Stress induces insertion of calcium-permeable AMPA receptors in the OFC–BLA synapse and modulates emotional behaviours in mice

Abstract

Stress increases the risk of neuropsychiatric disorders, such as major depression. Exposure to stress has been reported to induce various neuronal changes, such as alterations in synaptic transmission and structure. However, a causal link between stress-induced neural circuit alterations and changes in emotional behaviours is not well understood. In the present study, we focused on a projection pathway from the orbitofrontal cortex (OFC) to the basolateral nucleus of the amygdala (BLA) as a crucial circuit for negative emotions and examined the effect of stress on OFC–BLA excitatory synaptic transmission using optogenetic and whole-cell patch-clamp methods in mice. As a stress-inducing procedure, we used repeated tail-shock, which increased stress-related behaviours. We found greater α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)/N-methyl-d-aspartate current ratios and insertion of calcium-permeable AMPA receptors (AMPARs) in the OFC–BLA synapse after stress. These stress-induced synaptic and behavioural changes were reduced by a blockade of protein kinase A, which plays a principal role in stress-induced targeting of AMPARs into the synaptic membrane. To examine a possible causal relationship between alterations in synaptic transmission in the OFC–BLA pathway and stress-related behaviour, we performed optogenetic activation or chemogenetic inactivation of OFC–BLA transmission in mice. We found that optogenetic activation and chemogenetic inactivation of OFC–BLA transmission increased and decreased stress-related behaviour, respectively. In conclusion, we have demonstrated that stress altered the postsynaptic properties of the OFC–BLA pathway. These synaptic changes might be one of the underlying mechanisms of stress-induced behavioural alterations.

It Is All in the Right Amygdala: Increased Synaptic Plasticity and Perineuronal Nets in Male, But Not Female, Juvenile Rat Pups after Exposure to Early-Life Stress

“…The significant reduction of GluA2 in the right BLA of juvenile male rats after early stress is similar to the reduced GluA2 expression observed in the adult BLA after chronic stress (Yi et al, 2017) and could contribute to a postsynaptic mechanism for LTP facilitation. Chronic stress has also been shown to enhance the inward rectification of AMPAR in the BLA (Kuniishi et al, 2020), suggesting an increase in AMPARs lacking the GluA2 subunit. Given the regulation of calcium permeability of AMPAR by the GluA2 subunit (for review, see Wright and Vissel, 2012), a reduction of GluA2 could enhance LTP formation via increasing calcium influx (Jia et al, 1996).…”

Inhibition of AMPA receptors (AMPARs) containing transmembrane AMPAR regulatory protein γ‐8 with JNJ‐55511118 shows preclinical efficacy in reducing chronic repetitive alcohol self‐administration

“…Our prior research has shown that this procedure results in pharmacologically relevant blood alcohol (BAC; Faccidomo et al, 2009). BAC was not measured in the present study to prevent behavioral disruption and potential stress-induced insertion of calcium-permeable AMPARs (Kuniishi et al, 2020), which are functionally regulated by TARP γ-8 (Bats et al, 2013).…”

α2δ-1 switches the phenotype of synaptic AMPA receptors by physically disrupting heteromeric subunit assembly

“…CP-AMPARs are involved in the pathogenesis of Alzheimer disease (Whitehead et al, 2017), Parkinson disease (Kobylecki et al, 2010), epilepsy (Friedman and Koudinov, 1999), drug addiction (Conrad et al,Figure 6. Gabapentin and the a2d-1CT-Tat C terminus peptide restore heteromeric GluA1/GluA2 receptors diminished by a2d-1 coexpression Article ll OPEN ACCESS 2008), chronic stress (Kuniishi et al, 2020), neurogenic hypertension (Li et al, 2012), and ischemic stroke (Noh et al, 2005). Given the well-recognized role of CP-AMPARs in these neurological disorders, it is crucial to determine to what extent a2d-1 mediates the increased synaptic CP-AMPARs under these conditions so that rational treatments can be designed.…”

“…In addition, α2δ-1 is highly expressed in many brain regions and is expected to similarly regulate AMPAR subunit composition. CP-AMPARs are involved in the pathogenesis of Alzheimer disease ( Whitehead et al, 2017 ), Parkinson disease ( Kobylecki et al, 2010 ), epilepsy ( Friedman and Koudinov, 1999 ), drug addiction ( Conrad et al, 2008 ), chronic stress ( Kuniishi et al, 2020 ), neurogenic hypertension ( Li et al, 2012 ), and ischemic stroke ( Noh et al, 2005 ). Given the well-recognized role of CP-AMPARs in these neurological disorders, it is crucial to determine to what extent α2δ-1 mediates the increased synaptic CP-AMPARs under these conditions so that rational treatments can be designed.…”