| Popis: |
Major depressive disorder (MDD) is the most disorienting psychiatric disorder, causing a huge social and economic burden globally. Conventional treatment with classical antidepressants targeting the monoaminergic system have provided very limited efficacy in pacifying depression symptoms. Rapid-acting antidepressant Ketamine (Ket) has emerged as a novel therapeutic agent applicable in MDD and treatment resistant depression, over the recent decade. Antidepressant effects of Ket is attributed to its ability to block Glun2B subunits of NMDARs at inhibitory neurons, leading to bursting of glutamatergic transmission and subsequent AMPAR activation. However, unwanted side-effects and abuse potential of Ket cannot be ignored. Since 2016, numerous reports of antidepressive properties of major Ket metabolite Hydroxynorketamine (HNK) have emerged. Similar to Ket, HNK increased AMPAR activation and successfully mitigated depressive symptoms in rodent models of depression, but in an NMDAR-independent manner. Interestingly, HNK displayed no dissociative side-effects commonly seen with Ket administration, making it a promising candidate in antidepressive research. However, evidences of molecular and cellular signaling cascades important for HNK mediated effects on synaptic function remain ambiguous. Here, using mature cortical cultures, we demonstrate bidirectional and differential regulation of network-activity driven SV recycling upon HNK treatment. Using live antibody-uptake studies, we show that short-term HNK treatment leads to an acute weakening of exo-/endocytic cycle dependent presynaptic activity at both excitatory and inhibitory synapses. This is followed by a surprising delayed increase of the same, specifically in excitatory synapses. This exclusive biphasic effect on presynaptic efficacy involve HNK-mediated regulation of TRP and is dependent on the functional presence α7nAchRs, unlike its parent compound Ket. Using immunocytochemistry and quantitative immunoblotting, we have also shown that HNK induces ERK activation and regulates nuclear activity of its downstream target CREB, which are important in HNK mediated regulation of neuronal plasticity. Further, we reveal that HNK and Ket depict similar temporal regulation of activity-dependent genes like Arc and BDNF, which have been deemed of importance in antidepressant research. Additionally, we show modulation of nuclear translocation of transcriptional co-repressor CtBP1, which in some measure might regulate the temporal expression of HNK induced activity-dependent genes. Altogether, this study reveals converging and diverging effects of HNK and Ket on regulation of SV recycling and cellular signaling cascades, which would be important for future mechanistic understanding and comparison of antidepressant effects elicited by these drugs. |
