sgk inhibitor To date the recently proposed hypothesis

To date, the recently proposed hypothesis deciphering the mode of action of DBS points toward a functional inactivation of neuronal activity in the stimulated area, and an excitation of direct axonal and fiber pathways near the electrodes that would regulate distant structures (Montgomery and Gale, 2008; Vitek, 2002). In support to this hypothesis, our study demonstrated that high frequency stimulation of the IL-PFC produced a current-dependent increase of the presumed DRN 5-HT neuronal firing rate, suggesting an increased glutamatergic output from IL-PFC projections (Peyron et al., 1998; Celada et al., 2001). In agreement with a recent study (Veerakumar et al., 2014), our results showed that acute IL-DBS increased synaptogenesis within the DRN, an effect that should favor the glutamatergic tone exerted by IL-PFC terminals on serotoninergic neurons. Indeed, increased mRNA for the postsynaptic marker PSD-95 and the presynaptic protein synapsin were observed in the DRN of stimulated rats. In the same way, increased PSD-95 protein level indicate that this marker of postsynaptic density is increased within the DRN, suggesting that processes of synaptic growth have been triggered by vmPFC DBS. Besides, the fact that mRNA and protein levels of synapsin appear to be modulated in an opposite way by the stimulation suggest that the synthesis of this factor has increased within DRN cells, but that the protein itself has started to migrate outside the observed sgk inhibitor structure. This is in agreement with the presynaptic nature of synapsin as a promoter of vesicular formation, and would indicate that 5-HT neurons are more activated and more mobilized to release their transmitter after DBS. This explanation is fully compatible with the fact that both behavioral (i.e., in the forced swim test) and electrophysiological (i.e., on 5-HT neurons) effects of IL-DBS were still present after the stimulator had been turned off. This enhancement of 5-HT neurotransmission might be implicated in DBS-induced effects on dorsal and ventral hippocampi. Indeed, we demonstrated that the capacity of IL-DBS to block LTP induction depends on the integrity of the 5-HT system since 5-HT depletion produced by PCPA abolished this effect. Accordingly, it was shown that 5-HT is able to potentiate synaptic transmission through the activation 5-HT4 receptors (Kobayashi et al., 2008) which are known to play a key role in the regulation of synaptic plasticity in CA1 (Kemp and Manahan-Vaughan, 2004, 2005) and to influence learning and memory (Lamirault and Simon, 2001; Moser et al., 2002). In the same way, it has been reported that the effects of DBS in the FST are completely abolished in 5-HT lesioned rats (Hamani et al., 2012). Hence, these results strongly suggested that the effects of IL-DBS on synaptic plasticity and mitogenesis are mostly mediated by 5-HT and that the integrity of 5-HT system is crucial for the antidepressant efficacy of DBS. The present study reveals that an ibotenic acid lesion within the IL-PFC prevented the antidepressant-like effect of DBS, showing that local neuronal population is implicated in the effects of the stimulation, and is not just “inactivated” as currently hypothesized. When activated by DBS, pyramidal neurons and their axons would release an augmented quantity of glutamate, leading to an over-activity of presumed 5-HT neurons within the DRN and an increase of 5-HT release in terminal areas (Fig. 6). Taken together, these results support the view that the antidepressant-like effect of a cortical stimulation might be mediated by both the activation of local neuronal population and the excitation of axons and passing fibers that would enhance, among others, 5-HT neurotransmission (A more detailed discussion on this “excitation vs inhibition theory” is provided in the Supplementary Material). Accordingly, we demonstrated that the antidepressant-like effect of IL-DBS was associated with an increase of slow oscillatory activities within the stimulated area, an effect prevented by local l-AAA infusion. A similar increase has been observed following ECT therapy, associated with an augmentation of IL-PFC synaptogenesis and gliogenesis (Bouckaert et al., 2014). Together, these findings raise the interesting hypothesis that fast-acting AD strategies share the common feature of re-enforcing intra-IL-PFC connections, which in turn may strengthen the positive modulation exerted by pyramidal neurons on their subcortical targets like the DRN. If so, the involvement of astrocytes in the AD effects of DBS, would not be surprising given their importance in the processes of synaptic plasticity and reinforcement.