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Abstract

The mechanisms by which astrocytes modulate neural homeostasis, synaptic plasticity, and memory are still
poorly explored. Astrocytes form large intercellular networks by gap junction coupling, mainly composed of
two gap junction channel proteins, connexin 30 (Cx30) and connexin 43 (Cx43). To circumvent developmental
perturbations and to test whether astrocytic gap junction coupling is required for hippocampal neural circuit
function and behavior, we generate and study inducible, astrocyte-specific Cx30 and Cx43 double knock-
outs. Surprisingly, disrupting astrocytic coupling in adult mice results in broad activation of astrocytes and
microglia, without obvious signs of pathology. We show that hippocampal CA1 neuron excitability, excitatory
synaptic transmission, and long-term potentiation are significantly affected. Moreover, behavioral inspection
reveals deficits in sensorimotor performance and a complete lack of spatial learning and memory. Together,
our findings establish that astrocytic connexins and an intact astroglial network in the adult brain are vital for
neural homeostasis, plasticity, and spatial cognition.