, but he could recall her face based on her voice. MRI revealed a right temporo-occipital enhancing lesion with perifocal edema and dissemination that were indicative of brain metastasis from lung adenocarcinoma. Two weeks after open biopsy, he was started on TKI therapy with osimertinib at a dosage of 80 mg/day. An MRI scan taken 1 month later revealed shrinkage of the metastasis. In addition, he had recovered from transient prosopagnosia and returned to normal life. Conclusion: In this study, the TKI osimertinib was administered to a patient with brain metastasis of EGFR-mutated lung adenocarcinoma who presented with prosopagnosia, and the patient's lesion shrunk and his symptoms were reversed with this treatment.

Extracellular adenosine 5'-triphosphate elicits the expression of brain-derived neurotrophic factor exon IV mRNA in rat astrocytes.

A growing body of recent evidence indicates that ATP plays an important role in neuronal-glial communications. In this study, the authors demonstrated that extracellular ATP elicits the gene expression of brain-derived neurotrophic factor (BDNF), especially BDNF exon IV mRNA, in primary cultured rat cortical astrocytes but not in neurons. To investigate the mechanism by which ATP induces BDNF exon IV mRNA expression, the authors used immortalized astrocyte cell line RCG-12. ATP dose-dependently increased the expression of BDNF exon IV mRNA and activated BDNF promoter IV. P2Y receptor agonists (ADP and 2MeS-ADP) but not a P2X receptor agonist (alphabetaMeATP) induced the expression of BDNF exon IV mRNA. Moreover, ATP-induced BDNF exon IV mRNA upregulation was inhibited by a P2Y antagonist (MRS2179) but not by P2X antagonists (TNP-ATP and PPADS). These findings suggest the involvement of P2Y receptors in the ATP-induced transcription of the BDNF gene. Among the signal transduction inhibiters examined in this study, intracellular Ca(2+) chelator (BAPTA-AM) and Ca(2+)/calmodulin-dependent kinase (CaM kinase) inhibitors (KN-93 and W-7) attenuated ATP-induced BDNF exon IV mRNA upregulation. ATP transiently induced the phosphorylation of cAMP-responsive element-binding protein (CREB). ATP-induced CREB phosphorylation was repressed by P2Y antagonists, BAPTA-AM, and CaM kinase inhibitors. Overexpression of dominant negative CREB mutants reduced the activation of BDNF promoter IV and attenuated the upregulation of BDNF exon IV mRNA expression. These results suggest that ATP induces BDNF expression through P2Y receptor followed by the activation of CaM kinase and CREB in astrocytes. These mechanisms are likely to contribute to the enhancement of neuronal-glial networks.