Perineuronal nets are under the control of type-5 metabotropic glutamate receptors in the developing somatosensory...

mGlu5 metabotropic glutamate receptors are highly functional in the early postnatal life, and regulate developmental plasticity of parvalbumin-positive (PV⁺) interneurons in the cerebral cortex. PV⁺ cells are enwrapped by perineuronal nets (PNNs) at the closure of critical windows of cortical plasticity. Changes in PNNs have been associated with neurodevelopmental disorders. We found that the number of Wisteria Fluoribunda Agglutinin (WFA)⁺ PNNs and the density of WFA⁺/PV⁺ cells were largely increased in the somatosensory cortex of mGlu5^-/- mice at PND16. An increased WFA⁺ PNN density was also observed after pharmacological blockade of mGlu5 receptors in the first two postnatal weeks. The number of WFA⁺ PNNs in mGlu5^-/- mice was close to a plateau at PND16, whereas continued to increase in wild-type mice, and there was no difference between the two genotypes at PND21 and PND60. mGlu5^-/- mice at PND16 showed increases in the transcripts of genes involved in PNN formation and a reduced expression and activity of type-9 matrix metalloproteinase in the somatosensory cortex suggesting that mGlu5 receptors control both PNN formation and degradation. Finally, unilateral whisker stimulation from PND9 to PND16 enhanced WFA⁺ PNN density in the contralateral somatosensory cortex only in mGlu5^+/+ mice, whereas whisker trimming from PND9 to PND16 reduced WFA⁺ PNN density exclusively in mGlu5^-/- mice, suggesting that mGlu5 receptors shape the PNN response to sensory experience. These findings disclose a novel undescribed mechanism of PNN regulation, and lay the groundwork for the study of mGlu5 receptors and PNNs in neurodevelopmental disorders.