Seizures are almost like firestorms in the brain, causing neurons to fire uncontrollably and resulting in aberrant motor behavior and the loss of consciousness. Despite their seriousness, we still have no good way to treat them. However, a recent study by Taito Matsuda and colleagues from Japan has uncovered a novel pathway between hippocampal neurogenesis and the immune system, potentially providing a new treatment avenue for epilepsy.
Epilepsy is a neurological condition that causes individuals to have recurrent and unpredictable seizures, affecting 60 million people worldwide. While seizures induce neuronal loss in the brain area known as the hippocampus, recent work has shown that seizures can also significantly upregulate growth of adult neurons (termed adult neurogenesis). Preventing seizure-induced neurogenesis has been hypothesized to be a viable therapeutic option, given the significant inadequacies of current treatments.
The most common way to treat epilepsy is through medications called anti-epileptic drugs (AEDs). Despite more than 20 available AEDs, medications fail to prevent seizures in as many as 50 percent of patients and cause severe side effects such as mental dulling and even brain degeneration in the long run.
The failure of AEDs reflects a fundamental problem in the way we currently approach the treatment of epilepsy. AEDs aim to reduce seizures by reducing neuronal activity through manipulation of certain ion channels. However, underlying epilepsy is a complex and elaborate process of cellular and molecular changes that make the brain sick, setting up a permanent condition that increases the likelihood of seizures. By aiming to prevent seizures rather than the biological underpinnings, AEDs target the symptoms instead of the underlying cause.
Several pathways have been hypothesized to be viable candidate targets for newer and more efficacious epilepsy treatments. To study how seizures affect the brain, scientists have been administering drugs to artificially induce seizures in rodent models. In the late 1990s, it was discovered that the pharmacological induction of seizures resulted in the upregulation of newborn neurons in the hippocampus, the brain’s learning and memory center. Scientists thus hypothesized that manipulating neurogenesis could be a new treatment strategy for epilepsy. However, it is not clear how scientists and clinicians can effectively modulate neurogenesis, given that adult neurogenesis is a complex and elaborate process that is still poorly understood.
Besides neurogenesis, seizures have also been shown to affect the brain’s immune system. In the brain, resident immune cells known as microglia are activated in response to seizures. Increasing evidence now shows that activated microglia can modulate adult neurogenesis in both healthy and pathological conditions.
How exactly do microglia work? On the surfaces of microglia are toll-like receptors (TLRs) that detect the presence of cellular damage and pathogen. When neurons are injured, they release factors that bind to TLRs. Specifically, TLR7 and TLR9 are known to be activated by nucleic acids released by damaged neurons.
To investigate how TLR signaling is involved in seizure-induced neurogenesis, the Japanese researchers pharmacologically induced seizures in mice that lack TLR7 or TLR9. They discovered that mice without TLR9 had significantly increased neurogenesis compared to normal mice, whereas lack of TLR7 made no difference.
Following activation, microglia release certain chemical factors to trigger inflammation. Hypothesizing that some of these factors are responsible for modulation of neurogenesis, the scientists performed a test known as quantitative real-time PCR in order to analyze molecules released from activated microglia. Interestingly, they found that Tnf-α, a pro-inflammatory molecule, is significantly increased in mice that lacked TLR9 in comparison to normal mice at four days following seizure induction. Blocking Tnf-α in cultured neurons and in mice upregulated neurogenesis, suggesting that Tnf-α is indeed a factor that inhibits adult neurogenesis.
To test whether manipulating the TLR signaling pathway is a viable therapeutic option, the scientists analyzed how lack of TLR9 affects cognitive function after seizures. In humans, it is known that recurrent seizures result in loss of learning and memory abilities. Strikingly, the researchers found that lack of TLR9 exacerbated memory impairments following drug-induced seizures.
As a whole, this study demonstrates that interactions between the brain and the immune system represent powerful therapeutic opportunities for the development of better epilepsy treatments. Outside of epilepsy, the study also reveals a greater insight into the molecular mechanisms that govern adult neurogenesis, which may allow us to better harness the therapeutic potential of neural stem cells for treatments of other brain diseases in general.
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