Major depressive disorder (MDD) is a difficult to treat condition of epidemic proportions all over the world. In preclinical models, the depressive-like phenotype induced by chronic stress exposure is partly mediated by a down-regulation of dopamine (DA) transmission, likely to affect synaptic plasticity in the medial prefrontal cortex (mPFC) and related limbic circuits. Recently, the potential efficacy of ketamine as a fast-acting antidepressant has been reported, but we still lack sufficient knowledge about its mechanism of action. Here, male Sprague-Dawley rats were subjected to a chronic mild stress (CMS) protocol lasting 3-5 weeks, inducing anhedonia in a subset of ‘vulnerable’ rats, contrary to resilient ones, tested using a sucrose preference test (SPT; CMS-R vs CMS-V, p<10-3). We obtained electrophysiological recordings of DA-dependent long-term potentiation (DA-LTP) and depression (DA-LTD) on acute slices of the mPFC from control, CMS-R and CMS-V rats. DA-LTP was reliably induced in control and CMS-R rats while this was strongly occluded in vulnerable rats (CMS-R vs CMS-V: p < 0.01). On the contrary, DA-LTD induction was unaffected by CMS. Later, we tested the effects of sub-anesthetic ketamine (10 mg/kg) showing that this treatment seems to prevent DA-LTP occlusion (CMS-R w/KET vs CMS-V w/KET: n.s.). We then tested changes in the synaptic drive of two major pathways connecting mPFC to the basolateral amygdala (BLA), thought to mediate top-down control of emotion regulation. To this aim, we applied our recently developed approach SynaptoZip (SZ). Our analysis indicates that CMS increases prelimbic (PL) while reduces infralimbic (IL) to BLA synaptic drive, so that the overall PL/IL ratio is augmented. Interestingly, rats treated with ketamine (10 mg/kg) for 90 minutes display a rescue of the physiological PL/IL balance in our experiments. Financial support provided by the NARSAD YIG 2017 (ID: 26414; PI: J.L.).
CHRONIC MILD STRESS OCCLUDES DOPAMINE-DEPENDENT SYNAPTIC PLASTICITY IN THE MEDIAL PFC AND ALTERS PFC TO BASOLATERAL AMYGDALA SYNAPTIC DRIVE
Mattia Ferro;Sara Spadini;Antonio Malgaroli
2021-01-01
Abstract
Major depressive disorder (MDD) is a difficult to treat condition of epidemic proportions all over the world. In preclinical models, the depressive-like phenotype induced by chronic stress exposure is partly mediated by a down-regulation of dopamine (DA) transmission, likely to affect synaptic plasticity in the medial prefrontal cortex (mPFC) and related limbic circuits. Recently, the potential efficacy of ketamine as a fast-acting antidepressant has been reported, but we still lack sufficient knowledge about its mechanism of action. Here, male Sprague-Dawley rats were subjected to a chronic mild stress (CMS) protocol lasting 3-5 weeks, inducing anhedonia in a subset of ‘vulnerable’ rats, contrary to resilient ones, tested using a sucrose preference test (SPT; CMS-R vs CMS-V, p<10-3). We obtained electrophysiological recordings of DA-dependent long-term potentiation (DA-LTP) and depression (DA-LTD) on acute slices of the mPFC from control, CMS-R and CMS-V rats. DA-LTP was reliably induced in control and CMS-R rats while this was strongly occluded in vulnerable rats (CMS-R vs CMS-V: p < 0.01). On the contrary, DA-LTD induction was unaffected by CMS. Later, we tested the effects of sub-anesthetic ketamine (10 mg/kg) showing that this treatment seems to prevent DA-LTP occlusion (CMS-R w/KET vs CMS-V w/KET: n.s.). We then tested changes in the synaptic drive of two major pathways connecting mPFC to the basolateral amygdala (BLA), thought to mediate top-down control of emotion regulation. To this aim, we applied our recently developed approach SynaptoZip (SZ). Our analysis indicates that CMS increases prelimbic (PL) while reduces infralimbic (IL) to BLA synaptic drive, so that the overall PL/IL ratio is augmented. Interestingly, rats treated with ketamine (10 mg/kg) for 90 minutes display a rescue of the physiological PL/IL balance in our experiments. Financial support provided by the NARSAD YIG 2017 (ID: 26414; PI: J.L.).I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
