Chloride transporter KCC2-dependent neuroprotection depends on the N-terminal protein domain

Winkelmann, Aline; Semtner, Marcus; Meier, Jochen C.

doi:10.1038/cddis.2015.127

Cited by 15 publications

(11 citation statements)

References 53 publications

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“…In fact, KCC2 influences multiple components of neuronal activity including neuronal survival, inhibitory tone, synaptogenesis, and seizure threshold. 9,32,68,76,92,99 Loss of KCC2 expression occurs with epilepsy, 31 gliomas, 15,65 trauma, 11,12,67 and perinatal brain injury. 37,36,79 Developmentally regulated molecules essential for cerebral function are vulnerable to calpain including KCC2, 37,39,72,108 myelin basic protein, and phosphorylated neurofilament.…”

Section: Discussionmentioning

confidence: 99%

Imaging and serum biomarkers reflecting the functional efficacy of extended erythropoietin treatment in rats following infantile traumatic brain injury

Robinson

Winer

Berkner

et al. 2016

PED

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OBJECTIVE Traumatic brain injury (TBI) is a leading cause of death and severe morbidity for otherwise healthy full-term infants around the world. Currently, the primary treatment for infant TBI is supportive, as no targeted therapies exist to actively promote recovery. The developing infant brain, in particular, has a unique response to injury and the potential for repair, both of which vary with maturation. Targeted interventions and objective measures of therapeutic efficacy are needed in this special population. The authors hypothesized that MRI and serum biomarkers can be used to quantify outcomes following infantile TBI in a preclinical rat model and that the potential efficacy of the neuro-reparative agent erythropoietin (EPO) in promoting recovery can be tested using these biomarkers as surrogates for functional outcomes. METHODS With institutional approval, a controlled cortical impact (CCI) was delivered to postnatal Day (P)12 rats of both sexes (76 rats). On postinjury Day (PID)1, the 49 CCI rats designated for chronic studies were randomized to EPO (3000 U/kg/dose, CCI-EPO, 24 rats) or vehicle (CCI-veh, 25 rats) administered intraperitoneally on PID1–4, 6, and 8. Acute injury (PID3) was evaluated with an immunoassay of injured cortex and serum, and chronic injury (PID13–28) was evaluated with digitized gait analyses, MRI, and serum immunoassay. The CCI-veh and CCI-EPO rats were compared with shams (49 rats) primarily using 2-way ANOVA with Bonferroni post hoc correction. RESULTS Following CCI, there was 4.8% mortality and 55% of injured rats exhibited convulsions. Of the injured rats designated for chronic analyses, 8.1% developed leptomeningeal cyst–like lesions verified with MRI and were excluded from further study. On PID3, Western blot showed that EPO receptor expression was increased in the injured cortex (p = 0.008). These Western blots also showed elevated ipsilateral cortex calpain degradation products for αII-spectrin (αII-SDPs; p < 0.001), potassium chloride cotransporter 2 (KCC2-DPs; p = 0.037), and glial fibrillary acidic protein (GFAP-DPs; p = 0.002), as well as serum GFAP (serum GFAP-DPs; p = 0.001). In injured rats multiplex electrochemiluminescence analyses on PID3 revealed elevated serum tumor necrosis factor alpha (TNFα p = 0.01) and chemokine (CXC) ligand 1 (CXCL1). Chronically, that is, in PID13–16 CCI-veh rats, as compared with sham rats, gait deficits were demonstrated (p = 0.033) but then were reversed (p = 0.022) with EPO treatment. Diffusion tensor MRI of the ipsilateral and contralateral cortex and white matter in PID16–23 CCI-veh rats showed widespread injury and significant abnormalities of functional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD); MD, AD, and RD improved after EPO treatment. Chronically, P13–P28 CCI-veh rats also had elevated serum CXCL1 levels, which normalized in CCI-EPO rats. CONCLUSIONS Efficient translation of emerging neuro-reparative interventions dictates the use of age-appropriate preclinical models with human clinical trial–compatible biomarkers. In the present study, the authors showed that CCI produced chronic gait deficits in P12 rats that resolved with EPO treatment and that chronic imaging and serum biomarkers correlated with this improvement.

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Section: Discussionmentioning

confidence: 99%

Imaging and serum biomarkers reflecting the functional efficacy of extended erythropoietin treatment in rats following infantile traumatic brain injury

