Inhibitory neuron dysfunction occurs as a modulated mechanism of hyperexcitability

Inhibitory neuron dysfunction occurs as a modulated mechanism of hyperexcitability

A small group of brain cells connected in a circuit is responsible for triggering whole-brain seizures in a rare form of epilepsy that is influenced by blood sugar levels, a study led by researchers at UT Southwestern suggests. The finding, published in Science Translational Medicine, could lead to new treatments for other metabolic disorders in the brain, the authors said.

“There are broad implications for other diseases because this circuit is involved in dementia, schizophrenia, sleep and cognition,” said study leader Juan Pascual, MD, Ph.D., professor of neurology, pediatrics, physiology and the Eugene McDermott Center for Human Growth and Development. “Our lab is now moving toward studying these implications.”

Dr. Pascual, who directs the Rare Brain Disorders Program, said he and his colleagues in Pascual's lab at UTSW's Peter O'Donnell Jr. Brain Institute have long been interested in a disease known as GLUT1 deficiency syndrome because of its unusual characteristics. This disease, diagnosed in only a few hundred people worldwide, is caused by a congenital deficiency of a protein called glucose transporter type 1, which brings blood sugar into cells to be used as fuel.

From the first months of life, people with GLUT1 deficiency syndrome can suffer several hundred “absence” seizures every day, some of which are characterized by a few seconds of inattention. Patients with the disorder from across North America and the rest of the world seek medical care at UT Southwestern.

Blood sugar levels can significantly affect the number of attacks in patients, and therapeutic diets that increase glucose levels or keep them constant can significantly reduce the amount. Why these seizures are affected by glucose levels was unclear.

To answer this question, Dr. Pascual and his colleagues investigated the anatomical origin of these seizures in human patients. A combination of electroencephalography (EEG), functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) showed that the seizures originated from a relatively small region of the brain in the thalamus and somatosensory cortex.

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When blood sugar levels fell, abnormal electrical activity in the circuit formed by these areas spread throughout the brain. Strangely, the patients remained conscious and able to perform cognitive tests while the seizures occurred, even though EEGs showed racing seizure activity throughout the brain.

Using a mouse model of GLUT1 deficiency syndrome, the researchers showed that the metabolic byproducts of glucose - including neurotransmitters and other chemicals necessary for normal brain function - remained largely at normal levels in the animals' brains. However, electrical activity became dysregulated in brain cells responsible for inhibiting or slowing neural activity, causing them to fire much less frequently than usual, allowing the uncontrolled firing of other connected excitatory cells. When the researchers gave these animals an anti-seizure drug called perampanel, their seizures decreased significantly.

Dr. Pascual suggested that these findings may suggest a new treatment for this unusual type of epilepsy, as well as argue against a long-standing idea that normal function of cells in the thalamic and cortical circuits is necessary for consciousness.

These results refute decades of speculation about the role of the brain in consciousness. This was not entirely unexpected, however, since consciousness is a property of persons rather than brains.”

Juan Pascual, Professor, Neurology, Pediatrics, Physiology, UT Southwestern Medical Center

Other UTSW researchers who contributed to the study include Karthik Rajasekaran, Qian Ma, Levi B. Good, Gauri Kathote, Vikram Jakkamsetti, Peiying Liu, Adrian Avila, Sharon Primeaux, Isaac Marin-Valencia, Deepa Sirsi and Hanzhang Lu.

Dr. Pascual holds the Ed and Sue Rose Distinguished Professorship in Neurology and the Once Upon a Time Foundation Professorship in Pediatric Neurological Disorders.

Source:

UT Southwestern Medical Center

Reference:

Rajasekaran, K., et al. (2022) Metabolic modulation of synaptic failure and thalamocortical hypersynchronization with preserved consciousness in Glut1 deficiency. Science Translational Medicine. doi.org/10.1126/scitranslmed.abn2956.

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