Systematic analysis of goal-related movement sequences during maternal behaviour in a female mouse model for Rett syndrome.

Rodent dams seek and gather scattered pups back to the nest (pup retrieval), an essential aspect of maternal care. Systematic analysis of the dynamic sequences of goal-related movements that comprise the entire behavioural sequence, which would be ultimately essential for understanding the underlying neurobiology, is not well-characterized. Here, we present such analysis across 3 days in alloparental female mice (Surrogates or Sur) of two genotypes; Mecp2Heterozygotes (Het), a female mouse model for Rett syndrome and their wild type (WT) siblings. We analysed CBA/CaJ and C57BL/6J WT surrogates for within-strain comparisons. Frame-by-frame analysis over different phases was performed manually using DataVyu software. We previously showed that surrogate Het are inefficient at pup retrieval, by end-point analysis such as latency index and errors. Here, the sequence of searching, pup-approach and successful retrieval streamlines over days for WT, while Het exhibits variations in this pattern. Goal-related movements between Het and WT are similar in other phases, suggesting context-driven atypical patterns in Het during the pup retrieval phase. We identified proximal pup approach and pup grooming as atypical tactile interactions between pups and Het. Day-by-day analysis showed dynamic changes in goal-related movements in individual animals across genotypes and strains. Overall, our approach (1) highlights natural variation in individual mice on different days, (2) establishes a "gold-standard" manually curated dataset to help build behavioural repertoires using machine learning approaches, and (3) suggests atypical tactile sensory processing and possible regression in a female mouse model for Rett syndrome.

Loss of Ezh2 in the medial ganglionic eminence alters interneuron fate, cell morphology and gene expression profiles.

Introduction: Enhancer of zeste homolog 2 (Ezh2) is responsible for trimethylation of histone 3 at lysine 27 (H3K27me3), resulting in repression of gene expression. Here, we explore the role of Ezh2 in forebrain GABAergic interneuron development. Methods: We removed Ezh2 in the MGE by generating Nkx2-1Cre;Ezh2 conditional knockout mice. We then characterized changes in MGE-derived interneuron fate and electrophysiological properties in juvenile mice, as well as alterations in gene expression, chromatin accessibility and histone modifications in the MGE. Results: Loss of Ezh2 increases somatostatin-expressing (SST+) and decreases parvalbumin-expressing (PV+) interneurons in the forebrain. We observe fewer MGE-derived interneurons in the first postnatal week, indicating reduced interneuron production. Intrinsic electrophysiological properties in SST+ and PV+ interneurons are normal, but PV+ interneurons display increased axonal complexity in Ezh2 mutant mice. Single nuclei multiome analysis revealed differential gene expression patterns in the embryonic MGE that are predictive of these cell fate changes. Lastly, CUT&Tag analysis revealed that some genomic loci are particularly resistant or susceptible to shifts in H3K27me3 levels in the absence of Ezh2, indicating differential selectivity to epigenetic perturbation. Discussion: Thus, loss of Ezh2 in the MGE alters interneuron fate, morphology, and gene expression and regulation. These findings have important implications for both normal development and potentially in disease etiologies.

Lateralized Expression of Cortical Perineuronal Nets during Maternal Experience is Dependent on MECP2.

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+ (PV+) 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 PV+ GABAergic neurons. Here, we show novel changes in PNN density in the primary somatosensory cortex (SS1) of adult female mice after maternal experience [called surrogate (Sur)], 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 naive Mecp2-heterozygous (Het) females had increased PNN density in specific subregions in both hemispheres before maternal experience, compared with wild-type (WT) littermate controls. The laterality in PNN expression seen in naive Het (NH) was lost after maternal experience in Sur Het (SH) mice, 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.