A mechanistic link between glia and neuronal excitability in acute neuroinflammation

Activation of the innate immune system can induce inflammatory responses in the brain causing transient or persistent changes in brain structure, cognition, and behaviour. Experimental and clinical research of the last decade has revealed inflammatory mediators that act on the brain, which are produced either in the periphery as a consequence of systemic infection, or in the brain following seizures, neurotrauma, stroke, or neurodegenerative processes. Brain inflammation, in turn, may alter neuronal excitability and promote the genesis of seizures, thus potentially contributing to a self‐potentiating cycle of glial and neuronal activation (Vezzani et al. 2011). A widely used experimental approach to studying brain inflammation is the peripheral or intracranial application of lipopolysaccharide (LPS) endotoxin predominantly activating the Toll‐like receptor (TLR) signalling pathway via binding to microglial TLR4, which is upregulated following brain inflammation and considered to be the primary receptor mediating LPS‐induced microglial activation. As overactive microglia can induce neurotoxic effects by the excess production of cytotoxic factors such as superoxide, nitric oxide (NO) and tumour necrosis factor‐α (TNFα), microglia can cause additional neuronal loss or increase ongoing neuronal damage. Only a few of the mechanisms leading to neuronal and network hyperexcitability as a direct effect of acute inflammation are known, which include cytokine‐induced effects on synaptic transmission and plasticity, and changes in intrinsic properties determined by ion channel composition or function (Vezzani & Viviani, 2015).

In this issue of The Journal of Physiology, Tzour et al. (2017) present a novel mechanism with the potential to facilitate translational therapies. They demonstrate that acute LPS‐induced neuronal hyperexcitability in rat acute hippocampal slices is mediated by a complex glia‐to‐neuron signalling cascade that finally results in a functional downregulation of K_V7 voltage‐gated potassium channels, also known as M‐channels. Using a combination of single‐cell electrophysiology, pharmacology and calcium imaging, they established a signalling cascade induced by acute LPS application with sequential activation of microglia, astrocytes and neurons leading to a functional loss of K_V7/M‐channel activity in CA1 pyramidal neurons. Neuronal K_V7 channels, which are widely expressed in the brain, are mainly localized to presynaptic compartments such as axon initial segments and axons. As they activate close to the resting membrane potential and control subthreshold excitability and spike generation, K_V7/M‐channels are important regulators of neuronal excitability (Delmas & Brown, 2005). This role is also suggested by the genetic link between human epilepsy syndromes and K_V7 subunit dysfunction caused by mutations in KCNQ2 and KCNQ3, which encode the K_V7.2 and K_V7.3 α‐subunits of M‐channels. K_V7/M‐channel activity is modulated by neurotransmitters and hormones, including acetylcholine, glutamate and many others, through activation of G protein‐coupled receptors leading to their inhibition (Delmas & Brown, 2005). Starting from the finding that acute LPS application in murine brain slices triggers an increase in neuronal excitability of hippocampal neurons via microglia and astrocytes (Pascual et al. 2012), Tzour and colleagues found that it was the activation of neuronal group I metabotropic glutamate receptors (specifically mGluR5) through glutamate released from astrocytes that caused the release of Ca²⁺ from internal stores, the subsequent inhibition of K_V7/M‐currents and, thereby, the concomitant increase in neuronal excitability. For LPS to exert this action, activation of purinergic receptors on astrocytes by ATP – which is likely to originate from microglia – was required. Notably, application of the novel anticonvulsant drug retigabine, a K_V7 channel opener that acts by shifting the voltage dependence to more hyperpolarized membrane potentials, reversed the excitatory LPS effects.

If the attenuation of K_V7/M currents turns out to be a general finding in neuroinflammation‐induced hyperexcitability, drugs enhancing M‐channels could be a viable therapeutic option stabilizing cellular and network excitability. In this context, it is of note that retigabine is neuroprotective in rodent models of ischaemic stroke when administered within a critical period after the insult (Bierbower et al. 2015). These neuroprotective effects can be attributed to the prevention of ischaemia‐induced neuronal hyperexcitability following a massive release of glutamate induced by cell injury or neuronal dysfunction. In addition, retigabine also attenuated the inflammatory response by limiting the expression of CD40L, a membrane protein of the TNF receptor family playing an important role in the inflammatory response after acute ischaemic infarction (Bierbower et al. 2015). It remains to be investigated, however, whether the attenuation of K_V7/M‐currents also plays a role in chronic neuroinflammation, because homeostatic processes such as activity‐dependent transcriptional upregulation of K_V7 subunits (Zhang & Shapiro, 2012), or augmentation by reactive oxygen species (ROS), may preserve M‐channel function. As K_V7 channels are attractive pharmacological targets and retigabine has already been used as an anticonvulsant in human epilepsy patients, the present data encourage further studies addressing the potential benefit of enhancing K_V7 currents in neuroinflammation.

Additional information

Competing interests

The author does not have any conflict of interest.