Lateralized expression of cortical perineuronal nets during maternal experience is dependent on MECP2

Abstract

<jats:p>Cortical neuronal circuits along the sensorimotor pathways are shaped by experience during critical periods of heightened plasticity in early postnatal development. After closure of critical periods, measured histologically by the formation and maintenance of extracellular matrix structures called perineuronal nets (PNNs), the adult mouse brain exhibits restricted plasticity and maturity. Mature PNNs are typically considered to be stable structures that restrict synaptic plasticity on cortical parvalbumin+ GABAergic neurons. Changes in environment (i.e. novel behavioral training) or social contexts (i.e. motherhood) are known to elicit synaptic plasticity in relevant neural circuitry. However, little is known about concomitant changes in the PNNs surrounding the cortical parvalbumin+ GABAergic neurons. Here, we show novel changes in PNN density in the primary somatosensory cortex (SS1) of adult female mice after maternal experience, using systematic microscopy analysis of a whole brain region. On average, PNNs were increased in the right barrel field and decreased in the left forelimb regions. Individual mice had left hemisphere dominance in PNN density. Using adult female mice deficient in methyl-CpG-binding protein 2 (MECP2), an epigenetic regulator involved in regulating experience-dependent plasticity, we found that MECP2 is critical for this precise and dynamic expression of PNN. Adult naïve <jats:italic>Mecp2</jats:italic>-heterozygous females (Het) had increased PNN density in specific subregions in both hemispheres before maternal experience. The laterality in PNN expression seen in naïve Het was lost after maternal experience, suggesting possible intact mechanisms for plasticity. Together, our results identify subregion and hemisphere-specific alterations in PNN expression in adult females, suggesting extracellular matrix plasticity as a possible neurobiological mechanism for adult behaviors in rodents.</jats:p>

Multidimensional analysis of a social behavior identifies regression and phenotypic heterogeneity in a female mouse model for Rett syndrome

“…Similarly, ChABC injection in the auditory cortex of Het partially rescues pup retrieval performance, indicating value in developing therapeutics targeted at PNNs (Krishnan et al, 2017). We also reported abnormal increase in PNNs in the primary somatosensory cortex of Het which coincides with atypical tactile interactions with textures, pups, and poor pup retrieval performance (Krishnan et al, 2017;Lau, Layo, et al, 2020;Mykins et al, 2023;Stevenson et al, 2021). New tools for in-vivo imaging of PNNs will aid in determining how changes in PNN expression may contribute to impaired integration of social and sensory cues, and ultimately regression (Benbenishty et al, 2023).…”

“…Further in-depth analysis of cell-type specific MECP2 expression within our adult Het-NR and Het-R phenotypes is needed. Previously, we also reported lateralization of MECP2 and PNN expression in the adult primary somatosensory cortex, which could contribute to functional specialization of the adult cortex, and is dysregulated in the Het (Lau, Layo, et al, 2020). Future work will focus on identifying the nuanced expression and regulation of MECP2, an epigenetic master regulator with wide-ranging impact of gene expression.…”

“…Towards this end, we have established an ethologically relevant social behavioral assay called pup retrieval task as a model to study cellular and neural circuitry basis for social cognition, complex sensorimotor integration and experience-dependent plasticity (Dvorkin & Shea, 2022;Krishnan et al, 2015Krishnan et al, , 2017Lau, Layo, et al, 2020;Mykins et al, 2023;Stevenson et al, 2021;Xie et al, 2023). During this task, female mice integrate sensory cues to execute goal-directed motor sequences to retrieve scattered pups back to their home nest (Alsina-Llanes et al, 2015;Beach & Jaynes, 1956;Champagne et al, 2007;Champagne & Curley, 2016;Dunlap et al, 2020;Hemel, 1973;Koch & Ehret, 1989;Lonstein et al, 2015;Marlin et al, 2015;Stern, 1996;Stern & Mackinnon, 1978).…”