ABSTRACT
The leucine-rich repeat-containing family 8 member A (LRRC8A) is an essential subunit of the volume-regulated anion channel (VRAC). VRAC is critical for cell volume control, but its broader physiological functions remain under investigation. Recent studies in the field indicate that Lrrc8a disruption in the brain astrocytes reduces neuronal excitability, impairs synaptic plasticity and memory, and protects against cerebral ischemia. In the present work, we generated brain-wide conditional LRRC8A knockout mice (LRRC8A bKO) using NestinCre -driven Lrrc8aflox/flox excision in neurons, astrocytes, and oligodendroglia. LRRC8A bKO animals were born close to the expected Mendelian ratio and developed without overt histological abnormalities, but, surprisingly, all died between 5 and 9 weeks of age with a seizure phenotype, which was confirmed by video and EEG recordings. Brain slice electrophysiology detected changes in the excitability of pyramidal cells and modified GABAergic inputs in the hippocampal CA1 region of LRRC8A bKO. LRRC8A-null hippocampi showed increased immunoreactivity of the astrocytic marker GFAP, indicating reactive astrogliosis. We also found decreased whole-brain protein levels of the GABA transporter GAT-1, the glutamate transporter GLT-1, and the astrocytic enzyme glutamine synthetase. Complementary HPLC assays identified reduction in the tissue levels of the glutamate and GABA precursor glutamine. Together, these findings suggest that VRAC provides vital control of brain excitability in mouse adolescence. VRAC deletion leads to a lethal phenotype involving progressive astrogliosis and dysregulation of astrocytic uptake and supply of amino acid neurotransmitters and their precursors.
Subject(s)
Astrocytes/pathology , Gliosis/mortality , Glutamic Acid/metabolism , Membrane Proteins/physiology , Seizures/mortality , Animals , Astrocytes/metabolism , CA1 Region, Hippocampal/metabolism , CA1 Region, Hippocampal/pathology , Female , Gliosis/etiology , Gliosis/pathology , Ion Transport , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Seizures/etiology , Seizures/pathologyABSTRACT
Gliomatosis peritonei (GP) is commonly associated with ovarian teratoma and is not thought to have an adverse prognostic effect. However, the prognostic impact and characteristics of GP remain to be clarified. In this study, we investigated the clinicopathologic features of ovarian teratoma associated with GP, and we further compared ovarian immature teratoma (IT) with GP to ovarian IT without GP. During the study period, there were a total of 16 ovarian teratomas associated with GP. Among them, 15 cases were ovarian ITs of various grades. When ovarian IT with GP (n = 15) was compared to ovarian IT without GP (n = 27), it was found that ovarian IT patients with GP had larger tumor size (median, 19 vs. 13 cm; P < 0.001), more frequent recurrence (40 %, 6/15 vs. 3.7 %, 1/27; P = 0.005), and frequently elevated preoperative CA-125 level (100 %, 12/12 vs. 50 %, 10/20; P = 0.004). All recurrences occurred within 2 years of the initial surgery. Survival curves indicated that ovarian IT patients with GP had significantly shorter recurrence-free survival compared to those without GP (P = 0.002). The 2-year recurrence-free survival rates were 59.3 and 96.3 % in IT with GP and IT without GP, respectively. However, all but one case of IT with GP are currently alive. In conclusion, GP is an adverse prognostic factor characterized by frequent recurrence in patients with ovarian IT.
