Regulation of fear extinction versus other affective behaviors by discrete cortical scaffolding complexes associated with NR2B and PKA signaling

Abstract

In patients suffering from post-traumatic stress disorder (PTSD), fear evoked by trauma-related memories lasts long past the traumatic event and it is often complicated by general anxiety and depressed mood. This poses a treatment challenge, as drugs beneficial for some symptoms might exacerbate others. For example, in preclinical studies, antagonists of the NR2B subunit of N-methyl-d-aspartate receptors and activators of cAMP-dependent protein kinase (PKA) act as potent antidepressants and anxiolytics, but they block fear extinction. Using mice, we attempted to overcome this problem by interfering with individual NR2B and PKA signaling complexes organized by scaffolding proteins. We infused cell-permeable Tat peptides that displaced either NR2B from receptor for activated C kinase 1 (RACK1), or PKA from A-kinase anchor proteins (AKAPs) or microtubule-associated proteins (MAPs). The infusions were targeted to the retrosplenial cortex, an area involved in both fear extinction of remotely acquired memories and in mood regulation. Tat-RACK1 and Tat-AKAP enhanced fear extinction, all peptides reduced anxiety and none affected baseline depression-like behavior. However, disruption of PKA complexes distinctively interfered with the rapid antidepressant actions of the N-methyl-D-aspartate receptors antagonist MK-801 in that Tat-MAP2 blocked, whereas Tat-AKAP completely inverted the effect of MK-801 from antidepressant to depressant. These effects were unrelated to the MK-801-induced changes of brain-derived neurotrophic factor messenger RNA levels. Together, the findings suggest that NR2B–RACK1 complexes specifically contribute to fear extinction, and may provide a target for the treatment of PTSD. AKAP-PKA, on the other hand, appears to modulate fear extinction and antidepressant responses in opposite directions.

Microtubule and microtubule associated protein anomalies in psychiatric disease

“…Interestingly, MAP2 interacts with the NMDA‐type glutamate receptor subunit NR2B [Kapitein and Hoogenraad, ; Kapitein et al, ], and the antidepressant action of the NMDA receptor antagonist MK‐801 depends on this association. It also depends on the anchoring of PKA by MAP2 at this complex [Corcoran et al, ]. This data indicates that MAP2 plays an integral role in the regulation of mood homeostasis via glutamatergic signaling.…”

Network oscillatory activity driven by context memory processing is differently regulated by glutamatergic and cholinergic neurotransmission

“…Although not directly tested here, there is circumstantial evidence to support this possibility. In both humans (Costi et al, 2015; Drevets et al, 2013) and rodents (Autry et al, 2011; Corcoran et al, 2015; Navarria et al, 2015; Voleti et al, 2013), NMDA and muscarinic receptor antagonists have shown promise as rapid-acting antidepressants.…”

N-Methyl D-aspartate receptor subunit signaling in fear extinction

“…Some of the main signaling pathways triggered through this interaction are RACK1 - Receptor of activated protein C kinase 1 (RACK1) (Yaka et al 2002), A-kinase anchoring protein 150 (AKAP150) (Jurado et al 2010), microtubule-associated protein 2 (MAP2) (Buddle et al 2003), and neuronal nitric oxide synthase (nNOS) (Hillier et al 1999). Disrupting specific interactions with interfering peptides can facilitate fear extinction without affecting depression-like behavior (Corcoran et al 2015). …”

“…For example, disrupting the interaction between GluN2A and IQGAP1 specifically causes memory encoding impairments without affecting anxiety- or depression-like behavior (Gao et al 2011). On the other hand, targeting the interaction between GluN2B and receptor for activated C kinase 1 (RACK1), which inhibits NR2B function (Yaka et al 2002), enhances fear extinction without affecting depression-like behavior (Corcoran et al 2015). …”