Dataset Information

Kv1.3 activity perturbs the homeostatic properties of astrocytes in glioma.

ABSTRACT: Glial cells actively maintain the homeostasis of brain parenchyma, regulating neuronal excitability and preserving the physiological composition of the extracellular milieu. Under pathological conditions, some functions of glial cells could be compromised, exacerbating the neurotoxic processes. We investigated if the homeostatic activities of astrocytes and microglia could be modulated by the voltage-gated K+ channel Kv1.3. To this end we used in vitro and in vivo systems to model cell-to-cell interactions in tumoral conditions, using a specific inhibitor of Kv1.3 channels, 5-(4-phenoxybutoxy) psoralen (PAP-1). We demonstrated that PAP-1 increases astrocytic glutamate uptake, reduces glioma-induced neurotoxicity, and decreases microglial migration and phagocytosis. We also found in a tumor blood brain barrier model that Kv1.3 activity is required for its integrity. The crucial role of Kv1.3 channels as modulators of glial cell activity was confirmed in a mouse model of glioma, where PAP-1 treatment reduces tumor volume only in the presence of active glutamate transporters GLT-1. In the same mouse model, PAP-1 reduces astrogliosis and microglial infiltration. PAP-1 also reduces tumor cell invasion. All these findings point to Kv1.3 channels as potential targets to re-instruct glial cells toward their homeostatic functions, in the context of brain tumors.

SUBMITTER: Grimaldi A

PROVIDER: S-EPMC5955950 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Kv1.3 activity perturbs the homeostatic properties of astrocytes in glioma.

Grimaldi Alfonso A D'Alessandro Giuseppina G Di Castro Maria Amalia MA Lauro Clotilde C Singh Vikrant V Pagani Francesca F Sforna Luigi L Grassi Francesca F Di Angelantonio Silvia S Catacuzzeno Luigi L Wulff Heike H Limatola Cristina C Catalano Myriam M

Scientific reports 20180516 1

Glial cells actively maintain the homeostasis of brain parenchyma, regulating neuronal excitability and preserving the physiological composition of the extracellular milieu. Under pathological conditions, some functions of glial cells could be compromised, exacerbating the neurotoxic processes. We investigated if the homeostatic activities of astrocytes and microglia could be modulated by the voltage-gated K<sup>+</sup> channel Kv1.3. To this end we used in vitro and in vivo systems to model cel ...[more]

PMID: 29769580

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Project description:Prolonged high-fat diet (HFD) exposure is associated with hyperphagia, excess caloric intake and weight gain. After initial exposure to a HFD, a brief (24-48 h) period of hyperphagia is followed by the regulation of caloric intake and restoration of energy balance within an acute (3-5 day) period. Previous studies have demonstrated this occurs via a vagally mediated signalling cascade that increases glutamatergic transmission via activation of NMDA receptors located on gastric-projecting neurons of the dorsal motor nucleus of the vagus (DMV). The present study used electrophysiological recordings from thin brainstem slice preparations, in vivo recordings of gastric motility and tone, measurement of gastric emptying rates, and food intake studies to investigate the hypothesis that activation of brainstem astrocytes in response to acute HFD exposure is responsible for the increased glutamatergic drive to DMV neurons and the restoration of caloric balance. Pharmacological and chemogenetic inhibition of brainstem astrocytes reduced glutamatergic signalling and DMV excitability, dysregulated gastric tone and motility, attenuated the homeostatic delay in gastric emptying, and prevented the decrease in food intake that is observed during the period of energy regulation following initial exposure to HFD. Understanding the mechanisms involved in caloric regulation may provide critical insights into energy balance as well as into the hyperphagia that develops as these mechanisms are overcome. KEY POINTS: Initial exposure to a high fat diet is associated with a brief period of hyperphagia before caloric intake and energy balance is restored. This period of homeostatic regulation is associated with a vagally mediated signalling cascade that increases glutamatergic transmission to dorsal motor nucleus of the vagus (DMV) neurons via activation of synaptic NMDA receptors. The present study demonstrates that pharmacological and chemogenetic inhibition of brainstem astrocytes reduced glutamatergic signalling and DMV neuronal excitability, dysregulated gastric motility and tone and emptying, and prevented the regulation of food intake following high-fat diet exposure. Astrocyte regulation of glutamatergic transmission to DMV neurons appears to involve release of the gliotransmitters glutamate and ATP. Understanding the mechanisms involved in caloric regulation may provide critical insights into energy balance as well as into the hyperphagia that develops as these mechanisms are overcome.

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Kv1.3 activity perturbs the homeostatic properties of astrocytes in glioma.

Publications

Kv1.3 activity perturbs the homeostatic properties of astrocytes in glioma.

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