Metabolic modulation of synaptic failure and thalamocortical hypersynchronization with preserved consciousness in Glut1 deficiency

Abstract

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 18 F-deoxyglucose positron emission tomography ( 18 F-DG-PET) illustrated decreased glucose accumulation in this circuit. This pattern, reflected in a decreased thalamic to striatal 18 F 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, 18 F-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.

Identification of Glucose Transport Modulators In Vitro and Method for Their Deep Learning Neural Network Behavioral Evaluation in Glucose Transporter 1–Deficient Mice

“…Only modest glucose transport increases such as those experienced postprandially are beneficial to G1D patients (von Moers et al, 2002;Akman et al, 2010;Koy et al, 2011;Parolin et al, 2011;Rajasekaran et al, 2022). This suggests that relatively small (i.e., below two-fold) changes in net glucose transport can significantly ameliorate brain dysfunction in G1D.…”

“…Wild-type C57BL/6J mice were purchased from the Jackson Laboratory. G1D mice were previously described (Marin-Valencia et al, 2012;Rajasekaran et al, 2022). These mice uniformly display frank ataxia with normal lifespan and other habits.…”

“…This transporter is subject to haploinsufficiency, downregulation or upregulation in neurological and oncological diseases. For example, diminished Glut1 expression and brain glucose content is a hallmark of Glucose transporter 1 deficiency (G1D) (Pascual et al, 2002;Rajasekaran et al, 2022) and various types of dementia (Rosenberg and Pascual, 2020), whereas elevated Glut1 expression can signify cancer growth, invasiveness or adaptation (DeBerardinis and Chandel, 2016). Thus, there is a longstanding interest in stimulating or supressing glucose flux into neural or cancer cells via Glut1 or other mechanisms.…”

“…The clinical expression of G1D represents a multiform neurological disease with infantile onset. Despite constituting a disorder studied by numerous investigators (Klepper et al, 2020) and one for which an informative stable antisense mouse model exists (Marin-Valencia et al, 2012;Marin-Valencia et al, 2013;Rajasekaran et al, 2022), G1D has proven incompletely or inadequately treatable. Paradoxically, most antiseizure drugs aggravate or are ineffective against seizures when they are present (Wang et al, 1993;Rajasekaran et al, 2022).…”

“…Despite constituting a disorder studied by numerous investigators (Klepper et al, 2020) and one for which an informative stable antisense mouse model exists (Marin-Valencia et al, 2012;Marin-Valencia et al, 2013;Rajasekaran et al, 2022), G1D has proven incompletely or inadequately treatable. Paradoxically, most antiseizure drugs aggravate or are ineffective against seizures when they are present (Wang et al, 1993;Rajasekaran et al, 2022). Current therapies thus include a modified Atkins diet, a ketogenic diet, or a regular diet supplemented with triheptanoin (Pascual et al, 2014), the latter of which remains under investigation (clinical trial NCT03181399).…”