Differential roles of pyramidal and fast-spiking, GABAergic neurons in the control of glioma cell proliferation

Abstract

<jats:title>Abstract</jats:title><jats:p>Recent studies have demonstrated an active role for neurons in glioma progression. Specifically, peritumoral neurons establish functional excitatory synapses with glioma cells, and optogenetic stimulation of cortical pyramidal neurons drives tumor progression. However, the specific role of different subsets of cortical neurons, such as GABAergic interneurons, remains unexplored. Here, we directly compared the effects of optogenetic stimulation of pyramidal cells vs. fast-spiking, GABAergic neurons. In mice inoculated with GL261 cells into the motor cortex, we show that optogenetic stimulation of pyramidal neurons enhances glioma cell proliferation. In contrast, optogenetic stimulation of fast-spiking, parvalbumin-positive interneurons reduces proliferation as measured by BrdU incorporation and Ki67 immunolabelling. Since both principal cells and fast-spiking interneurons are directly activated by sensory afferent input, we next placed tumors in the occipital cortex to test the impact of visual stimulation/deprivation. We report that total lack of visual input via dark rearing enhances the density of proliferating glioma cells, while daily visual stimulation by gratings of different spatial frequencies and contrast reduces tumor growth. The effects of sensory input are region-specific, as visual deprivation has no significant effect on tumor proliferation in mice with gliomas in the motor cortex. We also report that sensory stimulation combined with temozolomide administration delays the loss of visual responses in peritumoral neurons. Altogether, these data demonstrate complex effects of different neuronal subtypes in the control of glioma proliferation.</jats:p><jats:sec><jats:title>Highlights</jats:title><jats:p><jats:list list-type="bullet"><jats:list-item><jats:p>Activity of GABAergic neurons reduces glioma cell proliferation</jats:p></jats:list-item><jats:list-item><jats:p>Levels of sensory afferent input regulate tumor proliferation</jats:p></jats:list-item><jats:list-item><jats:p>Effects of sensory input are region-specific</jats:p></jats:list-item></jats:list></jats:p></jats:sec>

Cortical Excitability and Connectivity in Patients With Brain Tumors

“…Therefore, it is likely that excitotoxicity at a chronic stage may result in a significant loss of motor neurons within primary motor area and a loss of CSTs as indexed by the increase in RMT and AMT and by the reduced slope of RC. The excitotoxicity promoted by infiltrating glioma cells may also in turn affect fast-spiking GABA A interneurons, and a reduced GABA availability may create a vicious circle where increased pyramidal neurons firing amplify glutamate excitotoxicity ( 27 ), producing neuronal cell death (see below).…”

“…Interestingly, it has been demonstrated that the selective optogenetic stimulation of parvalbumin-positive GABA A interneurons induces a significant reduction in glioma cell proliferation ( 27 ). Human glioblastoma cells may express functional GABA A receptors, and that endogenous GABA release may attenuate tumor proliferation ( 35 ).…”

Single Unit Analysis and Wide-Field Imaging Reveal Alterations in Excitatory and Inhibitory Neurons in Glioma

“…These findings may have implications for the clinical course of patients with diffusely infiltrating glioma. Recent reports have shown that aberrant neuronal activity can lead to glioma proliferation through various mechanisms 4, 8–10, 13, 15 . It is thus conceivable that mTOR-mediated restoration of surround inhibition could potentially reduce the spread of such aberrant firing and in turn decrease tumor progression.…”

Personalised, image-guided, noninvasive brain stimulation in gliomas: Rationale, challenges and opportunities

“…40 Hz) with the goal of restoring microglial function [57] . Considering the promising results in AD models and preliminary evidence in tumor animal models, human translational research is needed to explore eventual modulation of microglia and/or of specific neuron type (i.e., parvalbumin-positive interneurons) via one or more types of tES in brain tumour patients [58] .…”