Neuron-oligodendroglial interactions in health and malignant disease

Abstract

Experience sculpts brain structure and function. Activity-dependent modulation of the myelinated infrastructure of the nervous system has emerged as a dimension of adaptive change during childhood development and in adulthood. Myelination is a richly dynamic process, with neuronal activity regulating oligodendrocyte precursor cell proliferation, oligodendrogenesis and myelin structural changes in some axonal subtypes and in some regions of the nervous system. This myelin plasticity and consequent changes to conduction velocity and circuit dynamics can powerfully influence neurological functions, including learning and memory. Conversely, disruption of the mechanisms mediating adaptive myelination can contribute to cognitive impairment. The robust effects of neuronal activity on normal oligodendroglial precursor cells, a putative cellular origin for many forms of glioma, indicates that dysregulated or 'hijacked' mechanisms of myelin plasticity could similarly promote growth in this devastating group of brain cancers. Indeed, neuronal activity promotes the pathogenesis of many forms of glioma in preclinical models through activity-regulated paracrine factors and direct neuron-to-glioma synapses. This synaptic integration of glioma into neural circuits is central to tumour growth and invasion. Thus, not only do neuron-oligodendroglial interactions modulate neural circuit structure and function in the healthy brain, but neuron-glioma interactions also have important roles in the pathogenesis of glial malignancies.

Fig. 1 |. Myelin plasticity: evidence and implications from rodent models.

Neuronal activity-regulated changes in myelin are evident in rodent models with direct manipulation of neuronal activity using optogenetics and chemogenetics, and evident with changes in sensory, motor and social experience. Myelin plasticity contributes to a range of neurological functions, including spatial, fear and motor learning.

Fig. 2 |. Neuronal activity-regulated mechanisms of glioma growth.

Neuronal activity drives glioma proliferation, growth and progression through activity-regulated paracrine factors including neuroligin 3 (NLGN3)^,,, brain-derived neurotrophic factor (BDNF)^,, insulin-like growth factor 1 (IGF1), activity-regulated increases in potassium (K⁺) that evoke K⁺ currents in glioma cells^, and bona fide neuron-to-glioma synapses^,,,. K⁺-evoked currents are amplified through gap junction coupling between glioma cells via tumour microtubes^,. Activity-regulated interactions also induce gene expression changes in glioma cells relevant to multiple aspects of glioma network integration^,. In particular, NLGN3 signalling induces glioma gene expression changes that underpin other neuron–glioma interactions, including upregulating synapse-associated genes, the BDNF receptor tyrosine receptor kinase B (TrkB) (NTRK2), the synaptogenic factor thrombospondin 1 (TSP1), genes encoding K⁺ channels, tumour microtube-associated genes including connexin 43 (CX43) (GJA1) and axon guidance genes including semaphorins (implicated in glioma invasion). AMPAR, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor.

Fig. 3 |. Glioma membrane depolarization promotes tumour cell proliferation.

Gliomas exhibit multiple mechanisms of membrane depolarization, including calcium-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated neuron-to-glioma synapses^,, activity-dependent potassium-evoked currents^, and, in some glioma types, depolarizing GABAergic currents mediated by outward flux of chloride through GABA_A receptors. Membrane depolarization alone is sufficient to drive glioma proliferation. Membrane depolarization can trigger opening of voltage-gated ion channels and consequent intracellular signalling events, but the details of voltage-sensitive mechanisms in glioma remain to be elucidated.

Fig. 4 |. Neuron–glioma interactions drive glioma pathobiology.

Paracrine and synaptic interactions between neurons and glioma cells promote cancer cell proliferation, invasion and survival, driving tumour initiation and growth. Reciprocally, glioma cells remodel neural circuits and promote neuronal hyperexcitability, resulting in glioma-associated seizures and increased neuronal input to the tumour.