Intracellular chloride dynamics in autistic brain: a better understanding is needed for tailored cures.

Brain activity is finely tuned during sleep, wakefulness and cognitive tasks by the balancing act of principal neurons and interneurons. This is particularly relevant in pathological conditions since it is gradually emerging that a distortion of the dialogue between excitation and inhibition is likely to be at the basis of most, if not all, cognitive deficits. Inhibition shapes the activity of the brain and it operates by allowing the influx of the chloride ion that curtails the activity of nervous cells. A central tenet of our understanding of synaptic inhibition is that inhibitory activity always results in chloride influx, except in the early phases of development when intracellular chloride is high. This picture is challenged by some recent work of us that, by exploiting a novel technique that allows to measure intracellular chloride in vivo by means of two photon imaging, demonstrates that chloride regulation in pyramidal neurons of adult mice is far more dynamic than expected. In this project we will explore the role of this hitherto unsuspected dynamic of inhibitory transmission in three monogenic models of cognitive deficits and autism associated with the loss of the genes OPHN1, PTEN and MeCP2. Although defective Cl regulation could play an important part in brain pathologies, our understanding of its role in ASD and cognitive disorders is still limited. We will provide a stronger foundation to the hypothesis that chloride dysregulation plays an important role in brain disease by dissecting Cl homeostasis in the murine models. The final goal of this project is the design of tailored therapeutic strategies targeting Cl homeostasis according to the specificities of its regulation.