Connecting the Neurobiology of Developmental Brain Injury: Neuronal Arborisation as a Regulator of Dysfunction and Potential Therapeutic Target

Abstract

Neurodevelopmental disorders can derive from a complex combination of genetic variation and environmental pressures on key developmental processes. Despite this complex aetiology, and the equally complex array of syndromes and conditions diagnosed under the heading of neurodevelopmental disorder, there are parallels in the neuropathology of these conditions that suggest overlapping mechanisms of cellular injury and dysfunction. Neuronal arborisation is a process of dendrite and axon extension that is essential for the connectivity between neurons that underlies normal brain function. Disrupted arborisation and synapse formation are commonly reported in neurodevelopmental disorders. Here, we summarise the evidence for disrupted neuronal arborisation in these conditions, focusing primarily on the cortex and hippocampus. In addition, we explore the developmentally specific mechanisms by which neuronal arborisation is regulated. Finally, we discuss key regulators of neuronal arborisation that could link to neurodevelopmental disease and the potential for pharmacological modification of arborisation and the formation of synaptic connections that may provide therapeutic benefit in the future.

Dendritic spine and synapse pathology in chromatin modifier-associated autism spectrum disorders and intellectual disability

“…Using an Arid1b haploinsufficient mouse model, Jung et al (2017) demonstrated that treatment with a low dose of the GABA A receptor positive allosteric modulator, clonazepam, is effective in reversing inhibitory synaptic transmission as well as several ASD-like behaviors. This approach is based on the idea that neurodevelopmental disorders, particularly ASD, are caused by the disrupted homeostatic mechanism that leads to synaptic imbalance between excitation and inhibition ( Han et al, 2014 ; Jung et al, 2017 ; Goikolea-Vives and Stolp, 2021 ; Moffat et al, 2021 , 2022 ). The insufficient tone of inhibitory synapse is an easy target point for pharmacological manipulation as there are drugs available in clinics.…”

“…Abnormal dendrites and dendritic spines dramatically alter brain function ( Moffat et al, 2019 ; Ka et al, 2022 ). Abnormalities in dendrites and their spines consist of branching pattern, spine density, size, and morphology ( Goikolea-Vives and Stolp, 2021 ). Dendrites and dendritic spines play significant roles for a neuron in forming synapses to receive and process information from other neurons.…”