GLT-1 (EAAT2; slc1a2) is the major glutamate transporter in the brain, and is predominantly expressed in astrocytes, but at lower levels also in excitatory terminals. We generated a conditional GLT-1 knock-out mouse to uncover cell-type-specific functional roles of GLT-1. Inactivation of the GLT-1 gene was achieved in either neurons or astrocytes by expression of synapsin-Cre or inducible human GFAPCreERT2. Elimination of GLT-1 from astrocytes resulted in loss of ϳ80% of GLT-1 protein and of glutamate uptake activity that could be solubilized and reconstituted in liposomes. This loss was accompanied by excess mortality, lower body weight, and seizures suggesting that astrocytic GLT-1 is of major importance. However, there was only a small (15%) reduction that did not reach significance of glutamate uptake into crude forebrain synaptosomes. In contrast, when GLT-1 was deleted in neurons, both the GLT-1 protein and glutamate uptake activity that could be solubilized and reconstituted in liposomes were virtually unaffected. These mice showed normal survival, weight gain, and no seizures. However, the synaptosomal glutamate uptake capacity (V max ) was reduced significantly (40%). In conclusion, astrocytic GLT-1 performs critical functions required for normal weight gain, resistance to epilepsy, and survival. However, the contribution of astrocytic GLT-1 to glutamate uptake into synaptosomes is less than expected, and the contribution of neuronal GLT-1 to synaptosomal glutamate uptake is greater than expected based on their relative protein expression. These results have important implications for the interpretation of the many previous studies assessing glutamate uptake capacity by measuring synaptosomal uptake.

These findings suggest that the TRPV1 channel is a promising molecular target for seizure suppression, with female GEPR-3s exhibiting higher sensitivity than male GEPR-3s.

Background Cyclic AMP-dependent protein kinase (PKA) signaling is a key target for the action of alcohol and may therefore play a role in the pathophysiology of alcohol withdrawal seizures (AWSs). Here, we investigated the role of PKA activity with respect to increased seizure susceptibility in rats that were subjected to alcohol withdrawal. Methods Adult male Sprague-Dawley rats received three daily doses of ethanol (or vehicle) for four consecutive days. Rats were then tested for susceptibility to acoustically evoked AWSs 3, 24, and 48 hours after the last alcohol dose. In separate experiments, the inferior colliculus (IC) was collected at these same time points from rats subjected to alcohol withdrawal and control rats following alcohol withdrawal. PKA activity, catalytic Cα (PKACα) protein, regulatory RIIα (PKARIIα) protein, and RIIβ (PKARIIβ) protein were measured in the IC. Lastly, in situ pharmacological studies were performed to evaluate whether inhibiting PKA activity in the IC suppressed AWSs. Results In the ethanol-treated group, AWSs were observed at the 24-hour time point, but not at the 3-hour or 48-hour time points. In the IC, PKA activity was significantly higher both 3 hours (i.e., before AWS susceptibility) and 24 hours after the last alcohol dose (when AWS susceptibility peaked) than in control rats. Consistent with these findings, protein levels of the PKACα subunit were significantly increased in the IC both 3 hours and 24 hours after the last alcohol dose. Lastly, in situ inhibition of PKA activity within the IC suppressed AWSs. Conclusions The increase in PKA activity and PKACα protein expression in the IC preceded the occurrence of AWSs, and inhibiting PKA activity within the IC suppressed acoustically evoked AWSs. Together, these findings suggest that altered PKA activity plays a key role in the pathogenesis of AWSs.

Drug-induced liver injury (DILI) is a phenomenon that occurs with nearly all classes of medications. Cholestatic DILI represents a fraction of these cases and can present as bland cholestasis, cholestatic hepatitis, secondary sclerosis cholangitis, and vanishing bile duct syndrome. Risk factors have been identified for cholestatic DILI, including older age, genetic determinants, and certain medications such as amoxicillin-clavulanate. Here, we describe a complicated case of severe cholestatic DILI secondary to cephalosporin use. A 27-year-old female presented to the hospital initially with fever and abdominal pain for four weeks after an emergency C-section for pre-eclampsia and hemolysis, elevated liver enzymes, lowered platelets (HELLP) syndrome. She was found to have a retroperitoneal abscess and underwent bilateral drain placement. She was initially started on cefazolin, and then coverage was broadened to cefepime. Shortly after, alkaline phosphatase (ALP) rose and peaked at 3498 IU/L, with aspartate aminotransferase (AST) and alanine transaminase (ALT) elevated at 274 IU/L and 122 IU/L, respectively. Extensive testing for secondary causes and a liver biopsy were consistent with DILI. Liver enzymes downtrended with the cessation of cefepime. This case report highlights that prompt recognition of the culprit medication is paramount to recovering normal liver function.

Blastic plasmacytoid dendritic cell neoplasm is a rare and aggressive hematological malignancy associated with poor prognosis and limited treatment options. No guideline-directed therapy existed until the approval of tagraxofusp in 2018 by the Food and Drug Administration. Multiple clinical trials are undergoing as treatment options continue to evolve. We report a case refractory to tagraxofusp and pivekimab sunirine with subsequent remission achieved on venetoclax and azacitidine therapy.