Abstract
BackgroundAltered chloride homeostasis has been thought to be a risk factor for several brain disorders, while less attention has been paid to its role in liver disease. We aimed to analyze the involvement and possible mechanisms of altered chloride homeostasis of GABAergic neurons within the substantia nigra pars reticulata (SNr) in the motor deficit observed in a model of encephalopathy caused by acute liver failure, by using glutamic acid decarboxylase 67 - green fluorescent protein knock-in transgenic mice.MethodsAlterations in intracellular chloride concentration in GABAergic neurons within the SNr and changes in the expression of two dominant chloride homeostasis-regulating genes, KCC2 and NKCC1, were evaluated in mice with hypolocomotion due to hepatic encephalopathy (HE). The effects of pharmacological blockade and/or activation of KCC2 and NKCC1 functions with their specific inhibitors and/or activators on the motor activity were assessed.ResultsIn our mouse model of acute liver injury, chloride imaging indicated an increase in local intracellular chloride concentration in SNr GABAergic neurons. In addition, the mRNA and protein levels of KCC2 were reduced, particularly on neuronal cell membranes; in contrast, NKCC1 expression remained unaffected. Furthermore, blockage of KCC2 reduced motor activity in the normal mice and led to a further deteriorated hypolocomotion in HE mice. Blockade of NKCC1 was not able to normalize motor activity in mice with liver failure.ConclusionOur data suggest that altered chloride homeostasis is likely involved in the pathophysiology of hypolocomotion following HE. Drugs aimed at restoring normal chloride homeostasis would be a potential treatment for hepatic failure.
Highlights
Hepatic encephalopathy (HE) is a major neuropsychiatric disorder that occurs in patients with severe liver failure [1]
Mice showing a reduced locomotor activity were used in subsequent examinations, including measurements of intracellular chloride concentration in substantia nigra pars reticulata (SNr) GABAergic neurons as well as associated changes in two dominant chloride homeostasis-regulating genes (KCC2 and NKCC1) at both mRNA and protein levels
To assess whether TAA might alter the number of GABAergic neurons in the SNr, Nissl staining was combined with double immunostaining with an anti - green fluorescent protein (GFP) antibody to detect GABAergic neurons located in the SNr and an anti - tyrosine hydroxylase (TH) antibody to detect dopaminergic neurons located in the substantia nigra pars compacta (SNc)
Summary
Hepatic encephalopathy (HE) is a major neuropsychiatric disorder that occurs in patients with severe liver failure [1]. Substantia nigra pars reticulata (SNr) is a mesencephalic nucleus that functions as a relay area for basal ganglia output [12]. This structure is composed of GABA-containing projection neurons that receive GABA-mediated input from the striatum and globus pallidus and project their axons to thalamic motor nuclei, superior colliculus and brainstem motor areas as well as to dopamine neurons of the SN pars compacta [12]. We aimed to analyze the involvement and possible mechanisms of altered chloride homeostasis of GABAergic neurons within the substantia nigra pars reticulata (SNr) in the motor deficit observed in a model of encephalopathy caused by acute liver failure, by using glutamic acid decarboxylase 67 - green fluorescent protein knock-in transgenic mice
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