Abstract by Sofie Let Frandsen
Microglia and astrocytes, fundamental glial cells in the central nervous system, play crucial roles in both physiological and pathological conditions, including immune regulation, cellular homeostasis, and neuronal function. Parkinson’s disease (PD) is characterized by α-Synuclein (α-Syn) pathology and the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc). The role of neuroinflammation in the development and progression of PD is increasingly recognized, with microglia being key contributors. Astrocytes, involved in synaptic activity and gliotransmitter release, significantly influence neural circuits and behaviors. The overall aim of this thesis is to explore the roles of these glial cells in pathologies associated with midbrain circuits, focusing on their impact on motor control and affective state behaviors in mice.
The first aim was to achieve selective transduction of microglia in the SNc of microglia-specific Cx3cr1Cre mice using Cre-dependent adeno-associated viruses (AAVs), with the intention of addressing the challenge of effective microglia transduction. However, complications during experimental validation resulted in inconclusive findings regarding the achievement of microglia transduction.
The second aim was to investigate the early pathological mechanisms induced by overexpression of human α-Syn (hα-Syn) in the SNc of mice using an AAV-approach. Substantial hα-Syn expression in dopaminergic neurons led to motor dysfunctions and signs of negative affective behaviors without apparent loss of dopamine neurons in the SNc. Additionally, overexpression of hα-Syn resulted in a marked increase in microglia reactivity, characterized by both an elevated number of microglia and enhanced expression of inflammatory microglia and interferon responses. The study further identified distinct microglial subclusters and detected double-negative T cells in hα-Syn mice, thereby enhancing our understanding of microglial diversity in this early-stage PD model.
The third aim was to explore the outcomes of midbrain astrocyte activation via Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) in astrocyte-specific GFAP-Cre mice, employing a Cre-dependent AAV. We found that activation of midbrain astrocytes led to reduced repetitive behaviors like digging and grooming, and increased locomotor activity in an open-field setting.
This was accompanied by decreased concentrations of the gliotransmitters taurine and serine.
This thesis emphasizes the essential role of glial signaling within neural circuits, highlighting how the distinct roles and behaviors of microglia and astrocytes are influenced by specific subcircuits and conditions. It offers insights into the treatment of midbrain-related pathologies, suggesting that targeting glial cells could lead to innovative treatments for these complex conditions.