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  • As we previously observed in the NSFT Fukumoto et al

    2024-04-18

    As we previously observed in the NSFT (Fukumoto et al., 2014), the effect of LY341495 in the FST was also inhibited by a 5-HT1A receptor antagonist, indicating the role of the 5-HT1A receptor in the actions of LY341495. Among the 5-HT1A receptors, which exist both presynaptically and postsynaptically, the postsynaptic 5-HT1A receptor in the mPFC appear to be particularly important for the antidepressant effect of LY341495, because selective blockade of the mPFC 5-HT1A receptor was sufficient to completely block the antidepressant effect of LY341495. The critical role of postsynaptic 5-HT1A receptor stimulation in the mPFC has previously been demonstrated in the antidepressant effect of ketamine (Fukumoto et al., 2018). In addition, the important role of the mPFC in the pathophysiology and treatment of depression has been shown by both β-Tocotrienol imaging and postmortem studies (Holmes and Wellman, 2009; Murrough, 2012; Price and Drevets, 2010). Therefore, stimulation of the mPFC postsynaptic 5-HT1A receptor appears to be the common mechanism underlying the antidepressant effects of both mGlu2/3 receptor antagonists and β-Tocotrienol ketamine. Among the 5-HT1A receptor-mediated signaling cascades, we particularly focused on the PI3K/Akt signaling pathway due to its critical role in synaptic plasticity, which has been implicated in the sustained antidepressant effect of ketamine (Islam et al., 2014; Li et al., 2010; Polter et al., 2012). Although we detected a sustained antidepressant effect of LY341495 even at 24 h after its administration, the elimination half-life of LY341495 (10 mg/kg, i.p.) in the brain is only approximately 4.75 h, similar to that of ketamine, suggesting that LY341495 exerts its sustained antidepressant effect through inducing synaptic plasticity (Maxwell et al., 2006; Ornstein et al., 1998). Indeed, mGlu2/3 receptor antagonists, including LY341495, have been reported to increase synaptic protein synthesis (Dwyer et al., 2012) and to reverse chronic stress-reduced synaptic protein synthesis and spine density in the PFC (Dong et al., 2017), both of which also implicate the involvement of synaptic plasticity in their actions. In the present study, we showed that LY341495 activated PI3K/Akt signaling in the mPFC to exert a sustained antidepressant effect. Since phosphorylation of Akt induced by LY341495 was abrogated not only by a PI3K inhibitor, but also by a 5-HT1A receptor antagonist, LY341495 appears to activate PI3K/Akt signaling in the mPFC by stimulation of the 5-HT1A receptor. The present study also demonstrated the involvement of mTORC1 signaling, a downstream of PI3K/Akt signaling, in the mPFC in the sustained antidepressant effect of LY341495, which is consistent with the finding in a previous study that intracerebroventricular injection of rapamycin blocked the sustained antidepressant effects of LY341495 (Dwyer et al., 2012; Koike et al., 2011). Moreover, we previously demonstrated that the sustained antidepressant effect induced by stimulation of the mPFC 5-HT1A receptor is mediated via activation of mTORC1 signaling in the mPFC (Fukumoto et al., 2018). All these data indicate that LY341495 activates the 5-HT1A receptor-mediated PI3K/Akt/mTORC1 signaling pathway in the mPFC to enhance synaptic transmission and induce a sustained antidepressant effect. Moreover, it seems to share these mechanisms with ketamine, because ketamine also activates the 5-HT1A receptor and PI3K/Akt/mTORC1 signaling in the mPFC to exert a sustained antidepressant effect (Fukumoto et al., 2018). The precise mechanism by which mGlu2/3 receptor antagonists activate 5-HT1A receptor-mediated signaling in the mPFC remains largely unknown. We previously reported that mGlu2/3 receptor antagonists enhance serotonergic transmission, both serotonin release in the mPFC (Karasawa et al., 2005; Kawashima et al., 2005) and the firing rate of serotonin neurons in the DRN (Kawashima et al., 2005). Moreover, we also showed recently that LY341495 activates the DRN serotonin neurons via AMPA receptor-stimulated mPFC projections (Fukumoto et al., 2016), while LY341495 has also been reported to activate the DRN serotonin neurons via TREK-1 in the mPFC (Moha ou Maati et al., 2016). Notably, AMPA receptor activation in the infralimbic cortex (a part of the mPFC) has also been reported to increase serotonin release in the mPFC, possibly through increased activity of the neurons of the DRN. Therefore, it is conceivable that mGlu2/3 receptor antagonists indirectly stimulate the mPFC 5-HT1A receptor via increased serotonin release, and that activation of the DRN serotonin neurons may be responsible for the increase in serotonin release in the mPFC. Indeed, in the present study, we observed that silencing of the DRN neurons by microinjection of a GABAA receptor agonist into the DRN abrogated the sustained antidepressant effect of LY341495, indicating that activation of the DRN serotonin neurons may have a critical role in the antidepressant effect of LY341495. Therefore, it is hypothesized that mGlu2/3 receptor antagonists increase serotonin release in the mPFC by activating the DRN serotonin neurons via mPFC projections, and that the increased serotonin in the mPFC stimulates the postsynaptic 5-HT1A receptor, which triggers PI3K/Akt/mTORC1 signaling to exert the sustained antidepressant effects. On the other hand, involvement of the locally released serotonin in the mPFC by mGlu2/3 receptor antagonists in stimulating the postsynaptic 5-HT1A receptor can also not be ruled out. In either case, stimulation of the AMPA receptor has an important role in these events, because increase in serotonin release in the mPFC by mGlu2/3 receptor antagonists is mediated through stimulation of the AMPA receptor (Karasawa et al., 2005). This hypothetical scheme explained above is depicted in Fig. 5D.