CONICET | Buscador de Institutos y Recursos Humanos

Functional integration of newborn granule cells into hippocampal circuits is orchestrated by environmental signals and intrinsic programs. Little is known about the role of intrinsic neuronal activity in the development and plasticity of dendrites, axons and synaptic connections in newborn granule cells. To answer this question we designed a strategy to decrease intrinsic excitability of developing neurons of the adult dentate gyrus and analyze their morphological and functional properties. We constructed a retrovirus encoding an inward rectifier potassium channel (Kir2.1) and green fluorescent protein (GFP). A non-conductive channel bearing a point mutation (Kir2.1mut) was used as a negative control. The virus was delivered stereotaxically into the dentate gyrus of 67 week-old female mice. Brains were removed 2, 3 or 5 weeks post injection (wpi) and labeled cells were analyzed by electrophysiology and confocal imaging. At all time points Kir+ neurons expressed higher levels of immature neuronal markers doublecortin and calretinin and reduced levels of the mature marker Calbindin when compared to control cells. Kir+ neurons also displayed a reduced dendritic length consistent with a protracted development. The reduced neuronal size was also reflected in electrophysiological recordings that revealed a decreased membrane capacitance. Integration in the local circuitry was investigated by recordings of spontaneous miniature events. Neurons expressing Kir displayed a reduced frequency of both excitatory and inhibitory miniature events without changes in the amplitude, in agreement with the reduced number of excitatory synapses found by confocal microscopy. Our observations support the notion that intrinsic electrical activity is essential for a correct timing of integration and maturation of newborn granule cells of the adult dentate gyrus.