The classical complement system in post-traumatic thalamic neuroinflammation

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PROJECT SUMMARY AND ABSTRACT Traumatic brain injury (TBI) impacts 69 million individuals worldwide every year. Despite its prevalence, TBI continues to be undertreated, so much so that the Centers for Disease Control and Prevention has dubbed it a “silent epidemic”. TBI boasts no viable treatments, yet the long-term consequences can be profoundly disabling. For example, up to 50% of TBI patients will develop chronic post-traumatic epilepsy (PTE), and a majority will report sleep disturbances like sleep fragmentation and insomnia. A leading candidate for the origin of these post-traumatic deficits is thalamic inflammation. Deep-brain thalamic structures often show signs of robust gliosis and inflammation after TBI, even if the primary injury acutely affects the cortex. The thalamus is a nexus for sleep, and its dense reciprocal connectivity with the cortex render it highly epileptogenic. Studies in the Paz laboratory have shown that aberrant complement activation in the thalamus, and in particular high levels of complement factor C1q, can lead to the development of post-traumatic epileptic activity and a reduction in sleep spindles, electrophysiological signatures of non-REM sleep thought to be crucial for memory consolidation. The question now remains how C1q exerts its maladaptive effects. The proposed research will investigate the cellular source of maladaptive C1q through inducible genetic deletion, EEG, and immunohistochemistry, and will determine the role that microglia—cells whose function in synaptic pruning is known to be modulated by C1q—may play in mediating electrophysiological abnormalities due to C1q (Aim 1). The proposed research will also explore the extent of the classical complement pathway’s participation in the rise of epileptic events and sleep spindle loss by applying a highly novel nanobody against C4b, C1q’s immediate downstream effector (Aim 2), coupled with many of the EEG and molecular techniques described in Aim 1. These studies will be conducted with the ultimate goal of identifying avenues for potential therapeutic treatment for TBI and its resultant deficits, including PTE and sleep disruption. All research will be conducted at UCSF and at Gladstone Institutes and will benefit from the wealth of resources and training available at both institutions. They will be enriched by in-house data science and statistics tools and courses, and profit from internal and external collaborations. All experiments will be guided by the mentorship of supervising sponsor Dr. Jeanne Paz, and made available for feedback and presentation at conferences and meetings.