Role of the BDNF-TrkB pathway in KCC2 regulation and rehabilitation following neuronal injury: A mini review

doi:10.1016/j.neuint.2019.04.003

Neurochemistry International

Volume 128, September 2019, Pages 32-38

https://doi.org/10.1016/j.neuint.2019.04.003 Get rights and content

Highlights

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Exercise and mechanical stimulation are beneficial in spasticity and neuropathic pain.
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KCC2 expression is regulated via translational and post-translational mechanisms.
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Rehabilitation efforts may recover KCC2 expression without exogenous BDNF.

Abstract

In most mature neurons, low levels of intracellular Cl⁻ concentrations ([Cl⁻]_i) are maintained by channels and transporters, particularly the K⁺-Cl^- cotransporter 2 (KCC2), which is the only Cl⁻ extruder in most neurons. Recent studies have implicated KCC2 expression in the molecular mechanisms underlying neuronal disorders, such as spasticity, epilepsy and neuropathic pain. Alterations in KCC2 expression have been associated with brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin-related kinase B (TrkB). The present review summarizes recent progress regarding the roles of Cl⁻ regulators in immature and mature neurons. Moreover, we focus on the role of KCC2 regulation via the BDNF-TrkB pathway in spinal cord injury and rehabilitation, as prior studies have shown that the BDNF-TrkB pathway can affect both the pathological development and functional amelioration of spinal cord injuries. Evidence suggests that rehabilitation using active exercise and mechanical stimulation can attenuate spasticity and neuropathic pain in animal models, likely due to the upregulation of KCC2 expression via the BDNF-TrkB pathway. Moreover, research suggests that such rehabilitation efforts may recover KCC2 expression without the use of exogenous BDNF.

Introduction

Recent studies have implicated cation-chloride cotransporters (CCCs) in molecular mechanisms underlying disorders of the central and peripheral nervous systems (CNS and PNS, respectively), including spasticity (Boulenguez et al., 2010; Toda et al., 2014), seizures, epilepsy (Puskarjov et al., 2014; Woo et al., 2002), allodynia, and neuropathic pain (Coull et al., 2003; Tsuda et al., 2003; Zhou et al., 2012).

In most mature neurons, intracellular Cl⁻ ([Cl⁻]_i) is maintained at low concentrations by channels and transporters; in most neurons, this is performed only by the K⁺-Cl^- cotransporter 2 (KCC2) (Blaesse et al., 2009; Rivera et al., 1999). However, in immature neurons, [Cl⁻]_i is maintained at relatively high levels due to the inhibition of KCC2 expression. Therefore, GABA_A and glycine receptors, which act as inhibitory receptors in mature neurons, serve a “depolarizing” function in immature neurons (Rivera et al., 1999). In diseases of the CNS and PNS, alterations in KCC2 expression disrupt the normally low [Cl⁻]_i found in mature neurons. High [Cl⁻]_i results in hyperexcitability in the damaged mature neurons.

Changes in KCC2 expression have been associated with brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin-related kinase B (TrkB). Interestingly, the BDNF-TrkB pathway has been implicated in both the pathological development and functional amelioration of various neuronal disorders (Boulenguez et al., 2010; Rivera et al., 2004; Tashiro et al., 2015); and the overexpression of BDNF reportedly worsens pathological conditions (Boyce et al., 2012; Ziemlinska et al., 2014). However, recent reports have suggested that rehabilitation through exercise and mechanical stimulation can normalize the expression of KCC2 and thus improve the symptoms of neuronal disorders (Hahm et al., 2015; Hou et al., 2014; Tashiro et al., 2015).

In the present review, we summarize the recent progress regarding the roles of Cl⁻ regulators in immature and mature neurons, as well as the role of KCC2 regulation via the BDNF-TrkB pathway in spinal cord injury and rehabilitation.

Section snippets

Regulation of [Cl⁻]_i in neurons

In mature neurons, the levels of [Cl⁻]_i is regulated by several ion channels and transporters: 1) ligand-gated ion channels, such as GABA_A and glycine receptors; 2) voltage-gated Cl⁻ channels, such as ClC channels; 3) calcium-activated Cl⁻ channels, such as anoctamin channels; 4) pH-sensitive Cl⁻ channels, such as SLC4, SLC26, and CFTR (cystic fibrosis transmembrane conductance regulator) channels; and 5) CCCs, such as KCC2 and NKCC1 (Fig. 1) (Rahmati et al., 2018). Cl⁻ ions move across the

Role of KCC2 in developing and mature neuronal states

KCC2 expression is regulated via transcriptional and post-translational mechanisms. The transcriptional regulation of KCC2 expression can exert different effects on neuronal maturation.

Regulation of KCC2 expression and synaptic signaling after neuronal trauma

In models of neuropathic pain after PNS nerve and spinal cord injuries, activated microglial cells secrete BDNF into the extracellular space, where it binds to neuronal TrkB. Thus, in damaged neurons, KCC2 expression is downregulated following activation of both the PLCγ1 and Shc signaling cascades of the BDNF-TrkB pathway (Beggs et al., 2012; Coull et al., 2005; Kaila et al., 2014; Tsuda et al., 2003) (Fig. 5). In contrast, significant increases in the levels of activated microglia are

Effect of rehabilitation on injury-induced downregulation of KCC2

For the treatment of KCC2 in molecular mechanisms underlying disorders of CNS and PNS, damaged neurons are infused with exogenous BDNF to induce upregulation of KCC2 expression. However, upregulation of endogenous BDNF via rehabilitation strategies (e.g., exercise and mechanical stimulation) has been reported to promote recovery of KCC2 expression and improve spasticity and pain following injury.

