Purinergic Signalling Mediates Aberrant Excitability of Developing Neuronal Circuits in the Fmr1 Knockout Mouse Model

Area of Science:

• Neuroscience
• Developmental Biology
• Cellular Signaling

Background:

• Neuronal hyperexcitability is a hallmark of neurodevelopmental disorders like Fragile X Syndrome (FXS).
• Glial cells, particularly astrocytes, secrete factors influencing neuronal development and synaptogenesis via purinergic signaling.
• Previous work showed upregulated purinergic signaling in Fmr1 KO mouse astrocytes, affecting protein secretion.

Purpose of the Study:

• To investigate the impact of elevated astrocyte purinergic signaling on the morphology and connectivity of cortical neurons in a mouse model of FXS.
• To determine if astrocyte-derived soluble factors influence neuronal development in the Fmr1 KO model.
• To identify potential therapeutic targets for FXS-related aberrant neuronal activity.

Main Methods:

• Utilized conditioned media from primary Fmr1 KO and wildtype astrocytes.
• Assessed neuronal morphology (neurite extension, complexity) in cultured neurons.
• Examined neuronal firing patterns and synchrony in co-cultures using microelectrode arrays.
• Tested the effect of the P2Y2 receptor antagonist AR-C 118925XX on neuronal activity.

Main Results:

• Conditioned media from Fmr1 KO astrocytes enhanced neurite extension and complexity in both wildtype and Fmr1 KO neurons.
• Fmr1 KO neuron-astrocyte co-cultures exhibited increased neuronal firing but reduced synchrony.
• The P2Y2 receptor antagonist AR-C 118925XX partially normalized the aberrant firing patterns in Fmr1 KO co-cultures.

Conclusions:

• Astrocyte-secreted factors significantly influence neuronal morphology and connectivity in the Fmr1 KO model.
• Elevated purinergic signaling in astrocytes contributes to altered neuronal activity and synchrony deficits in FXS.
• P2Y2 purinergic receptors represent a potential therapeutic target for correcting pathological neuronal activity in FXS.