Prefrontal excitatory/inhibitory balance in stress and emotional disorders: Evidence for over-inhibition

Abstract

Chronic stress-related emotional disorders like anxiety and depression involve imbalances between the excitatory glutamatergic system and the inhibitory γaminobutyric acid (GABA) system in the prefrontal cortex (PFC). However, the precise nature and trajectory of excitatory/inhibitory (E/I) imbalances in these conditions is not clear, with the literature reporting glutamatergic and GABAergic findings that are at times contradictory and inconclusive. In this dissertation, I propose and discuss the hypothesis that chronic stress-induced anxiety involves hypoactivity of the PFC due to increased inhibition, mediated in part through increased activity of prefrontal parvalbumin (PV)-expressing inhibitory interneurons. Differing sensitivity of the prefrontal GABAergic system and PV neurons to chronic stress may also underlie sex differences in the prevalence of anxiety disorders, with women presenting with anxiety at higher rates than men. I first present evidence that chronic stress increases the activity of prefrontal PV neurons, and that increased activity of this cell population induces hypoactivity of the PFC. Furthermore, increasing prefrontal PV cell activity using DREADDs (designer receptors exclusively activated by designer drugs) induces anxietylike behaviors specifically in females (Chapter 2). However, acute inhibition of prefrontal PV cells using DREADDs is insufficient to rescue stress-induced anxiety-like behavior, though it does modulate activity and synaptic plasticity in the PFC in a sex

Suppression of pyramidal neuron G protein-gated inwardly rectifying K+ channel signaling impairs prelimbic cortical function and underlies stress-induced deficits in cognitive flexibility

“…Chronic stress-induced mPFC dysfunction is thought to reflect imbalances in excitation:inhibition, however the mechanism through which this occurs has yet to be identified (76). Using a previously established mouse model of CUS (59), we determined if CUS promotes enduring changes in PL pyramidal GABAB-GIRK signaling (Figure 5a).…”

Venlafaxine stimulates an MMP-9-dependent increase in excitatory/inhibitory balance in a stress model of depression

“…Untreated MDD increases one's risk for substance abuse, dementia, and suicide. Emerging evidence suggests that MDD is also associated with a reduction in overall excitatory to inhibitory (E/I) balance [reviewed in (Thompson et al, 2015;Page and Coutellier, 2019)]. For example, depressed patients show hypoactivity in the prefrontal cortex (PFC) (Fales et al, 2009).…”

Chemogenetic Inhibition of Infralimbic Prefrontal Cortex GABA-ergic Parvalbumin Interneurons Attenuates Chronic Stress Adaptions in Male Mice

“…It is known that antidepressants such as fluoxetine and ketamine reduce PV expression in the PFC (Ohira et al, 2013;Page and Coutellier, 2019;Zhou et al, 2015). Moreover, preventing the reduction in PV IN activity leads to loss of antidepressant efficacy, further suggesting that reduced activity of PV INs might be playing a role in therapeutic efficacy of antidepressants (Page and Coutellier, 2019;Zhou et al, 2015). Therefore based on prior studies and our findings, inhibition of PV INs during chronic stress may lead to more adaptive stress coping strategies and reverse some of the behavioral deficits associated with chronic stress.…”

“…GABA receptor antagonists have been shown to have antidepressant and anxiolytic properties (Bhutada et al, 2010;Mehta et al, 2017;SAMAD et al, 2018;Zanos et al, 2017). It is known that antidepressants such as fluoxetine and ketamine reduce PV expression in the PFC (Ohira et al, 2013;Page and Coutellier, 2019;Zhou et al, 2015). Moreover, preventing the reduction in PV IN activity leads to loss of antidepressant efficacy, further suggesting that reduced activity of PV INs might be playing a role in therapeutic efficacy of antidepressants (Page and Coutellier, 2019;Zhou et al, 2015).…”

“…Increases in expression of PV and enhancement of glutamatergic transmission onto PV-INs following chronic stress, are associated with prefrontal hypofunction, anxiogenesis and impaired coping behaviors in FST (Page et al, 2018;Shepard et al, 2016;Shepard and Coutellier, 2017). Reduction in PV expression in PFC is also associated with antidepressant efficacy (Ohira et al, 2013;Page and Coutellier, 2019;Zhou et al, 2015). In contrast to chronic, acute inhibition of PV INs in the PFC has opposing effects, resulting in increase in passive coping behavior such as learned helplessness in mice (Perova et al, 2015).…”