Downregulation of kainate receptors regulating GABAergic transmission in amygdala after early life stress is associated with anxiety-like behavior in rodents

Jonas Englund,Alexandra Shintyapina,Shyrley Paola Amarilla,Maria Ryazantseva,Tsvetomira Atanasova,Sari E Lauri,Juha Partanen,Vasilii Shteinikov,Joni Haikonen,Vootele Voikar

doi:10.1038/s41398-021-01654-7

Jonas Englund, Alexandra Shintyapina + Show 8 more

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https://doi.org/10.1038/s41398-021-01654-7

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Journal: Translational Psychiatry	Publication Date: Oct 18, 2021
Citations: 21	License type: open-access

Affiliation: University of Helsinki

Abstract

Early life stress (ELS) is a well-characterized risk factor for mood and anxiety disorders. GABAergic microcircuits in the amygdala are critically implicated in anxiety; however, whether their function is altered after ELS is not known. Here we identify a novel mechanism by which kainate receptors (KARs) modulate feedforward inhibition in the lateral amygdala (LA) and show that this mechanism is downregulated after ELS induced by maternal separation (MS). Specifically, we show that in control rats but not after MS, endogenous activity of GluK1 subunit containing KARs disinhibit LA principal neurons during activation of cortical afferents. GluK1 antagonism attenuated excitability of parvalbumin (PV)-expressing interneurons, resulting in loss of PV-dependent inhibitory control and an increase in firing of somatostatin-expressing interneurons. Inactivation of Grik1 expression locally in the adult amygdala reduced ongoing GABAergic transmission and was sufficient to produce a mild anxiety-like behavioral phenotype. Interestingly, MS and GluK1-dependent phenotypes showed similar gender specificity, being detectable in male but not female rodents. Our data identify a novel KAR-dependent mechanism for cell-type and projection-specific functional modulation of the LA GABAergic microcircuit and suggest that the loss of GluK1 KAR function contributes to anxiogenesis after ELS.

Highlights

Disturbed activity early in life has lasting effects on the limbic circuitry, which predisposes to pathological behavioral phenotypes later on in life
Maternal separation leads to loss of Grik1 expression in the lateral amygdala maternal separation (MS) is a widely used animal model of early life adversity
B Percentage of time spent in the central zone of the open field arena in the same test was significantly affected by MS (F(1, 71) = 9.997, p = 0.002) and there was a significant interaction effect between MS and gender (F(1, 71) = 17.57, p < 0.0001)

Summary

Introduction

Disturbed activity early in life has lasting effects on the limbic circuitry, which predisposes to pathological behavioral phenotypes later on in life. Life stress (ELS) correlates with an increased risk of developing mood and anxiety disorders and is associated with altered synaptic plasticity and excitability in the amygdala, a part of the limbic system regulating emotional responses (e.g., [1,2,3]). Stress-induced changes in the neuronal structure and function of the amygdala have been implicated in anxiogenic behavior both in humans and in rodent models Kainate receptors (KARs) represent a family of ionotropic glutamate receptors that regulate neuronal excitability, synaptic transmission and plasticity in various parts of the brain (reviewed by Lerma [7]). Pharmacological and genetic evidence supports that KARs, and in particular, GluK1 subunit-containing KARs, regulate anxiety-like behaviors in rodents [11, 12, 14,15,16,17,18]. Genes encoding KAR subunits, including GRIK1 encoding the subunit GluK1, have been implicated in mood disorders ([19,20,21,22,23]; reviewed by Lerma and Marquez [24])

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