Abstract Maintaining the balance between excitation and inhibition is essential for the appropriate control of neuronal network activity. Sustained excitation-inhibition (E-I) balance relies on the orchestrated adjustment of synaptic strength, neuronal activity and network circuitry. While growing evidence indicates that extracellular matrix (ECM) of the brain is a crucial regulator of neuronal excitability and synaptic plasticity, it remains unclear whether and how ECM contributes to neuronal circuit stability. Here we demonstrate that the integrity of ECM supports the maintenance of E-I balance by retaining inhibitory connectivity. Depletion of ECM in mature neuronal networks preferentially decreases the density of inhibitory synapses and the size of individual inhibitory postsynaptic scaffolds. After ECM depletion, inhibitory synapse strength homeostatically increases via the reduction of presynaptic GABA B receptors. However, the inhibitory connectivity reduces to an extent that inhibitory synapse scaling is no longer efficient in controlling neuronal network activity. Our results indicate that the brain ECM preserves the balanced network state by stabilizing inhibitory synapses. Significance statement The question how the brain’s extracellular matrix (ECM) controls neuronal plasticity and network activity is key for an appropriate understanding of brain functioning. In this study, we demonstrate that ECM depletion much more strongly affects the integrity of inhibitory than excitatory synapses in vitro and in vivo. We revealed that by retaining inhibitory connectivity, ECM ensures the efficiency of inhibitory control over neuronal network activity. Our work significantly expands our current state of knowledge about the mechanisms of neuronal network activity regulation. Our findings are similarly relevant for researchers working on the physiological regulation of neuronal plasticity in vitro and in vivo and for researchers studying the remodeling of neuronal networks upon brain injury, where prominent ECM alterations occur.

Extracellular matrix supports excitation-inhibition balance in neuronal networks by stabilizing inhibitory synapses