Modulation of Perineuronal Nets Regulating Parvalbumin Neuron Maturation in the Mouse Visual Cortex
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CitationBae, Haneui. 2020. Modulation of Perineuronal Nets Regulating Parvalbumin Neuron Maturation in the Mouse Visual Cortex. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.
AbstractEarly life experience shapes neural circuits during windows of plasticity called critical periods, allowing the circuit to specialize itself to the particular set of stimuli among a wide variety of possibilities. The onset of critical periods is regulated by experience-dependent maturation of inhibitory neurons, particularly that of parvalbumin (PV)-expressing large basket cells. Perineuronal nets (PNNs), specialized extracellular matrix that forms around PV neurons, regulate their maturation and in turn cortical plasticity. A fully formed PNN inhibits plasticity, and mice deficient in various PNN components show open-ended plasticity. On the other hand, PNNs also bind factors that promote PV neuron maturation and control the onset of critical periods. Thus, PNNs play a complex dual role in the regulation of PV neuron maturation and cortical plasticity.
In this study, I investigated two novel candidates of PNN modification: neprilysin and Chst15. Neprilysin (Nep) is a membrane-bound endopeptidase that is specifically expressed by PNN-enwrapped PV neurons in the visual cortex. The localization and cell type-specificity of Nep expression suggested it may play a role in PNN modification. Mice with targeted deletion of Nep (Nep KO), however, did not show a difference in the maturation or the morphology of PNNs. Instead, there were laminar reductions in the number of layer 4 (L4) inhibitory neurons in the visual cortex and in the maximal activation of L5 after white matter stimulation. These changes may have been caused by the highly laminar developmental expression of Nep gene in the cortex. Behaviorally, Nep KO mice showed a delay in the development of optomotor visual acuity, which is mediated by subcortical visual circuits to the accessory optic system (AOS). AOS is known to receive top-down cortical inputs from L5 pyramidal neurons, suggesting that the decrease of L5 activation may have functional consequences. Overall, Nep deficiency led to unexpected laminar defects in the visual cortex and in optomotor response, but no change in PNN development.
Chst15 gene encodes a sulfotransferase that transfers sulfate groups to polysaccharide chains decorating PNN core proteins. Deficiency in Chst15 leads to a total loss of CS-E disaccharides that interact with Otx2, a cell non-autonomous transcription factor necessary for PV neuron maturation. Contrary to the hypothesis that Chst15 KO mice would show decreased Otx2 binding and impaired PV maturation in the visual cortex, there were no differences in Otx2 accumulation or PV maturation. This result suggests that Chst15 is not necessary for Otx2 binding or that its loss may be fully compensated by other interactions within the PNNs.
Citable link to this pagehttps://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37365872
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