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

TLDR: The hypothesis that chronic stress-induced emotional dysfunction involves hypoactivity of the PFC due to increased inhibition is proposed and ideas for reconciling contradictory findings in support of the hypothesis of over-inhibition are proposed.

About: This article is published in Neuroscience & Biobehavioral Reviews.The article was published on 2019-10-01 and is currently open access. It has received 83 citations till now. The article focuses on the topics: Glutamatergic & Prefrontal cortex.

Figures

Figure 14. Chronic stress reduces prefrontal expression of Arc and Nptx2 in males. (A) Chronic stress significantly reduces Arc mRNA expression. (B) No significant differences in PSD-95 expression. (C) Chronic stress significantly reduces Nptx2 mRNA expression. N = 4-5 per group. In all figures, data are presented as mean ± SEM. *p ≤ 0.05; **p ≤ 0.01.

Table 2. Prefrontal E/I markers in adult rodent models of emotional dysfunction. GABAAR: GABAA receptor; mGluR-1: metabotropic glutamate receptor; EAAT2: excitatory amino acid transporter; mIPSC: miniature inhibitory post-synaptic current; PV: parvalbumin; CR: calretinin; CCK: cholecystokinin; GAD: glutamate decarboxylase; SST: somatostatin; NPY: neuropeptide Y

Figure 2. Time course of adult stress effects on glutamatergic transmission and activity in the prefrontal cortex. Acutely, stress exposure increases glutamatergic transmission and prefrontal activity. In cases of chronic stress exposure, this initial increase eventually results in reduced excitation and prefrontal hypoactivity. The nature of this trajectory is heterogeneous and impacted by multiple different factors including external ones relating to the stress itself, as well as internal ones such as sex and genetic vulnerability. E: excitation; I: inhibition.

Figure 18. LZ administration and chronic stress increase prefrontal pre-synaptic inhibition. (A) Lorazepam treatment increases prefrontal GAD1 expression and (B) decreases GABA-Aα1 expression. (C) Chronic stress trends towards decreasing Egr1 expression. In all figures, summary data are represented as mean ± SEM. N = 3-4 per group. *p ≤ 0.05. LZ: lorazepam.

Figure 26. Hypothesized changes in E/I balance due to development and chronic stress/emotional dysfunction. In adolescence, the PFC is more hyper-excitable and plastic. As development progresses into adulthood, increased PV cell activity and PNN coverage of PV cells enhances inhibition to stabilize the network, resulting in mature E/I balance and healthy prefrontaldependent emotional functioning. Chronic stress and affective disorders like anxiety and depression may involve increases in the same molecular mechanisms that are involved in GABAergic maturation, such as PV cells and PNNs, inducing hypoactivity. Treatment involves restoring levels of activity, potentially in part through reducing brakes on excitation such as PV cells and PNNs to restore a mature, functional E/I balance. E: excitation; I: inhibition; PV: parvalbumin; PNN: perineuronal net.

Figure 5. Chronic stress increases activity of prefrontal PV neurons in both sexes. (A) Representative image showing PV (red) and cFos (green) double-labeling (white arrow). Scale bar: 10 µm. (B) Chronic stress increases the number of PV/cFos double-labeled cells in the PFC of females and (C) males. In all figures, summary data are represented as mean ± SEM. *p = 0.05.

Frequently asked questions

Q1. What are the contributions mentioned in the paper "Chronic stress-related emotional disorders like anxiety and depression involve imbalances between the excitatory glutamatergic system and the inhibitory γ- aminobutyric 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 anxiety- like 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- iii dependent manner (chapter 3). furthermore, manipulating the prefrontal gabaergic system during chronic stress can incur vulnerability or resilience to anxiety. pharmacological enhancement of gabaergic transmission with the gaba positive allosteric modulator lorazepam during chronic stress exposure exacerbates prefrontal inhibition and anxiety-like behaviors in female mice" ?

Shepard et al. this paper used a chemogenetic approach in male and female chronic stress to test whether prefrontal PVogenic. 

