<EM>DLX5/6</EM> REGULATE PARVALBUMIN-POSITIVE NEURONS FUNCTION THROUGH PERINEURONAL NET STRUCTURE MODULATIONS IN THE CEREBRAL CORTEX

Parvalbumin-positive neurons (PVs), the main class of GABAergic interneurons, are essential for cortical network regulation. Mature PVs are enwrapped by the Perineuronal Net (PNN), a specialized extracellular matrix that contributes to PV neurons functions, notably by physically supporting the maintenance and stabilization of their synapses. Alterations in PVs and PNNs are linked to neurodevelopmental and psychiatric disorders, such as schizophrenia.
The homeobox transcription factors, DLX5 and DLX6, are essential for development, maturation, and adult function of PVs. We previously demonstrated that Dlx5/6 expression levels in GABAergic interneurons influence PVs density in the prelimbic cortex, correlating with anxiety- and obsessive-compulsive-like behaviors.
To investigate mechanisms of these genes, we used mice with selective Dlx5/6 inactivation in GABAergic interneurons and conducted high-resolution 3D analysis of the PNN that revealed structural alterations in both the somatosensory and prelimbic cortices, affecting the shape, intensity, and number of inhibitory and excitatory synapses. Electrophysiological and EEG recordings demonstrated functional deficits in PV neurons, and transcriptomic analysis showed deregulation of genes involved in PNN synthesis and remodeling.
These findings identify Dlx5/6 as crucial regulators of PNN organization and PVs activity. Altogether, our study highlights a novel role for Dlx5/6 genes in maintaining cortical inhibitory circuitry integrity and suggests their involvement in shaping neuronal plasticity and behavior through modulation of PNN-dependent mechanisms. Moreover, our model of Dlx5/6 invalidation in GABAergic neurons leads to molecular and structural changes reminiscent of those observed in schizophrenia models, providing new insights into the developmental origins of neuropsychiatric disorders.