HYPERACTIVITY IN BASOLATERAL AMYGDALA MAY CONTRIBUTE TO THE NEURAL CIRCUIT PATHOLOGY IN TREATMENT-RESISTANT DEPRESSION MODEL
Authors: Fukui *Kiyoshiro , Kawada Takuya , Fukumoto Kenichi 
Published: February 2025

Abstract

Background
Major depressive disorder (MDD) is one of the diseases that makes social life extremely difficult and has a heavy medical economic burden. Currently antidepressant agents such as selective serotonin reuptake inhibitors (SSRIs) are inefficient in improving depressive symptoms in about 30 % of patients, and there is a need for drugs with new mechanism of action.

Aims & Objective
Wistar Kyoto (WKY) rat strain has been suggested as a useful tool for investigating the pathophysiology of treatment-resistant depression because long-term administration of SSRIs can’ t improve depressive-like symptoms in WKY rat. However, the neural characteristics that WKY rat shows the phenotypes like patients who don’ t respond to antidepressants is unknown. The basolateral amygdala (BLA) plays critical roles that expressing moods and emotions including anxiety and depressive symptoms. Meta-analyses of 367 task-related fMRI experiments in mood disorders, posttraumatic stress disorder, and anxiety disorders have demonstrated that hyperactivity in the amygdala is associated with negative valence systems. Therefore, the hyperactivity in BLA could be a key pathophysiology in MDD. In this study, we evaluated the predictive validity and neural excitability of excitatory projection neurons (PNs) in BLA of WKY rat as a model of treatment-resistant depression.

Method & Result
First, we confirmed the predictive validity for SSRIs by performing the Forced Swim Test (FST). Consistent with previous studies, the immobility time of WKY rat was significantly longer than Wistar rat, which has same genetic background as WKY rat. Multiple administration of fluoxetine didn’ t reduce the immobility time of WKY rat. Next, we performed whole-cell patch clamp recording to investigate neural activity of PNs in BLA. The number of spontaneous action potentials was significantly increased in WKY rat compared with Wistar rat under the condition of voltage-clamp at -70 mV. Moreover, WKY rat exhibited a higher number of firings than Wistar rat in response to steady increasing stimulation. In the contrast, no significant differences were found in the frequency and amplitude of spontaneous inhibitory postsynaptic currents (sIPSC) between WKY rat and Wistar rat.

Discussion & Conclusion
Collectively, these results suggest that BLA PNs of WKY rat are hyperactive by increasing neural excitability but not inhibitory synaptic mechanism. Positive allosteric modulators for synaptic and extrasynaptic GABAA receptors have been found to elicit both immediate and long-lasting antidepressant effects in patients with Major Depressive Disorder (MDD) or Postpartum Depression (PPD). Recent findings suggest that activation of the extrasynaptic GABAARs may play a crucial role in the antidepressant effects. Hence, we now verify the effect of 4,5,6,7-tetrahydroisoxazolo (5,4-c) pyridin-3 (-ol) (THIP), a ligand with the activity of extrasynaptic GABAARs on the neural excitability of PNs in BLA to clarify the possible neural mechanisms underlying the antidepressant effects due to the activity of extrasynaptic GABAARs. We would like to show our new behavioral and electrophysiological data.