THE ROLE OF MICROGLIA IN THE DEVELOPMENT OF CORTICOLIMBIC GABAERGIC SYSTEM IN MICE

Microglia are essential for mediating numerous physiological functions in the brain, including correctly shaping neuronal synapses and circuits during early postnatal life. While most studies on microglia-synapse interactions have focused on glutamatergic synapses, recent reports indicate that selective GABA-receptive microglia are also involved in sculpting inhibitory transmission during synaptogenesis in the somatosensory cortex. These findings raise the intriguing possibility that microglia may also be involved in the development of GABAergic circuits that mediate anxiety-related behaviours, and that disruptions in this function may contribute to the pathogenesis of anxiety disorders. To address this question, we assessed the role of microglia in the development of the corticolimbic GABAergic system in mice, which is fundamental for mediating normal anxiety behaviour. We pharmacologically depleted microglia during postnatal days P1-P14 (synaptogenesis) and P15-P28 (synaptic refinement), and we examined the effects on inhibitory synapse structure and function as well as on anxiety behaviours. To test whether microglial GABA_B receptor expression is necessary for this function, similar experiments were conducted in a microglia-specific conditional GABAB1R KO line. Our results showed that microglia play a critical role in correctly shaping inhibitory systems in the corticolimbic regions during the period of synaptogenesis, but not during the period of synaptic refinement, with long-term effects on anxiety behaviour as evidenced by behavioural testing. In contrast, no comparable effects were observed after microglial GABAB1R gene deletion. These findings demonstrate that microglia play a key role in shaping synaptic inhibition in anxiety circuits, highlighting their potential role in the pathogenesis of anxiety disorders.