Circuit Formation in the Striatum in Health and Disease
Creators: name: Ahmed, Noorya
Publisher: name: The Australian National University
Year: 2023

description: Developing circuits form in a highly specific manner, reliant on a number OF steps including proliferation, differentiation, and synapse formation. However, developmental connection specificity is still poorly understood, particularly in subcortical structures such as the striatum, which represents a fundamental processing hub in the brain. Since developing striatal circuitry is vastly susceptible to alterations in genetic programming, any perturbations in network configuration can last into adulthood, and underlie the pathogenesis of a number of disorders, including autism spectrum disorder (ASD). In this thesis we hypothesised that certain cell populations critically shape the formation of functional striatal circuits, such that manipulating their genetic identity will cause abnormal wiring and network activity. In chapter one, we aimed to describe how genetic regulation of developing striatal interneuron circuitry is vital for maintaining developmental trajectory. We show that both cholinergic interneurons (CINs) and parvalbumin positive GABAergic interneurons (PV-INs) express the ETV1/Er81 transcription factor, which has a key role in regulating cell identity and activity. In the absence of Er81, we discovered developmental changes to striatal interneuron morphology, electrophysiology, and connectivity, which impacts striatal function and associated behaviour. In the second chapter, we demonstrated how striatal circuitry is highly dependent on neuromodulatory inputs. Whilst the acetylcholine-dopamine balance in the striatum is well studied, very little is known about serotonergic inputs and how their specific targeting is regulated during development, as well as how this innervation is important for behaviour. We found that Er81 is expressed in serotonergic neurons in the dorsal raphe nucleus, and is a key regulator of neuromodulatory signalling. We show that absence of Er81 alters serotonergic cell function and raphe-striatal innervation, as well as motor and anxiety-like behaviour. Striatal circuitry is susceptible to reshaping following altered genetic programming, which is reminiscent of many neuropathological disorders. As very little is known about the contribution of interneurons to ASD, in chapter three we investigated how these cells are impacted in the Cntnap2 knockout mouse model of ASD. We followed their maturation across embryonic and early postnatal stages and found increased cell proliferation and apoptosis, as well as further molecular and functional changes specifically to cholinergic interneurons. This unveils some of the mechanisms underlying the shift in the developmental trajectory of striatal interneurons, which greatly contribute to ASD pathogenesis. Together, we have found that striatal interneuron development is a highly intricate and regulated process; and show for the first time that deviations from typical genetic programming cascades and developmental trajectory cause the reshaping of striatal circuitry, leading to subsequent functional and behavioural alterations. This is especially pertinent in neuropathological disorders such as ASD, where perturbations to network formation and the excitation-inhibition balance are hallmarks of the disorder.