Epilepsy is a common consequence of brain insults, such as brain injuries, status epilepticus, and cerebrocortical stroke in the elderly and children. Despite ongoing research, there are no treatments that prevent epilepsy after brain insults. Each year, 15 million people worldwide suffer a stroke. Stroke is followed by a latent period (month to years) during which the brain goes through changes leading to the onset of chronic epilepsy. Understanding the maladaptive process so the development of epilepsy (epileptogenesis) during the latent period can be prevented or treated is the holy grail of epilepsy research. Our preliminary data that form the basis of this proposal suggest that persistent inflammation involving glial cells may be a key component of epileptogenesis after stroke in rats. We previously found that cerebrocortical stroke leads to neural reorganization in the thalamocortical system and that the thalamus becomes hyperexcitable within the first week after stroke. Silencing the thalamic hot spot with optogenetic tools is sufficient to abort the epileptic seizures in real-time. We previously showed these hot spots to be causally involved in epileptic seizures (after the onset of chronic post-stroke epilepsy). They are associated with neural circuit plasticity co-localized with a permanent and focal astrogliosis and microgliosis and a massive upregulation of C1q, an immune molecule of the complement cascade, in the region that is causally involved in epileptic seizures. C1q is known for its role in synaptic pruning and circuit plasticity during normal development in the visual system, but our findings suggest that C1q may have a role in circuit plasticity after brain insults such as stroke. Our pilot data indicae that anti-inflammatory treatments that modify the gliosis also prevent the circuit hyperexcitabilit and deficits in synaptic inhibition and that selectively inducing gliosis via viral approaches phenocopies the deficits in synaptic inhibition and induces circuit hyperexcitability. We hypothesize that the glial-induced inflammation and C1q in the thalamus have key roles in the maladaptive cellular and circuit plasticity that leads from stroke to epilepsy. The goal of the proposed research is to determine the role of gliosis in epileptogenic circuit reorganization in th thalamocortical system. We will combine cellular physiology, systems neuroscience, and bioengineering to determine whether gliosis and/or blocking C1q actions after stroke will prevent epileptogenesis and whether disrupting the gliosis and blocking C1q actions during the chronic epileptic phase (i.e., after epilepsy has developed) will be sufficient to go back in time to modify the disease and cure epilepsy. This project may lead to novel biomarkers in epilepsy (thalamic gliosis and C1q) and novel treatments to prevent epilepsy after brain lesions, such as stroke.
Cerebrocortical injuries, such as stroke, are a major source of disability and a common cause of epilepsy. This proposal aims to understand the role of glial cells and inflammation in the neural circuit reorganization after stroke and to understand what aspects of this reorganization can lead to epilepsy. This may lead to new insights on therapeutic approaches that target inflammation to promote functional recovery while limiting its health-impairing outcomes and preventing epilepsy.
| Vainchtein, Ilia D; Chin, Gregory; Cho, Frances S et al. (2018) Astrocyte-derived interleukin-33 promotes microglial synapse engulfment and neural circuit development. Science 359:1269-1273 |
| Clemente-Perez, Alexandra; Makinson, Stefanie Ritter; Higashikubo, Bryan et al. (2017) Distinct Thalamic Reticular Cell Types Differentially Modulate Normal and Pathological Cortical Rhythms. Cell Rep 19:2130-2142 |
| Sorokin, Jordan M; Paz, Jeanne T; Huguenard, John R (2016) Absence seizure susceptibility correlates with pre-ictal ? oscillations. J Physiol Paris 110:372-381 |
| Lui, Hansen; Zhang, Jiasheng; Makinson, Stefanie R et al. (2016) Progranulin Deficiency Promotes Circuit-Specific Synaptic Pruning by Microglia via Complement Activation. Cell 165:921-35 |
