Excessive Microglia Activation May Underly Seizure Onset in CLN1

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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The number of activated microglia — the brain’s resident immune cells — are significantly increased by the time seizures start to occur in a mouse model of infantile Batten disease, also known as CLN1 disease, a study shows.

Suppressing P2X7R, a receptor protein mainly found at the surface of microglia, significantly reduced the number and total duration of seizures in these mice.

These findings suggest that microglia activation contributes to the development of seizures in infantile Batten, and its suppression may be a new therapeutic avenue for this condition, the researchers noted.

The study, “Seizures in PPT1 Knock-In Mice Are Associated with Inflammatory Activation of Microglia,” was published in the International Journal of Molecular Sciences.

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Batten disease is a group of rare neurodegenerative conditions caused by mutations in at least 13 different genes. These mutations lead to the toxic accumulation of waste molecules inside lysosomes — the cells’ recycling compartments — mainly in brain cells, leading to nerve cell, or neuron, damage and death.

Infantile Batten disease is caused by a deficiency in the PPT1 enzyme due to mutations in the CLN1 gene and is “the fastest developing and most severe type” of Batten, the researchers wrote.

Increasing evidence suggests that microglia and its cell surface receptor P2X7R are involved in seizure activation.

“Activated by ATP that is released from neuronal terminals, leaked from the damaged cellular membrane of neurons, or outpoured from astrocytes, P2X7 mediates inflammatory activation of microglia,” the researchers wrote.

ATP is the energy-storing molecule that enables all cells to function. Astrocytes are brain cells involved in providing neuronal support and nutrition, but whose abnormal activity has been implicated in neurological disorders.

“Activated microglia release inflammatory [molecules], which results in neuronal inflammation, damage, and seizure onset,” the researchers wrote.

The levels of microglial markers in the brain’s hippocampus are significantly higher in people with seizures than in those without. The hippocampus is a brain region involved in memory and learning and whose shrinkage is associated with epilepsy and neurodegenerative diseases such as Batten.

However, the mechanisms underlying seizure occurrence in infantile Batten remain largely unclear.

Now, a team of researchers at Xinxiang Medical University in China discovered that P2X7R and microglia activation may indeed contribute to seizures in CLN1 disease.

Using a mouse model of infantile Batten that carries R151X, the most common disease-causing CLN1 mutation, the researchers first found that seizures started at the age of 7 months — a few months after the reported development of significant motor deficits.

Also, the number of microglia and the levels of CD68, a marker of activated microglia, in the hippocampus were stable between the animals’ first and sixth month of life, but showed a significant increase at 7 months old.

This increase in microglia activation by the time of seizure onset was accompanied by significantly impaired inhibitory, or suppressive, neuronal signaling and a significant increase in neuronal death in the hippocampus. Notably, the loss of inhibitory neurons or input is associated with Batten disease and epilepsy.

No significant changes in these cells or markers were observed with increasing age in the hippocampus of healthy mice.

At 7 months of age, the hippocampus of mice with infantile Batten-like disease also showed significantly higher levels of ATP and pro-inflammatory TNF-alpha relative to healthy mice. ATP levels were even more increased when 7-month-old mice were experiencing seizures.

Moreover, treatment with A-438079, a suppressor of P2X7R, significantly reduced the number and duration of seizures in mice with infantile Batten-like disease.

These findings highlight the role of P2X7R and microglia activation in the development of seizures in CLN1 disease.

Interestingly, pronounced hippocampal astrocyte activation was found to occur earlier in time, with the levels of GFAP, a marker of activated astrocytes, being significantly increased from 4 months of age onward and with no major differences between months 6 and 7.

While this is not consistent with the timing of seizure onset in mice with infantile Batten-like disease, “the early and dramatic increase in GFAP expression” observed in this and previous studies suggests that “astrocytes play a role in neuroinflammation and microglial activation … in response to neuronal damage and death,” the researchers wrote.

Based on these findings, the team hypothesized that ATP’s release by damaged neurons and/or activated astrocytes and its subsequent binding to P2X7R at the surface of microglia are key to activate microglia and increase the production of pro-inflammatory molecules.

These molecules promote neuroinflammation, increasing the release of ATP and glutamate, the major “excitatory” chemical messenger in the brain, which in turn causes excess neuronal activation and seizures.

Seizures result in more nerve cell damage and ATP release, leading to a never-ending cycle of neuroinflammation, seizures, and neuronal damage and death.

As such, therapeutic approaches based on the suppression of microglia activation, either targeting P2X7R or ATP, “may be effective for the treatment of [infantile Batten],” the team wrote.