Rapid and reversible compensatory restructuring of cortical dendritic spines triggered by pharmacological disruption of E/I balance in vivo
Altug Kamacioglu1, Pamela Osuna-Vargas 2,3, Petros E. Vlachos2,*, Dominik Aschauer1, Jochen Triesch2,3, Matthias Kaschube2,3, Simon Rumpel1
1 Institute of Physiology, FTN, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany
2 Frankfurt Institute for Advanced Studies, Frankfurt am Main, Germany
3 Goethe University Frankfurt, Frankfurt am Main, Germany
*Email: pvlachos@fias.uni-frankfurt.de
Introduction
A balance between cortical excitation and inhibition is essential for healthy brain function. Shifts from this balance can lead to learning and cognitive deficiencies as well as pathological behaviour. Multiple mechanisms are employed to ensure that an equilibrium is maintained [1]. Understanding the consequences of E/I imbalance and the nature and latent interactions of the regulatory mechanisms is critical for developing targeted therapeutic interventions. In this work, we explore how the pharmacological disruption of cortical E/I balance shapes the intrinsic dynamics of excitatory connectivity and investigate the underlying mechanism using a computational model.
Methods
We collect chronic 3D live cell imaging data following acute diazepam treatment, known to increase inhibitory synaptic transmission [2], in the auditory cortex of GFP-M transgenic mice. We develop a modular framework that enables large-scale automatic extraction and tracking of dendritic spines, postsynaptic sites of excitatory connections, achieving state-of-the-art performance for spine detection. To validate the results of our analysis, we build a cortical network model of spiking neurons. The model is designed based on biological principles to encompass the diverse apparatus of dendritic spine plasticity.
Results
Using the automated tracking framework we identify and characterize individual dendritic spines (N=15.500) across time. We analyze the data and evaluate the structural and morphological alterations due to diazepam compared to control. We report a rapid compensatory increase in spine sizes after 1 hour of diazepam injection not present in control. The effect is reversible and multiplicative in nature, suggesting a scaling rather than a redistribution of resources. Using the spiking network model, we replicate these results and suggest potential mechanisms that can explain the experimental data.
Discussion
Here, we explore the consequences of induced disruption of E/I balance on the morphology and dynamics of dendritic spines. Our results provide evidence for a prompt counterbalancing response in the auditory cortex in vivo. Our analysis and computational model suggest that the effect could be attributed to synaptic scaling, challenging the assumption that synaptic scaling operates over hours to days. Moreover, we observe a remarkable stability of spine turnover rates across dendrites. Finally, we introduce a framework that, to the best of our knowledge, is the first to propose an approach for spine tracking. Taken together, our results offer a potential mechanistic understanding of the compensatory effects in response to E/I imbalance.
This work was supported by the German Research Foundation (DFG) - SPP 2041, Project number 347573108 "The dynamic connectome: dynamics of learning"; DFG Project number 414985841 GRK 2566 "iMOL Research Training Group"; and the Johanna Quandt foundation (JT).
[1] Turrigiano, G. (2012). Homeostatic synaptic plasticity: local and global mechanisms for stabilizing neuronal function. Cold Spring Harbor perspectives in biology, 4(1), a005736.
[2] Zheng, F., Adelsberger, H., Müller, M. R., Fritschy, J. M., Werner, S., & Alzheimer, C. (2009). Activin tunes GABAergic neurotransmission and modulates anxiety-like behavior. Molecular psychiatry, 14(3), 332-346.
