Microglia in the wiring of Inhibitory circuits during sensory cortex critical periods – MicroSENSO

Background
Brain wiring can be perturbed by environmental signals. In particular, prenatal inflammation constitutes a risk factor for neurodevelopmental disorders including Schizophrenia (SCZ) and Autism Spectrum Disorders (ASD). Remarkably, prenatal inflammation in rodents using maternal immune activation (MIA) is sufficient to induce behavioral deficits in the offspring. However, we still have a limited knowledge of how early neuroimmune interactions impact on cerebral functioning.
Microglia, the resident brain macrophages, have been shown to modulate brain wiring and are also perturbed by prenatal inflammation, revealing a remarkable coordination in the development of the neural and immune systems. In addition to the well-described postnatal role of microglia in shaping of excitatory synapses, we recently found that embryonic microglia in mice modulate the migration of a subset of inhibitory cortical interneurons (INs), which later express Parvalbumin (PV). These PV INs are key for the excitation/inhibition (E/I) balance, the proper functioning of cortical circuits and control critical periods of development of sensory cortices during which activity shapes the emergence of adult circuits. We have preliminary data indicating that embryonic microglia perturbations (depletion or MIA) have a profound impact on the developmental trajectory of the inhibition provided by PV INs in the input layer of the somatosensory cortex, leading to hyper-inhibition in juvenile mice and to hypo-inhibition in adult animals.

Objectives
These findings raise a number of important questions: what are the cellular and molecular mechanisms involved? Are microglia and immune challenges specific to PV INs or sexually dimorphic? Does the impact in juveniles particularly perturb critical periods, with life-long consequences?

To address these major issues, our project will develop along 3 main objectives aiming at
- Identifying the mechanisms by which microglia control INs migration and positioning
- Determining the impact and mechanisms of microglia dysfunction on INs circuit functional wiring
- Assessing the long-term consequences of embryonic microglial perturbation on critical periods and behavior
Achieving our goals relies on the complementary expertise of the three partners in mouse genetics, developmental neuroanatomy, single-cell transcriptomics, electrophysiology, optogenetics, in vivo imaging and behavioral studies across the somatosensory and visual cortices.

Impact and Originality of the Project
While microglia are known to regulate the postnatal development of excitatory synapses, our results reveal that these cells also regulate the early wiring of inhibitory circuits. Achieving our goals will thus be instrumental for characterizing the roles of microglia in establishing the functionally important E/I balance across development. Our project will also be instrumental in providing a novel framework for the etiology of neurodevelopmental disorders. In spite of the fact that ASD and SCZ patients show clear sensory deficits and occur with a higher prevalence in males, studies focusing on the developmental trajectories of the sensory cortices in both sexes are extremely limited. Our project will decipher how microglia and inflammation regulate the development of inhibitory circuits in sensory cortices, impact critical periods and the emergence of adult circuits. Bridging expertise in microglia/neuronal development, transcriptomics, cutting-edge imaging, electrophysiology and behavior will be instrumental to unravel how neuroimmune interactions regulate normal and pathological brain wiring and lead to the design of adapted interventional therapies.