Q2. What have the authors stated for future works in "Chronic stress-related emotional disorders like anxiety and depression involve imbalances between the excitatory glutamatergic system and the inhibitory γ- aminobutyric 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 anxiety- like 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- iii dependent manner (chapter 3). furthermore, manipulating the prefrontal gabaergic system during chronic stress can incur vulnerability or resilience to anxiety. pharmacological enhancement of gabaergic transmission with the gaba positive allosteric modulator lorazepam during chronic stress exposure exacerbates prefrontal inhibition and anxiety-like behaviors in female mice" ?

Future studies must continue to take sex differences into account, as well as continue to investigate the complex interplay between excitatory and inhibitory transmission both in and out of balance. Back to the future: J 159 Neurosci 33:1116–1129. Labro AJ, Priest MF, Lacroix JJ, Snyders DJ, Bezanilla F ( 2015 ) Kv3. 1 uses a timely resurgent K ( + ) current to secure action potential repolarization. 

Q3. What is the role of the prefrontal PV cells in mood disorders?

They are integral to balancing activity levels of pyramidal cells in the PFC and therefore, increased PV-dependent GABAergic transmission could be contributing to the hypoactivity of the PFC observed in mood disorders. 

Q4. What is the main conclusion from this experiment?

The main conclusion from this experiment is that acute prefrontal PV cell inhibition is insufficient to rescue stress-induced anxiety-like behaviors in both males and females. 

Q5. What is the effect of ketamine on the prefrontal PV cells?

an antagonist of M1-type muscarinic acetylcholine receptors and fastacting antidepressant, has anxiolytic effects that do not depend on prefrontal PV cells (Wohleb et al., 2016). 

Q6. What is the role of the PFC in the extinction of learned fear?

PFC activation is also necessary for the extinction of learned fear (Fucich et al., 2018; Ramanathan et al., 2018) via decreasing activity in the amygdala (Quirk et al., 2003). 

Q7. What is the likely explanation for the increase in PV cell counts?

The reported increase in the number of PV-positive cells most likely reflects an activitydependent increase in PV protein expression levels (Kinney et al., 2006; Filice et al., 2016) that allows for immunohistochemistry detection. 

Q8. What is the role of prefrontal PV cells in anxiety?

Prefrontal PV cells may still represent a therapeutic target for anxiety, but chronic inhibition of this cell population is likely necessary. 

Q9. How were the mice kept after weaning?

After weaning, mice were maintained group-housed per sex (3-5 mice per cage) and undisturbed (aside from regular cage cleaning) until experimental procedures started. 

Q10. How long does diazepam treatment reduce spine density in male mice?

Chronic diazepam treatment over 21 days has been found to reduce spine density in prefrontal pyramidal neurons of male mice (Curto et al., 2016). 

Q11. What are the experiments used to manipulate the GABAergic system?

The experiments presented here manipulate the GABAergic system using chemogenetic, pharmacological, or transgenic methods to causally connect increases or decreases in inhibition with behavioral outcomes. 

Q12. What is the effect of chronic activation of prefrontal PV cells on anxiety-like behavior?

Acute activation of prefrontal PV cells does not induce changes in anxiety-like behaviors in females After observing that chronic excitation of prefrontal PV induces anxiety-like behavior only in females, the authors next determined whether acute activation was sufficient to elicit an anxiogenic effect. 

Q13. What is the role of stress in the development of anxietylike behaviors in female mice?

Only female mice were used as a follow-up to their previous research showing thatfemales are more susceptible to stress-induced anxiety and increased prefrontal PV cell activity (Shepard et al., 2016), and that increased prefrontal inhibition induces anxietylike behaviors in female mice only (Chapter 2). 

Q14. What is the reason for the increased expression of Kv3.1 in the frontal cortex?

In male rats, chronic stress increases frontal cortex expression of Kv2.1, which is rescued by fluoxetine treatment (there was a non-statistically significant increase in expression of Kv3.1 in the frontal cortex by chronic stress) (Chen et al., 2015). 

Q15. What did the authors observe in the OF after acute activation of prefrontal PV cells?

In both females and males, the authors did not observe any significant change in anxiety-like behavior as measured in the OF after acute activation of prefrontal PV cells (Figure 9). 

Q16. What was the cDNA sequence used in the CFX96 Real-Time PCR?

The target cDNA and the reference target59glyceraldehyde-3-phosphate dehydrogenase (GAPDH) were amplified simultaneously in the CFX96 Real-Time PCR Detection System (Bio-Rad Laboratories, Hercules, CA, USA).