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The rodent visual thalamus has served as a powerful model to elucidate the cellular and molecular mechanisms that underlie sensory circuit formation and function. Despite significant advances in our understanding of the role of axon-target interactions and neural activity in orchestrating circuit formation in visual thalamus, the role of non-neuronal cells, such as astrocytes, is less clear. In fact, we know little about the transcriptional identity and development of astrocytes in mouse visual thalamus. To address this gap in knowledge, we studied the expression of canonical astrocyte molecules in visual thalamus using immunostaining, in situ hybridization, and reporter lines. While our data suggests some level of heterogeneity of astrocytes in different nuclei of the visual thalamus, the majority of thalamic astrocytes appeared to be labelled in Aldh1l1-EGFP mice. This led us to use this transgenic line to characterize the neonatal and postnatal development of these cells in visual thalamus. Our data show that not only have the entire cohort of astrocytes migrated into visual thalamus by eye-opening but they also have acquired their adult-like morphology, even while retinogeniculate synapses are still maturing. Furthermore, ultrastructural, immunohistochemical, and functional approaches revealed that by eye-opening, thalamic astrocytes ensheath retinogeniculate synapses and are capable of efficient uptake of glutamate. Taken together, our results reveal that the morphological, anatomical, and functional development of astrocytes in visual thalamus occurs prior to eye-opening and the emergence of experience-dependent visual activity. This article is protected by copyright. All rights reserved.

Epileptic seizures are among the most common presenting symptom in patients with glioma. The etiology of glioma‐related seizures is complex and not completely understood. Studies using adult glioma patient tissue and adult glioma mouse models, show that neurons adjacent to the tumor mass, peritumoral neurons, are hyperexcitable and contribute to seizures. Although it is established that there are phenotypic and genotypic distinctions in gliomas from adult and pediatric patients, it is unknown whether these established differences in pediatric glioma biology and the microenvironment in which these glioma cells harbor, the developing brain, differentially impacts surrounding neurons. In the present study, we examine the effect of patient‐derived pediatric glioma cells on the function of peritumoral neurons using two pediatric glioma models. Pediatric glioma cells were intracranially injected into the cerebrum of postnatal days 2 and 3 (p2/3) mouse pups for 7 days. Electrophysiological recordings showed that cortical layer 2/3 peritumoral neurons exhibited significant differences in their intrinsic properties compared to those of sham control neurons. Peritumoral neurons fired significantly more action potentials in response to smaller current injection and exhibited a depolarization block in response to higher current injection. The threshold for eliciting an action potential and pharmacologically induced epileptiform activity was lower in peritumoral neurons compared to sham. Our findings suggest that pediatric glioma cells increase excitability in the developing peritumoral neurons by exhibiting early onset of depolarization block, which was not previously observed in adult glioma peritumoral neurons., The effect of pediatric glioma cells on the function of surrounding neurons during early development is unknown. We intrancranially injected patient‐derived pediatric glioma cells in young pups and examined on the function of peritumoral neurons. Pediatric glioma cells induced changes in the intrinsic properties of periturmoral neurons, lowered the threshold of hyperexcitability and exhibited an early onset of depolarization block.

Epilepsy is a neurological disorder afflicting ~65 million people worldwide. It is caused by aberrant synchronized firing of populations of neurons primarily due to imbalance between excitatory and inhibitory neurotransmission. Hence, the historical focus of epilepsy research has been neurocentric. However, the past two decades have enjoyed an explosion of research into the role of glia in supporting and modulating neuronal activity, providing compelling evidence of glial involvement in the pathophysiology of epilepsy. The mechanisms by which glia, particularly astrocytes and microglia, may contribute to epilepsy and consequently could be harnessed therapeutically are discussed in this Review.

Unprovoked recurrent seizures are a serious comorbidity affecting most patients who suffer from glioma, a primary brain tumor composed of malignant glial cells. Cellular mechanisms contributing to the development of recurrent spontaneous seizures include the release of the excitatory neurotransmitter glutamate from glioma into extracellular space. Under physiological conditions, astrocytes express two high affinity glutamate transporters, Glt-1 and Glast, which are responsible for the removal of excess extracellular glutamate. In the context of neurological disease or brain injury, astrocytes become reactive which can negatively affect neuronal function, causing hyperexcitability and/or death. Using electrophysiology, immunohistochemistry, fluorescent in situ hybridization, and Western blot analysis in different orthotopic xenograft and allograft models of human and mouse gliomas, we find that peritumoral astrocytes exhibit astrocyte scar formation characterized by proliferation, cellular hypertrophy, process elongation, and increased GFAP and pSTAT3. Overall, peritumoral reactive astrocytes show a significant reduction in glutamate and potassium uptake, as well as decreased glutamine synthetase activity. A subset of peritumoral astrocytes displayed a depolarized resting membrane potential, further contributing to reduced potassium and glutamate homeostasis. These changes may contribute to the propagation of peritumoral neuronal hyperexcitability and excitotoxic death. Funding was provided by the National Institutes of Health (NIH) RO1 NS036692 (HS), RO1 NS082851 (HS), RO1 NS052634 (HS), RO1 NS105807 (SR). SR was also supported by the Epilepsy Foundation and the American Brain Tumor Association (ABTA). Accepted version