Central relaxin-3 receptor (RXFP3) activation impairs social recognition and modulates ERK-phosphorylation in specific GABAergic amygdala neurons

Abstract

In mammals, the extended amygdala is a neural hub for social and emotional information processing. In the rat, the extended amygdala receives inhibitory GABAergic projections from the nucleus incertus (NI) in the pontine tegmentum. NI neurons produce the neuropeptide relaxin-3, which acts via the G i/o-protein-coupled receptor, RXFP3. A putative role for RXFP3 signalling in regulating social interaction was investigated by assessing the effect of intracerebroventricular infusion of the RXFP3 agonist, RXFP3-A2, on performance in the 3chamber social interaction paradigm. Central RXFP3-A2, but not vehicle, infusion, disrupted the capacity to discriminate between a familiar and novel conspecific subject, but did not alter differentiation between a conspecific and an inanimate object. Subsequent studies revealed that agonist-infused rats displayed increased pERK-immunoreactivity in specific amygdaloid nuclei at 20 min post-infusion, with levels similar to control again after 90 min. In parallel, we used immunoblotting to profile ERK phosphorylation dynamics in whole amygdala after RXFP3-A2 treatment; and multiplex histochemical labelling techniques to reveal that after RXFP3-A2 infusion and social interaction, pERK-immunopositive neurons in amygdala expressed vesicular GABA-transporter mRNA and displayed differential profiles of RXFP3 and oxytocin receptor mRNA. Overall, these findings demonstrate that central relaxin-3/RXFP3 signalling can modulate social recognition in rats via effects within the amygdala and likely interactions with GABA and oxytocin signalling.

Chronic activation of the relaxin‐3 receptor on GABA neurons in rat ventral hippocampus promotes anxiety and social avoidance

“…Importantly, impairments in social interaction are a common feature in psychiatric disorders, including ADs (Kennedy & Adolphs, ); and the involvement of relaxin‐3/RXFP3 circuitry in regulating anxiety is consistent with an impact on social behavior. Together, our findings point to a role for relaxin‐3/RXFP3 signaling in the vHip in social behavior and expression of anxiety‐like behaviors (see also Albert‐Gasco et al, ).…”

MAP/ERK Signaling in Developing Cognitive and Emotional Function and Its Effect on Pathological and Neurodegenerative Processes

“…In the case of social behavior, considering its overlap with other systems, such as anxiety, stress, and aggression, this convergence might be even more complex. For example, the oxytocin and relaxin-3 pathway lead to opposite effects on social recognition memory; while oxytocin promotes it [ 12 ], RLN3 impairs it [ 15 ]. At the same time, relaxin-3 is known to be involved in the response to stress [ 114 ].…”

Involvement of the Nucleus Incertus and Relaxin-3/RXFP3 Signaling System in Explicit and Implicit Memory

“…In vivo, intracerebroventricular (icv) infusions of an RXFP3 agonist increased ERK phosphorylation in the septum (Albert-Gascó et al, 2017) and amygdala (Albert-Gasco et al, 2019) reaching a peak at 20 min and returning to baseline (control) values by 90 min. However, this pERK activation was largely produced in RXFP3 mRNA negative neurons in these regions, suggesting this in vivo ERK activation was an indirect effect (Albert-Gasco et al, 2019).…”

“…This argument is supported by the fact that activating RXFP3 during this behavioral paradigm significantly increased the number of RXFP3-expressing neurons which contained pERK compared to controls, suggesting a direct effect on these neurons. However, all studies where RXFP3 agonists increased pERK were quantified after assessing retrieval of memories (Albert-Gascó et al, 2017;Albert-Gasco et al, 2019). So, it is possible, given the transient nature of MAPK activation, that these approaches are likely to have missed the complete direct increase of pERK in RXFP3-expressing neurons due to RXPF3 agonist activation.…”