Accelerated Hyper-Maturation of Parvalbumin Circuits in the Absence of MeCP2

Abstract

Methyl-CpG-binding protein 2 (MeCP2) mutations are the primary cause of Rett syndrome, a severe neurodevelopmental disorder. Cortical parvalbumin GABAergic interneurons (PV) make exuberant somatic connections onto pyramidal cells in the visual cortex of Mecp2-deficient mice, which contributes to silencing neuronal cortical circuits. This phenotype can be rescued independently of Mecp2 by environmental, pharmacological, and genetic manipulation. It remains unknown how Mecp2 mutation can result in abnormal inhibitory circuit refinement. In the present manuscript, we examined the development of GABAergic circuits in the primary visual cortex of Mecp2-deficient mice. We identified that PV circuits were the only GABAergic interneurons to be upregulated, while other interneurons were downregulated. Acceleration of PV cell maturation was accompanied by increased PV cells engulfment by perineuronal nets (PNNs) and by an increase of PV cellular and PNN structural complexity. Interestingly, selective deletion of Mecp2 from PV cells was sufficient to drive increased structure complexity of PNN. Moreover, the accelerated PV and PNN maturation was recapitulated in organotypic cultures. Our results identify a specific timeline of disruption of GABAergic circuits in the absence of Mecp2, indicating a possible cell-autonomous role of MeCP2 in the formation of PV cellular arbors and PNN structures in the visual cortex.

Maternal experience-dependent cortical plasticity in mice is circuit- and stimulus-specific and requires MECP2

“…Asaka et al, 2006;Blackman et al, 2012;Na et al, 2013). Our results here are consistent with a model in which augmented PV neuron maturation (Patrizi et al, 2019) in Mecp2 het constrains neuronal plasticity in the auditory cortex. We speculate that this plasticity is an important component of early maternal learning.…”

Complex IV subunit isoform COX 6A2 protects fast‐spiking interneurons from oxidative stress and supports their function

“…However, Cox6a2 À/À led to decreased parvalbumin expression in PV + interneurons (Fig 3B and C), which might affect PV + interneurons activity, given the role of parvalbumin as a calcium buffer (Caillard et al, 2000). Decrease in parvalbumin expression was also reported in mouse models of mental disorders (Mukherjee et al, 2019;Patrizi et al, 2020) and human patients (Enwright et al, 2016). Furthermore, Cox6a2 À/À reduced the number of PV + interneuron-derived synaptic contacts onto cortical principal neurons ( Fig 3D), which might indicate impaired connectivity between PV + interneurons and principal neurons.…”

“…Error bars represent SD. (Lu et al, 2014)), whereas few other parameters such as parvalbumin expression and enwrapping by PNNs continue to be changed after P30 up to P60 (Patrizi et al, 2020). Although Cox6a2 À/À did not affect the resting membrane potential (V rest ) and spike amplitude in PV + interneurons ( Fig 6A and B), Cox6a2 À/À and WT PV + interneurons differed in the threshold for action potentials, which increased during maturation in WT, but such maturational increase was abolished in Cox6a2 À/À PV + neurons (Fig 6C and D).…”

Inhibition of mTOR during a postnatal critical sensitive window rescues deficits in GABAergic PV cell connectivity and social behavior caused by loss ofTSC1

“…Cortical PV cell activity modulates sensory responses (Cardin et al, 2009, Cao et al, 2018a, which are required for the development of normal social interaction behaviours (Orefice et al, 2016). Postmortem analysis of brains from ASD patients as well as animal models for ASD (such as Mecp2 and Shank3 mutants) revealed abnormalities in PV cell circuits in multiple brain regions, including primary sensory cortices (Mierau et al, 2016, Chao et al, 2010, Patrizi et al, 2019, Orefice et al, 2019, Selimbeyoglu et al, 2017, Zikopoulos and Barbas, 2013, Nelson and Valakh, 2015, Vogt et al, 2018, Tomassy et al, 2014, Hashemi et al, 2017, Fukuda et al, 2005, Filice et al, 2016. Targeting PV cell circuit impairments might thus be a rational approach to ameliorate social interaction problems, however the developmental and cellular processes that lead to PV cell dysfunction are likely dependent of the underlying aetiology.…”

“…The development of PV cell circuit connectivity is a prolonged process, terminating around the end of adolescence in rodents and primates , Chattopadhyaya et al, 2007, Baho et al, 2019, Baho and Di Cristo, 2012, Fish et al, 2013. PV cells dysfunction has been found in several mouse models of autism (Selimbeyoglu et al, 2017, Mierau et al, 2016, Chao et al, 2010, Patrizi et al, 2019, Vogt et al, 2018. Conversely, stimulating PV cells has been shown to be sufficient to ameliorate social behaviour (Yizhar et al, 2011, Cao et al, 2018b, Selimbeyoglu et al, 2017.…”