The early excitatory action of striatal cholinergic-GABAergic microcircuits conditions the subsequent GABA inhibitory shift

Abstract

Cholinergic interneurons of the striatum play a role in action selection and associative learning by activating local GABAergic inhibitory microcircuits. We investigated whether cholinergic-GABAergic microcircuits function differently and fulfill a different role during early postnatal development, when GABAA actions are not inhibitory and mice pups do not walk. We focused our study mainly on dual cholinergic/GABAergic interneurons (CGINs). We report that morphological and intrinsic electrophysiological properties of CGINs rapidly develop during the first post-natal week. At this stage, CGINs are excited by the activation of GABAA receptors or GABAergic synaptic inputs, respond to cortical stimulation by a long excitation and are linked by polysynaptic excitations. All these excitations are replaced by inhibitions at P12-P15. Early chronic treatment with the NKCC1 antagonist bumetanide to evoke premature GABAergic inhibitions from P4 to P8, prevented the GABA polarity shift and corticostriatal pause response at control postnatal days. We propose that early excitatory cholinergic-GABAergic microcircuits are instrumental in the maturation of GABAergic inhibition.