Seizures and disturbed brain potassium dynamics in the leukodystrophy megalencephalic leukoencephalopathy with subcortical cysts

Abstract

ObjectiveLoss of function of the astrocyte‐specific protein MLC1 leads to the childhood‐onset leukodystrophy “megalencephalic leukoencephalopathy with subcortical cysts” (MLC). Studies on isolated cells show a role for MLC1 in astrocyte volume regulation and suggest that disturbed brain ion and water homeostasis is central to the disease. Excitability of neuronal networks is particularly sensitive to ion and water homeostasis. In line with this, reports of seizures and epilepsy in MLC patients exist. However, systematic assessment and mechanistic understanding of seizures in MLC are lacking.MethodsWe analyzed an MLC patient inventory to study occurrence of seizures in MLC. We used two distinct genetic mouse models of MLC to further study epileptiform activity and seizure threshold through wireless extracellular field potential recordings. Whole‐cell patch‐clamp recordings and K+‐sensitive electrode recordings in mouse brain slices were used to explore the underlying mechanisms of epilepsy in MLC.ResultsAn early onset of seizures is common in MLC. Similarly, in MLC mice, we uncovered spontaneous epileptiform brain activity and a lowered threshold for induced seizures. At the cellular level, we found that although passive and active properties of individual pyramidal neurons are unchanged, extracellular K+ dynamics and neuronal network activity are abnormal in MLC mice.InterpretationDisturbed astrocyte regulation of ion and water homeostasis in MLC causes hyperexcitability of neuronal networks and seizures. These findings suggest a role for defective astrocyte volume regulation in epilepsy. Ann Neurol 2018;83:636–649

Megalencephalic Leukoencephalopathy with Subcortical Cysts Disease-Linked MLC1 Protein Favors Gap-Junction Intercellular Communication by Regulating Connexin 43 Trafficking in Astrocytes

“…In human and mouse brains, the MLC1/GlialCAM protein complex is highly expressed at perivascular astrocyte end-feet contacting the BBB and is particularly enriched at astrocyte–astrocyte junctions, where it establishes interactions with ZO-1 and Cx43 [ 24 , 40 ]. The diffuse brain edema characterizing the magnetic resonance imaging (MRI) of MLC patients and astrocyte vacuolation/swelling observed by histological analysis of brain tissue (see Reference [ 46 ] and the reference therein) along with alterations of chloride, potassium, and calcium fluxes reported in MLC disease models [ 27 , 48 , 49 , 50 ] suggest that intercellular communication and glial syncytium properties might be affected directly or indirectly by MLC1 mutations. A further support to this hypothesis is provided by the finding that in astrocytoma cells GlialCAM pathological mutations disrupt GlialCAM/Cx43 interactions, decreasing Cx43 stability at the plasma membrane [ 40 ].…”

“…Altered astrocyte connectivity could also explain astrocyte end-feet swelling and the diffuse cerebral edema observed in MLC patients. A recent study indicating that loss of function of MLC1 leads to dysregulation of potassium ion (K + ) homeostasis [ 49 ] suggests that, after astrocyte-mediated K + uptake occurring at synaptic levels, defects in Cx43/gap junction coupling may affect K + spatial buffering and expulsion at BBB sites [ 56 ]. Worth noting, Cx43 is needed for astroglial perivascular connectivity during postnatal BBB maturation [ 15 , 57 ], a process where also the MLC1/GlialCAM complex is involved [ 58 ].…”

Megalencephalic leukoencephalopathy with subcortical cysts

“…The study confirms that epilepsy is a common feature in MLC. 25 It is puzzling that most patients have well-controlled epilepsy while few patients have refractory epilepsy and ∼25% remain seizure-free. A salient observation is that a considerable proportion of patients with classic MLC exhibit only very mild signs during the disease course; in 2 patients with MLC1, a considerable improvement of the MRI abnormalities occurred.…”

Genetic defects disrupting glial ion and water homeostasis in the brain

“…Seizures are typically easily controlled by medication. Mild head trauma is an important provoking factor for seizures, and status epilepticus occurs relatively often in MLC patients . The clinical picture of patients with recessive MLC1 mutations (classic MLC or MLC1) or recessive GLIALCAM mutations (MLC2A) is indistinguishable.…”