Dlx5/6 regulate perineuronal net-synapse coupling and stabilize adult cortical Parvalbumin neurons networks

Abstract

The transcriptional mechanisms that maintain adult Parvalbumin (PV) interneuron function and cortical network stability remain poorly understood. We previously showed that the inactivation in GABAergic neurons of Dlx5/6, coding for transcription factors, disrupts social interaction and reduces PV interneuron density in the prefrontal cortex. Here, combining transcriptional and histological analyses with ex vivo electrophysiological and in vivo electroencephalographical (EEG) recordings, we show that Dlx5/6 regulate a molecular program controlling perineuronal net (PNN) homeostasis in the adult cortex. Dlx5/6 inactivation dysregulated the expression of multiple PNN-associated genes and induced region-specific remodelling of PNN mesh architecture in the prefrontal and somatosensory cortices. These structural changes were accompanied by alterations in excitatory and inhibitory synaptic organization and by a disrupted coupling between local PNN structure and synaptic properties. Ex vivo electrophysiological recordings revealed that fast-spiking interneurons displayed altered intrinsic properties and reduced excitatory synaptic drive in a region-specific manner, while EEG recordings during social interaction showed impaired recruitment of prefrontal gamma oscillations. Together, these findings identify Dlx5/6 as regulators of adult PV interneuron stability, linking extracellular matrix homeostasis to synaptic organization and cortical network dynamics. More broadly, it provides a new mechanistic framework connecting Dlx5/6 function to PV-related pathological phenotypes, including neuropsychiatric disorders. GRAPHICAL ABSTRACT