Lack of IL-1R8 results in dysregulation of brain excitatory and inhibitory networks

In years growing evidence has indicated that neuroinflammation may affect the proper excitatory/inhibitory balance in the brain, which is required for the optimal processing of information and cognitive function. Even minor inflammatory hits, particularly during pregnancy and early postnatal development, may have detrimental consequences on the correct development of brain circuits. This disturbance could increase the risk or the severity of brain diseases, from neurodevelopmental (autism, schizophrenia) to neurological (epilepsy) disorders. Our research on the immune-deregulated IL-1R8 KO mouse model unveils that the hyperactivation of IL-1R pathway has important consequences on brain functioning, among which changes in both excitatory and inhibitory compartments. In particular the excessive IL-1R activity in IL-1R8 KO mice impacts excitatory neurotransmission through the upregulation of mTOR pathway and the increased expression of MeCP2 protein. These alterations cause morphological and functional impairments at the level of excitatory synapses, including disruption of dendritic spine morphology, synaptic plasticity and plasticity-related gene expression, thus leading to a severe hypofunction of the excitatory synaptic compartment. Pharmacological inhibition of IL-1R activation by Anakinra corrects transcriptional changes, restores MeCP2 levels and spine plasticity. Accordingly, the same treatment ameliorates learning and memory defects observed in IL-1R8 KO mice by means of behavioural analyses. Of note, MeCP2 has been shown to play a fundamental role in the normal function and development of GABAergic inhibitory circuits. Morphological analyses in IL-1R8 KO adult mice revealed increased number of GABAergic interneurons, mainly in parvalbumin- and calretinin-expressing specific subpopulations, changes in the number of inhibitory synapses and the expression of genes strictly related to the GABAergic synapse and signalling. Transcriptomic analyses of IL-1R8 KO Medial Ganglionic Eminences (MGE), the embryonic region containing inhibitory neuron precursors, highlight modification in the expression of genes that are fundamental for the functional diversification and development of GABAergic interneurons. In addition, IL-1R8 KO embryos display enhanced precursor cell proliferation at the level of developing MGE that could explain the increased number of GABAergic interneurons observed in the adult mice. Therefore, these data indicate that the lack of IL-1R8 affects the molecular processes that regulate inhibitory interneurons generation in the developing MGEs. Our study shows that IL-1R8 KO mice display alteration in both excitatory and inhibitory circuitry formation and the consequences of this process may be at the basis of the cognitive defects observed in this model.