Suppressing microglial cells is a disease modifying intervention for comorbidities in the self-sustained status epilepticus mouse model of mesial temporal lobe epilepsy (MTLE)
Abstract number :
1.404
Submission category :
1. Basic Mechanisms / 1D. Mechanisms of Therapeutic Interventions
Year :
2021
Submission ID :
1886456
Source :
www.aesnet.org
Presentation date :
12/9/2021 12:00:00 PM
Published date :
Nov 22, 2021, 06:56 AM
Authors :
Peravina Thergarajan, BSc (Hons) - Monash University; Bianca Jupp, PhD – Research Fellow, Department of Neuroscience, Monash University, Melbourne, Australia; Mohammad B Haskali, PhD – Radiopharmaceutical Scientist, Department of Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne,Australia, Peter MacCallum Cancer Centre, Melbourne, Australia; Terence J. O’Brien, MD – Professor, Department of Neuroscience, Monash University, Melbourne, Australia; Nigel C. Jones, PhD – Associate Professor, Department of Neuroscience, Monash University, Melbourne, Australia; Idrish Ali, PhD – Research Fellow, Department of Neuroscience, Monash University, Melbourne, Australia
Rationale: Neuroinflammation is believed to play an important role in epilepsy pathogenesis. Chronic neuroinflammation with sustained microglial activation occurs following an epileptogenic insult and is believed to contribute to subsequent neurodegeneration and the development of the epilepsy. The role of microglia proliferation and activation in the development of acquired epilepsy is unknown; thus, this study aimed to investigate the effects of microglial depletion immediately following status epilepticus (SE) in a mesial temporal lobe epilepsy (MTLE) mouse model by measuring the expression of neuroinflammatory markers and characterizing epilepsy severity and cognitive and behavioural comorbidities of MTLE.
Methods: Self-sustained status epilepticus (SSSE) was induced in mice via electrical stimulation. Following termination of SSSE, mice received intraperitoneal injections of a colony-stimulating factor 1 receptor (Csf1R) inhibitor (PLX5622) (50mg/kg ip twice daily), which reversibly depletes microglia, or vehicle injections, for one week. For the acute timepoint study (n=8/group), the effects of PLX treatment on gene expression following the SSSE at the time of cessation of PLX treatment was evaluated. In the chronic epileptic period (n=12/group), mice underwent a series of behavioural tests (8-weeks after SSSE) to examine depression and anxiety-like behaviour and cognitive function, and seizure frequency via continuous video electroencephalography (vEEG) monitoring.
Results: Microglial depletion with PLX5622 significantly downregulated mRNA expression of proinflammatory cytokines such as IL-1α (p=0.0013), IL-6 (p= 0.0006), and CD86 (p=0.0002) without affecting the expression of the anti-inflammatory cytokines such as TGF-β (p=0.7369), PPAR-γ (p=0.6614), Arg1 (p=0.9097) except IL-10RA which was downregulated (p=0.0001). During the chronic epilepsy period, PLX treated mice displayed improved memory, evidenced by prolonged time spent in the novel arm in the Y-maze test (p=0.0011), compared to vehicle-treated mice. In addition, there were signs of reduced depressive behaviour with significantly lower immobility time on the tail suspension test (p=0.0297), and a trend towards higher preference for sucrose consumption (p=0.0923) in PLX treated SSSE animals when compared to the vehicle treated SSSE animals.
Conclusions: Transient microglia depletion during the early phase of epileptogenesis in this mouse model of MTLE results in markedly improved long-term cognitive and behavioural comorbidities. This suggests that microglia-mediated neuroinflammation plays an important role in the pathogenesis of these common comorbidities of MTLE. Csf1R inhibition may provide a clinically feasible approach to limit neurological dysfunction following epileptogenic insults and could be a potential target for improving disease outcomes.
Funding: Please list any funding that was received in support of this abstract.: This work was supported by a NHMRC Program APP1091593 and Investigator APP1176426 Grants to TJO, and a start-up grant by Monash University to TJO.
Basic Mechanisms