Authors :
Presenting Author: Jerome Clasadonte, PhD – UCB Biopharma SRL
Georges Mairet-Coello, PhD – Early Solutions, Neuroscience TA – UCB Biopharma SRL; Gabriel Stephens, PhD – Neuroscience – Memory and Brain Research Center - Baylor College of Medicine; Tania Deprez, BS – Early Solutions, Neuroscience TA – UCB Biopharma SRL; Pierre-Yves Cortin, BS – Early Solutions, Neuroscience TA – UCB Biopharma SRL; Maxime Boutier, PhD – UCB Biopharma SRL; Aurore Frey, PhD – Early Solutions, Neuroscience TA – UCB Biopharma SRL; Jeannie Chin, PhD – Neuroscience – Memory and Brain Research Center - Baylor College of Medicine; Marek Rajman, PhD – Early Solutions, Neuroscience TA – UCB Biopharma SRL
Rationale:
Activity induced transcription factor ΔFosB plays a key role in different disorders of the central nervous system including epilepsy, Alzheimer’s disease (AD), and addiction. Recent findings suggest that ΔFosB drives cognitive deficits in epilepsy and together with efforts to identify small molecule inhibitors of ΔFosB activity makes it an interesting therapeutic target. However, whether ΔFosB contributes to pathophysiology or provides protection in drug-resistant epilepsy is still unclear. Here, we investigated the pathophysiological consequences of disrupting ΔFosB function in two different mouse models that exhibit spontaneous recurrent seizures (SRSs), a mouse pilocarpine model of mesial temporal lobe epilepsy (mTLE) and a transgenic mouse model of AD neuropathology that expresses the mutant human amyloid precursor protein (APP).
Methods:
ΔFosB was specifically downregulated for four to eight weeks by stereotactically delivering an AAV-shRNA against ∆FosB in chronically epileptic mice several months after status epilepticus was induced by intraperitoneal pilocarpine. Seizure monitoring was performed with a proprietary system (UCB Pharma) using simultaneous video recording and monitoring of locomotor activity with a 3D micro-accelerometer chip secured to the back of the mouse with a harness. ΔFosB activity was also directly inhibited in the hippocampus of APP mice by stereotactically delivering AAV-∆JunD to block ΔFosB signaling for four or twelve weeks. In both models, brains were collected several weeks after AAV delivery and prepared for immunohistochemistry analysis to evaluate the histopathological consequences of ΔFosB hypofunction.
Results:
Immunohistochemistry analyses showed that prolonged downregulation of ΔFosB led to exacerbation of neuroinflammatory markers of astrogliosis and microgliosis, reduction of mossy fiber sprouting markers, a decrease in adult neurogenesis, and granule cell dispersion in the hippocampus of mTLE mice. Similar histopathological observations were made in the hippocampus of APP mice after prolonged inhibition of ΔFosB signaling, characterized by increased neuroinflammation and decreased mossy fiber sprouting of NPY-positive fibers.
Conclusions:
All together, these data suggest that seizure-induced ∆FosB, regardless of seizure-etiology, is part of a homeostatic mechanism that protects the epileptic brain from further deterioration.
Funding: N/A