While there are many different kinds of epileptic seizures, and a diversity of known causes, they share one thing in common: seizures are the result of imbalances in the brain between excitation and inhibition—factors that excite activity among neurons and factors that inhibit such activity.

When the exquisite balance between excitation and inhibition tips decisively in favor of excitation, the brain can literally seize up, causing a variety of symptoms including vigorous shaking and convulsions, unusual behavior, loss of awareness, and sometimes even loss of consciousness.

Disruptions of the balance between excitation and inhibition are also thought to play a role in autism spectrum disorders and schizophrenia.

A large class of ubiquitous nerve-cell receptors called GPCRs (G-protein-coupled receptors) tightly regulates the ratio between excitation and inhibition in the brain. The receptors can do this by various means, via interactions with molecules that directly excite or inhibit neural transmission, or contribute to these actions. In the context of GPCRs, those factors that excite nerve signals are called agonists and those that inhibit them are called antagonists of the receptor.

A research team led by Richard W. Tsien, Ph.D., Chair of the Department of Physiology and Neuroscience and Director of the Neuroscience Institute at New York University, recently published results of research shedding important new light on how GPCR agonists and antagonists influence the receptors, and in turn, their ability to regulate the balance in the brain between excitation and inhibition.

Specifically, the investigators sought to discover why cannabidiol (CBD), the non-psychoactive component of cannabis, can reduce seizure activity, an impact seen both in animal models of epilepsy and in human patients with treatment-resistant epilepsy.

Among members of the team were Simon Chamberland, Ph.D., a 2019 BBRF Young Investigator, and György Buzsáki, M.D., Ph.D., winner of BBRF’s 2021 Goldman-Rakic Prize for Outstanding Achievement in Cognitive Neuroscience. Evan C. Rosenberg, Ph.D., was first author of the team’s paper, which appeared in Neuron.

Efficacy of plant-derived CBD in Phase III trials led the FDA in 2018 to approve the drug Epidolex for use in certain rare and severe epilepsy-related disorders. CBD, Dr. Tsien’s team notes, “reduces spontaneous recurrent seizures and regulates the excitation/inhibition ratio in acute seizures, yet the molecular signaling underlying these actions remains poorly understood.”

Hoping to learn more about how CBD works, the team used rodent models to confirm past findings that a fatty molecule called LPI (lysophosphatidylinositol) modifies neural transmission by binding to a GCPR called GPR55. When this occurs in a cell poised to send a signal to another neuron—a “pre-synaptic” neuron—the neuron is encouraged to release glutamate, which is the brain’s most common excitatory neurotransmitter.

Interestingly, in the neuron receiving the signal—the “post-synaptic” neuron—LPI’s interaction with GPR55 has the effect of weakening inhibition. Thus, in its roles on either side of the synapse, the LPI-GPR55 interaction promotes excitation. This mechanism supports the propagation of an imbalance between excitation and inhibition, which could lead to seizures, the team noted.

To test this hypothesis, the researchers performed experiments in rodents that had been genetically modified to lack the GPR55 receptor. When the receptor was absent, LPI was unable to have its dual effect of encouraging excitation and weakening inhibition. The team also treated normal rodents with plant-derived CBD before subjecting them to stimuli that induce seizures. Again, the dual effects of LPI in boosting excitation and blocking inhibition were not observed.

The researchers propose that CBD blocks “a positive feedback loop” in which seizures increase the LPI-GPR55 signaling interaction—which likely encourages more seizures; and these seizures, in turn, increase levels of both LPI and GPR55 in nerve cells, resulting in a vicious cycle. This could help explain repeated epileptic seizures, they suggested.

In addition to having potential relevance in studies of excitation/inhibition imbalances in autism and schizophrenia, the study could influence the development of new epilepsy therapies, for example drugs that might inhibit LPI production in nerve cells. LPI also “might serve as a biomarker of seizures or predictor of clinical responsiveness to CBD,” the team said.