In the previous study we demonstrated

In the previous study, we demonstrated the importance of the mPFC postsynaptic 5-HT1A receptor in the sustained antidepressant effects, because a sustained antidepressant effect was obtained with intra-mPFC injection, but not systemic injection of 8-OH-DPAT, a 5-HT1A receptor agonist (Fukumoto et al., 2018), suggesting that selective stimulation of the mPFC 5-HT1A receptor is necessary. Moreover, the 8-OH-DPAT-induced sustained antidepressant effect was attenuated by intra-mPFC injection of a PI3K inhibitor or mTORC1 inhibitor (Fukumoto et al., 2018). PI3K/Akt signaling and its downstream signaling pathway (mTORC1 signaling) play critical roles in synaptic plasticity, which is known to underlie the sustained antidepressant actions (Duman et al., 2016; Hoeffer and Klann, 2010; Islam et al., 2014; Li et al., 2010; Polter et al., 2012). These results indicate that stimulation of mPFC 5-HT1A receptor-mediated PI3K/Akt/mTORC1 signaling can induce a sustained antidepressant effect. It would be interesting to confirm if stimulation of the postsynaptic 5-HT1A receptor in the mPFC can also increase synaptic protein synthesis and spine density, as observed in the treatment with mGlu2/3 receptor antagonists or ketamine. It should be noted that the importance of selective stimulation of the postsynaptic 5-HT1A receptor is also supported by the finding that F15599, a 5-HT1A receptor agonist that preferentially acts on the postsynaptic 5-HT1A receptor, exerted a more potent and sustained antidepressant effect than 5-HT1A receptor agonists that act on both the postsynaptic and presynaptic 5-HT1A receptor (Assié et al., 2010). It should be noted that stimulation of the mPFC 5-HT1A receptor exerts an inhibitory input on subpopulation of serotonin FAK Inhibitor 14 receptor in the DRN (Celada et al., 2001; Hajos et al., 1999; Martin-Ruiz and Ugedo, 2001), which inhibits serotonergic transmission. Therefore, blockade but not stimulation of the mPFC 5-HT1A receptor is expected to exert the acute antidepressant effects. It has been reported that combination of a 5-HT4 receptor agonist and spadin, both of which stimulate the DRN serotonin neuron firing rate, paradoxically reduced serotonin firing (Moha ou Maati et al., 2016). Based on this finding, we cannot fully rule out possibility that the same effects may occur when both LY341495 and WAY100635 were used. However, the role of the inhibitory input of the mPFC 5-HT1A receptor on the DRN serotonin neurons in the acute antidepressant effects is largely unknown. Therefore, synaptic/neural mechanisms underlying the acute antidepressant effects after the mPFC 5-HT1A receptor stimulation needs to be further investigated.
Conclusions The present study indicates that stimulation of the postsynaptic 5-HT1A receptor and the consequent activation of PI3K/Akt/mTORC1 signaling in the mPFC have critical roles in the sustained antidepressant effects of mGlu2/3 receptor antagonists, as demonstrated for the case of ketamine. Moreover, mGlu2/3 receptor antagonists may also indirectly stimulate mPFC 5-HT1A receptor-mediated signaling via mPFC-DRN projections. Taking all of our findings into consideration, we propose that selective stimulation of the mPFC 5-HT1A receptor and its PI3K/Akt signaling pathway is an effective strategy for the treatment of depression, although further studies are needed to verify this hypothesis.
Conflicts of interest
Acknowledgements
Introduction The etiology of major depressive disorder (MDD) is poorly understood (Foley et al., 2001, Ripke et al., 2013, Verduijn et al., 2015), however for at least a proportion of MDD patients there is experimental evidence suggesting a connection to altered hippocampal biology. For example, several studies have demonstrated reduced hippocampal volume among MDD patients (Videbech and Ravnkilde, 2004) which can be reversed via antidepressant treatment (Malykhin et al., 2010). Other studies have observed an inverse relationship between a patient’s hippocampal volume and the duration and number of depressive episodes they have experienced, as well as their performance in tests assessing cognitive functions such as memory (Dale et al., 2016). Functional magnetic resonance imaging (fMRI) studies in MDD patients performing working memory tasks have shown an over activity in the hippocampus (and in the dorsolateral prefrontal cortex) compared to healthy subjects (Harvey et al., 2005, Walsh et al., 2007), suggesting a need to recruit more neural resources in order to function appropriately. In addition to anatomical impairments, a number of biological and biochemical alterations have been reported in hippocampal tissue of depressed patients. Thus, post-mortem studies have shown a decrease in cell number, reduction in neuronal synaptic density proteins and impaired signaling activity of glutamate, monoamines and γ-aminobutyric acid (GABA) in subjects diagnosed with mood disorders (Stockmeier et al., 2004, Knable et al., 2004, Pehrson and Sanchez, 2015). Postmortem and imaging studies examining the density of 5-HT receptors in the hippocampus produced varying results, perhaps due to methodological differences and heterogeneity of the patients included in these studies (reviewed in Stockmeier, 2003). However, several reports have shown a robust reduction in the expression and binding potential of 5-HT1A and 5-HT2A receptors in the hippocampus (Lopez-Figueroa et al., 2004, Drevets et al., 2000, Sargent et al., 2000, Savitz et al., 2010, Rosel et al., 2000, Mintun et al., 2004. A study by Duric et al. (2013) also found a reduction in the expression of genes encoding 5-HT4 and 5-HT7 receptors as well a decrease in the expression of synaptic and microtubule-associated proteins (SNAP25, MAP1A) critical for synaptic plasticity (Duric et al., 2013). Collectively these results suggest that neuronal plasticity and 5-HT signaling may be impaired in the hippocampus of patients with depression. Thus, it is possible that changes in hippocampal biology play an important role in the pathophysiology of MDD.