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

ABSTRACT: 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.

SUBMITTER: Mascio G

PROVIDER: S-EPMC7889908 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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

Mascio Giada G Bucci Domenico D Notartomaso Serena S Liberatore Francesca F Antenucci Nico N Scarselli Pamela P Imbriglio Tiziana T Caruso Stefano S Gradini Roberto R Cannella Milena M Di Menna Luisa L Bruno Valeria V Battaglia Giuseppe G Nicoletti Ferdinando F

Translational psychiatry 20210218 1

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 o ...[more]

PMID: 33597513

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Project description:Stroke causes life long disabilities where few therapeutic options are available. Using electrical and magnetic stimulation of the brain and physical rehabilitation, recovery of brain function can be enhanced even late after stroke. Animal models support this notion, and housing rodents in an enriched environment (EE) several days after experimental stroke stimulates lost brain function by multisensory mechanisms. We studied the dynamics of functional recovery of rats with a lesion to the fore and hind limb motor areas induced by photothrombosis (PT), and with subsequent housing in either standard (STD) or EE. In this model, skilled motor function is not significantly enhanced by enriched housing, while the speed of recovery of sensori-motor function substantially improves over the 9-week study period. In particular, this stroke lesion completely obliterates the fore and hind limb placing ability when visual and whisker guidance is prevented, a deficit that persists for up to 9 weeks of recovery, but that is markedly restored within 2 weeks by enriched housing. Enriched housing after stroke also leads to a significant loss of perineuronal net (PNN) immunoreactivity; detection of aggrecan protein backbone with AB1031 antibody was decreased by 13-22%, and labelling of a glycan moiety of aggrecan with Cat-315 antibody was reduced by 25-30% in the peri-infarct area and in the somatosensory cortex, respectively. The majority of these cells are parvalbumin/GABA inhibitory interneurons that are important in sensori-information processing. We conclude that damage to the fore and hind limb motor areas provides a model of loss of limb placing response without visual guidance, a deficit also seen in more than 50% of stroke patients. This loss is amenable to recovery induced by multiple sensory stimulation and correlates with a decrease in aggrecan-containing PNNs around inhibitory interneurons. Modulating the PNN structure after ischemic damage may provide new therapies enhancing tactile/proprioceptive function after stroke.

Project description:Background and purposeWe recently proposed the existence of mGlu3 -preferring autoreceptors in spinal cord terminals and of mGlu2 -preferring autoreceptors in cortical terminals. This study aims to verify our previous conclusions and to extend their pharmacological characterization.Experimental approachWe studied the effect of LY566332, an mGlu2 receptor positive allosteric modulator (PAM), and of LY2389575, a selective mGlu3 receptor negative allosteric (NAM) modulator, on the mGlu2/3 agonist LY379268-mediated inhibition of glutamate exocytosis [measured as KCl-evoked release of preloaded [3 H]-D-aspartate]. The mGlu2 PAM BINA and the mGlu3 NAM ML337, as well as selective antibodies recognizing the N-terminal of the receptor proteins, were used to confirm the pharmacological characterization of the native receptors.Key resultsCortical synaptosomes possess LY566332-sensitive autoreceptors that are slightly, although significantly, susceptible to LY2389575. In contrast, LY566332-insensitive and LY2389575-sensitive autoreceptors are present in spinal cord terminals. BINA and ML337 mimicked LY566332 and LY2389575, respectively, in controlling LY379268-mediated inhibition of glutamate exocytosis from both cortical and spinal cord synaptosomes. Incubation of cortical synaptosomes with anti-mGlu2 antibody prevented the LY379268-induced inhibition of glutamate exocytosis, and this response was partially reduced by the anti-mGlu3 antibody. Incubation of spinal cord synaptosomes with the anti-mGlu3 antibody abolished LY379268-mediated reduction of glutamate exocytosis from these terminals, while the anti-mGlu2 antibody was inactive. Western blot analysis and confocal microscopy data were largely consistent with these functional observations.Conclusions and implicationsWe confirmed that mGlu3 -preferring autoreceptors exist in spinal cord terminals. Differently, cortical glutamatergic terminals possess mGlu2 /mGlu3 heterodimers, whose inhibitory effect is largely mediated by mGlu2 receptors.

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

Publications

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

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