Perineuronal nets (PNNs) are extracellular matrices that stabilize synapses and inhibit synaptic plasticity. This study investigates the role of PNNs in maintaining synaptic homeostasis in the adult mouse somatosensory cortex. The authors found that synaptic terminals of fast-spiking interneurons localize to holes in PNNs, where they form tripartite synapses with astrocytic processes expressing Kir4.1 and glutamate and GABA transporters. PNN disruption impairs astrocytic uptake of glutamate and potassium, leading to the spillage of these ions into the extrasynaptic space. In Alzheimer's disease and epilepsy models, PNN disruption causes increased astrocytic coverage of neuronal somata without altering synapse density. The study concludes that PNNs and astrocytes cooperate to contain synaptically released signals, and their combined action is altered in neurodegenerative and epileptic conditions.Perineuronal nets (PNNs) are extracellular matrices that stabilize synapses and inhibit synaptic plasticity. This study investigates the role of PNNs in maintaining synaptic homeostasis in the adult mouse somatosensory cortex. The authors found that synaptic terminals of fast-spiking interneurons localize to holes in PNNs, where they form tripartite synapses with astrocytic processes expressing Kir4.1 and glutamate and GABA transporters. PNN disruption impairs astrocytic uptake of glutamate and potassium, leading to the spillage of these ions into the extrasynaptic space. In Alzheimer's disease and epilepsy models, PNN disruption causes increased astrocytic coverage of neuronal somata without altering synapse density. The study concludes that PNNs and astrocytes cooperate to contain synaptically released signals, and their combined action is altered in neurodegenerative and epileptic conditions.