Biology subjects

MacDonald, J. L.

Publications and source records attributed to MacDonald, J. L..

3 recordsLinked to original sources

bioRxiv2025

Astrocytic Regulation of aberrant perineuronal net formation in Mecp2-null Neocortex

Rett syndrome (RTT), caused by mutations in MECP2, is a complex neurological disorder characterized by myriad physiological disruptions, including early closure of the critical period of developmental plasticity and precocious formation of perineuronal nets (PNNs). PNNs are lattice-like substructures of extracellular matrix (ECM) that enwrap specific subpopulations of neurons. PNNs are essential in the modulation of neuronal plasticity and brain maturation, and their enzymatic disruption can partially restore plasticity in adults and improve memory. Although precocious PNN formation is well-established in RTT, little is known of the cellular, molecular, or biochemical underpinnings of their precocious formation, or whether precocious PNN formation is due to cell-autonomous or non-cell-autonomous mechanisms. While PNNs form on subsets of neurons throughout the brain, astrocytes secrete many ECM components that form PNNs, and they play a central role in controlling closure of the critical period. We find that Mecp2-null astrocyte conditioned media induces the expression of the key PNN component Hapln1 and causes enhanced PNN formation on wildtype neurons, suggesting that Mecp2-null astrocytes play a key role in the precocious formation of PNNs in RTT. Further, we identify increased expression of HAPLN1 and other PNN / ECM components in the developing Mecp2-null cortex, and demonstrate that PNNs are structurally and biochemically mature at an earlier developmental stage. These results provide essential insight into the mechanisms and structure of aberrant PNNs in Mecp2-null cortex and identify potential new avenues for targeted rescue or reversal of the precocious closing of the critical period in RTT.

neuroscience↗

bioRxiv2021

Vitamin D modulates cortical transcriptome and behavioral phenotypes in an Mecp2 heterozygous Rett syndrome mouse model

Rett syndrome (RTT) is an X-linked neurological disorder caused by mutations in the transcriptional regulator MECP2. Mecp2 loss-of-function leads to the disruption of many cellular pathways, including aberrant activation of the NF-{kappa}B pathway. Genetically attenuating the NF-{kappa}B pathway in Mecp2-null mice ameliorates hallmark phenotypes of RTT, including reduced dendritic complexity, raising the question of whether NF-{kappa}B pathway inhibitors could provide a therapeutic avenue for RTT. Vitamin D is a known inhibitor of NF-{kappa}B signaling; further, vitamin D deficiency is prevalent in RTT patients and male Mecp2-null mice. We previously demonstrated that vitamin D rescues the aberrant NF-{kappa}B activity and reduced neurite outgrowth of Mecp2-knockdown cortical neurons in vitro, and that dietary vitamin D supplementation rescues decreased dendritic complexity and soma size of neocortical projection neurons in both male hemizygous Mecp2-null and female heterozygous mice in vivo. Here, we have identified over 200 genes whose dysregulated expression in the Mecp2+/- cortex is modulated by dietary vitamin D. Genes normalized with vitamin D supplementation are involved in dendritic complexity, synapses, and neuronal projections, suggesting that the rescue of their expression could underpin the rescue of neuronal morphology. Further, motor and anxiety-like behavioral phenotypes in Mecp2+/- mice correlate with circulating vitamin D levels, and there is a disruption in the homeostasis of the vitamin D synthesis pathway in Mecp2+/- mice. Thus, our data indicate that vitamin D modulates RTT pathology and its supplementation could provide a simple and cost-effective partial therapeutic for RTT.

neuroscience↗

bioRxiv2020

Atypical Neocortical Development in the Cited2 Conditional Knockout Leads to Behavioral Deficits Associated with Neurodevelopmental Disorders

The mammalian neocortex develops from a single layer of neuroepithelial cells to form a six-layer heterogeneous mosaic of differentiated neurons and glial cells. This process requires a complex choreography of temporally and spatially restricted transcription factors and epigenetic regulators. Even subtle disruptions in this regulation can alter the way the neocortex forms and functions, leading to a neurodevelopmental disorder. One epigenetic regulator that is essential for the precise development of the neocortex is CITED2 (CBP/p300 Interacting Transactivator with ED-rich termini). Cited2 is highly expressed by intermediate progenitor cells in the subventricular zone during the generation of the superficial layers of the neocortex. A forebrain-specific conditional knockout of Cited2 (cKO) exhibits reduced proliferation of intermediate progenitor cells embryonically, leading to reduced thickness of the superficial layers and a specific reduction in the somatosensory neocortical length postnatally. Further, the Cited2 cKO displays decreased corpus callosum volume and dysregulation of precise neuronal connectivity within the somatosensory cortex. Here, we explore the behavioral consequences resulting from this aberrant neocortical development. We demonstrate that Cited2 cKO mice display decreased maternal separation-induced ultrasonic vocalizations as neonates, and an increase in the repetitive behavior of rearing and lack of habituation following repeated acoustic startle as adults. They do not display alterations in anxiety-like behavior, overall locomotor activity or social interactions. Together with the morphological, molecular, and connectivity disruptions, these results identify the Cited2 cKO neocortex as an ideal system to study mechanisms underlying neurodevelopmental and neuroanatomical disruptions with relevance to human neurodevelopmental disorders.

neuroscience↗