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Brain atrophy and overexpression of ADK in RE (A-C) The brain MRI (axial T2-weighted fluid attenuated inversion recovery image) of patient no. 1 displayed a typical progressive abnormal signal area expansion and atrophy of the left hemisphere (A, 1 months, B, 13 months, C, 15 months after the first seizure onset). (D, E) GFAPpositive reactive astrocytes were demonstrated in cortical gray matter (D, arrows) and white matter (E, arrows) within the lesion area. (F, G) Cytoplasmic localization of ADK immunoreactivity in cells with typical astroglial morphology (F, arrows) and a subpopulation of the remnant of neurons (F, arrowheads in inset) in cortical gray matter and white matter (G, arrows) within the lesion. (H) Cytoplasmic staining showed ADK in perivascular reactive astrocytes (arrows) and endothelial cells arrowheads within the lesions. Scale bars = (D-G) 50μm; (H) 12.5μm.
Source publication
Adenosine kinase (ADK) is the chief adenosine removing enzyme in the brain. Experimental
research has highlighted that ADK is a diagnostic and a therapeutic marker for epilepsy. Clinical
research from patients with pharmacoresistant epilepsy also indicated that maladaptive
changes of ADK lead to recurrent seizures in human chronic epilepsy, includi...
Contexts in source publication
Context 1
... is developmental malformation of the cerebral cortex that is highly associated with pharmacoresistant epilepsy in children and young adults [37,38]. One of the commonest forms of FCD in children is FCD type IIB (FCDIIB) [39], which is characterized by cytomegalic dysmorphic neurons ( Figure 2E) and a unique population of abnormal cells known as balloon cells (BCs) ( Figure 2E) [40][41][42]. Balloon cells are identified as abnormal elements characterized by huge size, ill-defined membrane, pale cytoplasm and one or more eccentric nuclei. ...
Context 2
... is developmental malformation of the cerebral cortex that is highly associated with pharmacoresistant epilepsy in children and young adults [37,38]. One of the commonest forms of FCD in children is FCD type IIB (FCDIIB) [39], which is characterized by cytomegalic dysmorphic neurons ( Figure 2E) and a unique population of abnormal cells known as balloon cells (BCs) ( Figure 2E) [40][41][42]. Balloon cells are identified as abnormal elements characterized by huge size, ill-defined membrane, pale cytoplasm and one or more eccentric nuclei. ...
Context 3
... cells in patients with FCDIIB are thought to originate from glioneuronal progenitor cells, strongly suggesting that defects of neuronal and glial specifications are important in the histogenesis of FCDIIB [44]. Neuroimaging hallmarks include hyperintense T2-signaling (Figure 2A-C) and a ''transmantle sign''. Clinical electrophysiological recordings demonstrate relative specific interictal spike patterns [40]. ...
Context 4
... of the ADK concomitant with astrogliosis within the lesions of FCDIIB has been demonstrated in the recent study [21]. Reactive astrocytes, characterized by a hypertrophic morphology with larger soma and increased length and width of astrocytic stellar, were found in in the lesion area ( Figure 2F). Marked GFAP-positive reactive astrogliosis was ...
Context 5
... observed around BCs ( Figure 2F) in the lesions of FCDIIB. 45% BCs were observed to be GFAP positive ( Figure 2F). ...
Context 6
... observed around BCs ( Figure 2F) in the lesions of FCDIIB. 45% BCs were observed to be GFAP positive ( Figure 2F). Cytoplasmic expression of ADK was found in reactive astrocytes (Figure 2G), and a total of 77% of BCs were ADK positive ( Figure 2G [25]. ...
Context 7
... BCs were observed to be GFAP positive ( Figure 2F). Cytoplasmic expression of ADK was found in reactive astrocytes (Figure 2G), and a total of 77% of BCs were ADK positive ( Figure 2G [25]. Radial glial cells in the ventricular zone are the source of BCs in patients with FCDIIB, which retain an embryonic phenotype [45]. ...
Context 8
... BCs were observed to be GFAP positive ( Figure 2F). Cytoplasmic expression of ADK was found in reactive astrocytes (Figure 2G), and a total of 77% of BCs were ADK positive ( Figure 2G [25]. Radial glial cells in the ventricular zone are the source of BCs in patients with FCDIIB, which retain an embryonic phenotype [45]. ...
Similar publications
Adenosine kinase (ADK) is the chief adenosine removing enzyme in the brain. Experimental research has highlighted that ADK is a diagnostic and a therapeutic marker for epilepsy. Clinical
research from patients with pharmacoresistant epilepsy also indicated that maladaptive changes of ADK lead to recurrent seizures in human chronic epilepsy, includi...
Citations
Objective
Low-level somatic mosaicism in the brain has been shown to be a major genetic cause of intractable focal epilepsy. However, how a relatively few mutation-carrying neurons are able to induce epileptogenesis at the local network level remains poorly understood.
Methods
To probe the origin of epileptogenesis, we measured the excitability of neurons with MTOR mutation and nearby non-mutated neurons recorded by whole-cell patch-clamp and array-based electrodes comparing the topographic distribution of mutation. Computational simulation is used to understand neural network-level changes based on electrophysiological properties. To examine the underlying mechanism, we measured inhibitory and excitatory synaptic inputs in mutated neurons and nearby neurons by electrophysiological and histological methods using the mouse model and postoperative human brain tissue for cortical dysplasia. To explain non-cell autonomous hyperexcitability, an inhibitor of adenosine kinase was injected into mice to enhance adenosine signaling and to mitigate hyperactivity of nearby non-mutated neurons.
Results
We generated mice having a low-level somatic mutation in MTOR presenting spontaneous seizures. The seizure-triggering hyperexcitability was originated from non-mutated neurons near mutation-carrying neurons which proved to be less excitable than non-mutated neurons. Interestingly, the net balance between excitatory and inhibitory synaptic inputs onto mutated neurons remained unchanged. Additionally, we found that inhibition of adenosine kinase, which affects adenosine metabolism and neuronal excitability, reduced the hyperexcitability of non-mutated neurons.
Interpretation
This study showed that neurons carrying somatic mutations in MTOR lead to focal epileptogenesis via non-cell autonomous hyperexcitability of nearby non-mutated neurons.
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