Striatal Subregion-selective Dysregulated Dopamine Receptor-mediated Intracellular Signaling in a Model of DOPA-responsive Dystonia.

Although the mechanisms underlying dystonia are largely unknown, dystonia is often associated with abnormal dopamine neurotransmission. DOPA-responsive dystonia (DRD) is a prototype disorder for understanding dopamine dysfunction in dystonia because it is caused by mutations in genes necessary for the synthesis of dopamine and alleviated by the indirect-acting dopamine agonist l-DOPA. Although adaptations in striatal dopamine receptor-mediated intracellular signaling have been studied extensively in models of Parkinson's disease, another movement disorders associated with dopamine deficiency, little is known about dopaminergic adaptations in dystonia. To identify the dopamine receptor-mediated intracellular signaling associated with dystonia, we used immunohistochemistry to quantify striatal protein kinase A activity and extracellular signal-related kinase (ERK) phosphorylation after dopaminergic challenges in a knockin mouse model of DRD. l-DOPA treatment induced the phosphorylation of both protein kinase A substrates and ERK largely in D1 dopamine receptor-expressing striatal neurons. As expected, this response was blocked by pretreatment with the D1 dopamine receptor antagonist SCH23390. The D2 dopamine receptor antagonist raclopride also significantly reduced the phosphorylation of ERK; this contrasts with models of parkinsonism in which l-DOPA-induced ERK phosphorylation is not mediated by D2 dopamine receptors. Further, the dysregulated signaling was dependent on striatal subdomains whereby ERK phosphorylation was largely confined to dorsomedial (associative) striatum while the dorsolateral (sensorimotor) striatum was unresponsive. This complex interaction between striatal functional domains and dysregulated dopamine-receptor mediated responses has not been observed in other models of dopamine deficiency, such as parkinsonism, suggesting that regional variation in dopamine-mediated neurotransmission may be a hallmark of dystonia.

Microvascular decompression for a unique case of glossopharyngeal neuralgia with provokable symptomatic bradycardia: 2-Dimensional operative video.

BACKGROUND: Glossopharyngeal neuralgia is a rare neurovascular compression syndrome that can lead to paroxysmal craniofacial pain and sometimes cardiovascular symptoms.[1,2] The characteristic pathology involves a vessel (commonly a branch/loop of PICA) compressing the nerve at the root entry/exit zone at the brainstem.[1] Microvascular decompression is a commonly used treatment approach for patients that have failed conservative measures.[2]. CASE DESCRIPTION: A 72-year-old male presented to the ED following four episodes of syncope. The patient had a multi-year history of right-sided burning/stabbing pain involving the submandibular area and posterior throat. His syncope was related to symptomatic bradycardia that would occur during episodes of pain. His pain was exacerbated by speaking and swallowing and could be triggered by placing his finger in the right external auditory meatus. Interestingly, this maneuver would also trigger his bradycardia. The patient had failed previous pharmacotherapy, and a pacemaker had been placed to protect him from periods of hypotension. MRI/MRA of the brain and cervical spine were unremarkable. Due to his profoundly symptomatic status, the patient was offered a right retrosigmoid craniotomy for microvascular decompression of the right glossopharyngeal nerve. The patient had complete resolution of his pain and bradycardia immediately post-operatively. He was discharged on the second postoperative day and his pacemaker was ultimately removed. The patient continues to be pain free and off medication. CONCLUSION: Here we present a video case report of microvascular decompression with favorable outcome for an interesting presentation of glossopharyngeal neuralgia. The patient gave informed consent for surgery and video recording.

Induced pluripotent stem cells from subjects with Lesch-Nyhan disease.

Lesch-Nyhan disease (LND) is an inherited disorder caused by pathogenic variants in the HPRT1 gene, which encodes the purine recycling enzyme hypoxanthine-guanine phosphoribosyltransferase (HGprt). We generated 6 induced pluripotent stem cell (iPSC) lines from 3 individuals with LND, along with 6 control lines from 3 normal individuals. All 12 lines had the characteristics of pluripotent stem cells, as assessed by immunostaining for pluripotency markers, expression of pluripotency genes, and differentiation into the 3 primary germ cell layers. Gene expression profiling with RNAseq demonstrated significant heterogeneity among the lines. Despite this heterogeneity, several anticipated abnormalities were readily detectable across all LND lines, including reduced HPRT1 mRNA. Several unexpected abnormalities were also consistently detectable across the LND lines, including decreases in FAR2P1 and increases in RNF39. Shotgun proteomics also demonstrated several expected abnormalities in the LND lines, such as absence of HGprt protein. The proteomics study also revealed several unexpected abnormalities across the LND lines, including increases in GNAO1 decreases in NSE4A. There was a good but partial correlation between abnormalities revealed by the RNAseq and proteomics methods. Finally, functional studies demonstrated LND lines had no HGprt enzyme activity and resistance to the toxic pro-drug 6-thioguanine. Intracellular purines in the LND lines were normal, but they did not recycle hypoxanthine. These cells provide a novel resource to reveal insights into the relevance of heterogeneity among iPSC lines and applications for modeling LND.