Cellular scale neuroimmune network mechanisms underlying antibody-driven autoimmune encephalitis

• Applicants: Privatdozentin Dr. Julika Pitsch; Privatdozent Dr. Michael Wenzel
• Subject Area: Experimental Models for the Understanding of Nervous System Diseases
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 528363921

Temporal lobe epilepsy (TLE) is the most common focal epilepsy in adulthood, and does not sufficiently respond to antiepileptic drugs in about 30% of cases. An increasing body of work suggests autoimmune encephalitis (AE) as one major cause of adult-onset pharmacoresistant TLE, with a clinical spectrum comprising seizures, memory impairment, psychosis, and hippocampal sclerosis (HS). Typically, AE is caused by autoreactive immune cells or autoantibodies (Ab) that erroneously attack the central nervous system. To date, various antineuronal Ab have been associated with AE. Of those, human AE with Ab against γ-aminobutyric acid receptor type A (GABAAR) represents a severe form of AE that is often fatal. How GABAAR Ab exposure drives AE remains unclear. Although microglia have recently emerged as important immunoregulators of neuronal excitability, their role in epileptogenesis, and maintenance of chronic epileptic networks in the context of AE remains both poorly understood, and debated. As patients with AE may benefit from tailored immunotherapy, and in light of the severity of GABAAR AE, further work on cellular and network level mechanisms underlying this disease is sorely needed. In a novel mouse model of GABAAR AE, this project will scrutinize neuroimmune mechanisms of AE with unprecedented precision in vivo, across molecular, cellular, network and behavioural levels, and from its earliest time point all the way to chronic disease stages. To this end, we will first combine longitudinal field electrophysiology, cellular resolution dual-colour in vivo imaging of microglial dynamics and neuronal activity, and hippocampal scRNA sequencing, to obtain and link detailed information on the dynamic relationship between Ab exposure, network excitability, microglial dynamics, cellular composition and clinical AE phenotype. This multimodal, longitudinal approach will provide fine-scaled insight into the pathophysiology of Ab-mediated AE. Then, using the same multimodal experimental framework, we will evaluate the potential impact of timed transient or continued microglial depletion on AE disease severity and course. By linking longitudinal cellular scale neuroimmune network dynamics to GABAAR AE development and clinical course, this project will allow unprecedented insight into fundamental mechanisms of AE, across anatomical scales that are likely crucial for this devastating disease. Importantly, we will test if interference with microglial activation may provide a new therapeutic target in AE, which may also carry implications for other immune-driven focal epilepsies.

• DFG Programme: Research Grants