| Autor: |
Rajasekaran, Karthik, Ma, Qian, Good, Levi B., Kathote, Gauri, Jakkamsetti, Vikram, Liu, Peiying, Avila, Adrian, Primeaux, Sharon, Enciso Alva, Julio, Markussen, Kia H., Marin-Valencia, Isaac, Sirsi, Deepa, Hacker, Peter M. S., Gentry, Matthew S., Su, Jianzhong, Lu, Hanzhang, Pascual, Juan M. |
| Předmět: |
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| Zdroj: |
Science Translational Medicine; 10/5/2022, Vol. 14 Issue 665, p1-15, 15p |
| Abstrakt: |
Individuals with glucose transporter type I deficiency (G1D) habitually experience nutrient-responsive epilepsy associated with decreased brain glucose. However, the mechanistic association between blood glucose concentration and brain excitability in the context of G1D remains to be elucidated. Electroencephalography (EEG) in G1D individuals revealed nutrition time-dependent seizure oscillations often associated with preserved volition despite electrographic generalization and uniform average oscillation duration and periodicity, suggesting increased facilitation of an underlying neural loop circuit. Nonlinear EEG ictal source localization analysis and simultaneous EEG/functional magnetic resonance imaging converged on the thalamus-sensorimotor cortex as one potential circuit, and 18F-deoxyglucose positron emission tomography (18F-DG-PET) illustrated decreased glucose accumulation in this circuit. This pattern, reflected in a decreased thalamic to striatal 18F signal ratio, can aid with the PET imaging diagnosis of the disorder, whereas the absence of noticeable ictal behavioral changes challenges the postulated requirement for normal thalamocortical activity during consciousness. In G1D mice, 18F-DG-PET and mass spectrometry also revealed decreased brain glucose and glycogen, but preserved tricarboxylic acid cycle intermediates, indicating no overall energy metabolism failure. In brain slices from these animals, synaptic inhibition of cortical pyramidal neurons and thalamic relay neurons was decreased, and neuronal disinhibition was mitigated by metabolic sources of carbon; tonic-clonic seizures were also suppressed by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor inhibition. These results pose G1D as a thalamocortical synaptic disinhibition disease associated with increased glucose-dependent neuronal excitability, possibly in relation to reduced glycogen. Together with findings in other metabolic defects, inhibitory neuron dysfunction is emerging as a modulable mechanism of hyperexcitability. Fuel-dependent inhibition: Glucose transporter type I deficiency (G1D) is characterized by reduced brain glucose and development of treatment-resistant epilepsy. Here, Rajasekaran et al. use electroencephalography and imaging data from individuals with G1D and showed that the thalamus/sensorimotor cortex circuit might be a critical area involved in the increased brain excitability and the development of seizures. In a mouse model of G1D, the authors showed no energy metabolism impairments, whereas synaptic inhibition of cortical pyramidal and thalamic cells was reduced. Switch in carbon source restored inhibitory activity, and inhibition of AMPA receptor reduced seizures in mice, suggesting that failure of the inhibitory synapses of the circuit might be the main cause of seizure activity in G1D. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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