Blocking Astrocytic GABA Restores Synaptic Plasticity in Prefrontal Cortex of Rat Model of Depression.

Ipsit Srivastava,Erika Vazquez-Juarez,Marta Gómez-Galán,Maria Lindskog,Lukas Henning

doi:10.3390/cells9071705

Ipsit Srivastava, Erika Vazquez-Juarez + Show 3 more

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https://doi.org/10.3390/cells9071705

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Journal: Cells	Publication Date: Jul 16, 2020
Citations: 8	License type: CC BY 4.0

Affiliation: Karolinska Institutet

Abstract

A decrease in synaptic plasticity and/or a change in excitation/inhibition balance have been suggested as mechanisms underlying major depression disorder. However, given the crucial role of astrocytes in balancing synaptic function, particular attention should be given to the contribution of astrocytes in these mechanisms, especially since previous findings show that astrocytes are affected and exhibit reactive-like features in depression. Moreover, it has been shown that reactive astrocytes increase the synthesis and release of GABA, contributing significantly to tonic GABA inhibition. In this study we found decreased plasticity and increased tonic GABA inhibition in the prelimbic area in acute slices from the medial prefrontal cortex in the Flinders Sensitive Line (FSL) rat model of depression. The tonic inhibition can be reduced by either blocking astrocytic intracellular Ca2+ signaling or by reducing astrocytic GABA through inhibition of the synthesizing enzyme MAO-B with Selegiline. Blocking GABA synthesis also restores the impaired synaptic plasticity in the FSL prefrontal cortex, providing a new antidepressant mechanism of Selegiline.

Highlights

Despite impressive progress in our understanding of major depressive disorder (MDD) in the last decade, we still do not have a coherent picture of the etiology of the disease
To overcome the strong inhibition present in the prefrontal cortex that could be preventing LTP induction, we performed the LTP protocol in the presence of a subsaturating concentration of the GABAA receptor antagonist, bicuculline. In this condition, LTP was significantly stronger in the Flinders Sensitive Line (FSL) rats compared to the SD rats (Figure 1A; mean potentiation at 40–45 min after induction 130 ± 3.9% and 111 ± 4.9% of baseline respectively, p < 0.05, t-test). This is in contrast to the decreased plasticity that we observed in the hippocampus, and raises the possibility that rather than a change in plasticity per se, the increase is due to a higher sensitivity to blocking GABAA receptors
We show that astrocytes in the prefrontal cortex of the FSL rat display an atrophic morphology potentiation observed insoma slicessize

Summary

Introduction

Despite impressive progress in our understanding of major depressive disorder (MDD) in the last decade, we still do not have a coherent picture of the etiology of the disease. The importance of the prefrontal cortex is further supported by the fact that transcranial magnetic stimulation of this area is an effective treatment for depression [6]. At the neuronal level, reduced activity or an imbalance in excitation/inhibition in the prefrontal cortex has been suggested as an underlying mechanism of depression [7,8,9]. Neuronal plasticity has been proven to be part of the pathology, with reduced plasticity consistently reported in depressed patients, as well as in animal models of the disease [10,11,12,13,14]. The interplay between the imbalance in excitation/inhibition and reduced plasticity, and their implications in depression, have not been explored in detail

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