Robinson

Winer

Berkner

et al. 2016

PED

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“…Tonic inhibition of neuronal excitation through this mechanism may however bear risks for neurodegeneration under conditions of reduced expression levels of the chloride transporter KCC2 as is the case in chronic adulthood epilepsy (Eichler et al, 2008; Legendre et al, 2009; Rivera et al, 2002; Rivera et al, 2004; Winkelmann et al, 2015). Although neurodegeneration was not assessed in our studies with acute administration of the GlyT1 inhibitor LY2365109, the chronic deletion of GlyT1 from hippocampal neurons in mice was not associated with any signs of neurodegeneration (Yee et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Glycine transporter 1 is a target for the treatment of epilepsy

et al. 2015

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Glycine is the major inhibitory neurotransmitter in brainstem and spinal cord, whereas in hippocampus glycine exerts dual modulatory roles on strychnine-sensitive glycine receptors and on the strychnine-insensitive glycineB site of the N-methyl-D-aspartate receptor (NMDAR). In hippocampus, the synaptic availability of glycine is largely under control of glycine transporter 1 (GlyT1). Since epilepsy is a disorder of disrupted network homeostasis affecting the equilibrium of various neurotransmitters and neuromodulators, we hypothesized that changes in hippocampal GlyT1 expression and resulting disruption of glycine homeostasis might be implicated in the pathophysiology of epilepsy. Using two different rodent models of temporal lobe epilepsy (TLE) – the intrahippocampal kainic acid model of TLE in mice, and the rat model of tetanic stimulation-induced TLE – we first demonstrated robust overexpression of GlyT1 in the hippocampal formation, suggesting dysfunctional glycine signaling in epilepsy. Overexpression of GlyT1 in the hippocampal formation was corroborated in human TLE samples by quantitative real time PCR. In support of a role of dysfunctional glycine signaling in the pathophysiology of epilepsy, both the genetic deletion of GlyT1 in hippocampus and the GlyT1 inhibitor LY2365109 increased seizure thresholds in mice. Importantly, chronic seizures in the mouse model of TLE were robustly suppressed by systemic administration of the GlyT1 inhibitor LY2365109. We conclude that GlyT1 overexpression in the epileptic brain constitutes a new target for therapeutic intervention, and that GlyT1 inhibitors constitute a new class of antiictogenic drugs. These findings are of translational value since GlyT1 inhibitors are already in clinical development to treat cognitive symptoms in schizophrenia.

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“…Indeed, the broad multi-tasking spectrum of KCC2 functions has earned the KCC2 co-transporter the designation of a multi-functional “moon-lighting” protein (Blaesse and Schmidt, 2015 ). Ion-independent functions include regulating neural tube formation (Horn et al, 2010 ), synapse formation (Tanis et al, 2009 ; Blaesse and Schmidt, 2015 ), interneuron migration (Bortone and Polleux, 2009 ), neuronal survival (Pellegrino et al, 2011 ; Winkelmann et al, 2015 ), and dendritic spine formation (Li et al, 2007 ; Fiumelli et al, 2013 ; Llano et al, 2015 ). Cortical KCC2 expression is also tightly linked with maturation of GABA A receptors (Chudotvorova et al, 2005 ; Kanold and Shatz, 2006 ; Jantzie et al, 2015 ).…”

Section: Discussionmentioning

confidence: 99%

Prenatal Hypoxia–Ischemia Induces Abnormalities in CA3 Microstructure, Potassium Chloride Co-Transporter 2 Expression and Inhibitory Tone

Jantzie

Getsy

Denson

et al. 2015

Front. Cell. Neurosci.

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Infants who suffer perinatal brain injury, including those with encephalopathy of prematurity, are prone to chronic neurological deficits, including epilepsy, cognitive impairment, and behavioral problems, such as anxiety, inattention, and poor social interaction. These deficits, especially in combination, pose the greatest hindrance to these children becoming independent adults. Cerebral function depends on adequate development of essential inhibitory neural circuits and the appropriate amount of excitation and inhibition at specific stages of maturation. Early neuronal synaptic responses to γ-amino butyric acid (GABA) are initially excitatory. During the early postnatal period, GABAAR responses switch to inhibitory with the upregulation of potassium-chloride co-transporter KCC2. With extrusion of chloride by KCC2, the Cl− reversal potential shifts and GABA and glycine responses become inhibitory. We hypothesized that prenatal hypoxic–ischemic brain injury chronically impairs the developmental upregulation of KCC2 that is essential for cerebral circuit formation. Following late gestation hypoxia–ischemia (HI), diffusion tensor imaging in juvenile rats shows poor microstructural integrity in the hippocampal CA3 subfield, with reduced fractional anisotropy and elevated radial diffusivity. The loss of microstructure correlates with early reduced KCC2 expression on NeuN-positive pyramidal neurons, and decreased monomeric and oligomeric KCC2 protein expression in the CA3 subfield. Together with decreased inhibitory post-synaptic currents during a critical window of development, we document for the first time that prenatal transient systemic HI in rats impairs hippocampal CA3 inhibitory tone. Failure of timely development of inhibitory tone likely contributes to a lower seizure threshold and impaired cognitive function in children who suffer perinatal brain injury.

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Chloride transporter KCC2-dependent neuroprotection depends on the N-terminal protein domain

Cited by 15 publications

References 53 publications

Imaging and serum biomarkers reflecting the functional efficacy of extended erythropoietin treatment in rats following infantile traumatic brain injury

Imaging and serum biomarkers reflecting the functional efficacy of extended erythropoietin treatment in rats following infantile traumatic brain injury

Glycine transporter 1 is a target for the treatment of epilepsy

Prenatal Hypoxia–Ischemia Induces Abnormalities in CA3 Microstructure, Potassium Chloride Co-Transporter 2 Expression and Inhibitory Tone

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