Tashiro and colleagues (Tashiro et al., 2015) reported that 2 weeks of gait training (70–80% weight

Conclusion

The downregulation of KCC2 that underlies disorders of the CNS and PNS may be reversed by targeting the BDNF-TrkB. However, signaling cascades of compensatory KCC2 upregulation have not yet been identified and should thus be explored by future research. On the other hand, KCC2 selective analogs CLP257 and CLP 290, which is a carbamate prodrug of CLP257, have been found to activate KCC2 and thereby treat neuropathic pain and spinal cord injury (Chen et al., 2018; Gagnon et al., 2013). While the

Declaration of interest

None.

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Brain derived neurotrophic factor (BDNF) is a member of nerve growth factor family that plays an important role in the regulation of KCC2 expression (Lee-Hotta et al., 2019; Mapplebeck et al., 2019; Porcher et al., 2018; Richner et al., 2019; Rivera et al., 2002). The increased release of BDNF from spinal active microglia after nerve injuries decreases the protein level of KCC2 via binding to its cognate TrkB receptors on superficial dorsal horn neurons, leading to the loss of inhibition and pronounced pain hypersensitivity (Lee-Hotta et al., 2019; Mapplebeck et al., 2019; Rivera et al., 2002; Sorge et al., 2015). However, the precise mechanisms by which BDNF induces the degradation of KCC2 remain to be elucidated.
The K⁺-Cl^- co-transporter 2 (KCC2) is a neuron-specific Cl⁻ extruder in the dorsal horn of spinal cord. The low intracellular Cl⁻ concentration established by KCC2 is critical for GABAergic and glycinergic systems to generate synaptic inhibition. Peripheral nerve lesions have been shown to cause KCC2 dysfunction in adult spinal cord through brain-derived neurotrophic factor (BDNF) signaling, which switches the hyperpolarizing inhibitory transmission to be depolarizing and excitatory. However, the mechanisms by which BDNF impairs KCC2 function remain to be elucidated. Here we found that BDNF treatment enhanced KCC2 ubiquitination in the dorsal horn of adult mice, a post-translational modification that leads to KCC2 degradation. Our data showed that spinal BDNF application promoted KCC2 interaction with Casitas B-lineage lymphoma b (Cbl-b), one of the E3 ubiquitin ligases that are involved in the spinal processing of nociceptive information. Knockdown of Cbl-b expression decreased KCC2 ubiquitination level and attenuated the pain hypersensitivity induced by BDNF. Spared nerve injury significantly increased KCC2 ubiquitination, which could be reversed by inhibition of TrkB receptor. Our data implicated that KCC2 was one of the important pain-related substrates of Cbl-b and that ubiquitin modification contributed to BDNF-induced KCC2 hypofunction in the spinal cord.

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Role of the BDNF-TrkB pathway in KCC2 regulation and rehabilitation following neuronal injury: A mini review

Highlights

Abstract

Introduction

Section snippets

Regulation of [Cl−]i in neurons

Role of KCC2 in developing and mature neuronal states

Regulation of KCC2 expression and synaptic signaling after neuronal trauma

Effect of rehabilitation on injury-induced downregulation of KCC2

Conclusion

Declaration of interest

Cell

Neuron

Neurobiol. Dis.

Trends Neurosci.

Biochem. Biophys. Res. Commun.

Lancet

Mech. Dev.

Trends Mol. Med.

Auris Nasus Larynx

Neuroscience

Brain Res.

J. Biol. Chem.

Neuropeptides

Brain Res.

Neuron

Exp. Neurol.

Trends Neurosci.

Neuroscience

J. Biol. Chem.

Bioorg. Med. Chem. Lett

J. Biol. Chem.

J. Biol. Chem.

Brain Res Dev Brain Res

J. Biol. Chem.

A natural classification of the basic helix-loop-helix class of transcription factors

Proc. Natl. Acad. Sci. U. S. A.

Tonic activation of group I mGluRs modulates inhibitory synaptic strength by regulating KCC2 activity

J Physiol

P2X4R+ microglia drive neuropathic pain

Nat. Neurosci.

Activation of 5-HT2A receptors upregulates the function of the neuronal K-Cl cotransporter KCC2

Proc. Natl. Acad. Sci. U. S. A.

Down-regulation of the potassium-chloride cotransporter KCC2 contributes to spasticity after spinal cord injury

Nat. Med.

Differential effects of brain-derived neurotrophic factor and neurotrophin-3 on hindlimb function in paraplegic rats

Eur. J. Neurosci.

Thermodynamic regulation of NKCC1-mediated Cl- cotransport underlies plasticity of GABA(A) signaling in neonatal neurons

J. Neurosci.

The small molecule CLP257 does not modify activity of the K(+)-Cl(-) co-transporter KCC2 but does potentiate GABAA receptor activity

Nat. Med.

Reactivation of dormant relay pathways in injured spinal cord by KCC2 manipulations

Cell

Upstream stimulatory factors are mediators of Ca2+-responsive transcription in neurons

J. Neurosci.

Serotonin receptor and KCC2 gene expression in lumbar flexor and extensor motoneurons posttransection with and without passive cycling

J. Neurophysiol.

Exercise modulates chloride homeostasis after spinal cord injury

J. Neurosci.

BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain

Nature

Trans-synaptic shift in anion gradient in spinal lamina I neurons as a mechanism of neuropathic pain

Nature

Regulation of [Cl⁻]_i in neurons