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Optogenetic stimulation of medial prefrontal cortex Drd1 neurons produces rapid and long-lasting antidepressant effects.

ABSTRACT: Impaired function in the medial prefrontal cortex (mPFC) contributes to depression, and the therapeutic response produced by novel rapid-acting antidepressants such as ketamine are mediated by mPFC activity. The mPFC contains multiple types of pyramidal cells, but it is unclear whether a particular subtype mediates the rapid antidepressant actions of ketamine. Here we tested two major subtypes, Drd1 and Drd2 dopamine receptor expressing pyramidal neurons and found that activating Drd1 expressing pyramidal cells in the mPFC produces rapid and long-lasting antidepressant and anxiolytic responses. In contrast, photostimulation of Drd2 expressing pyramidal cells was ineffective across anxiety-like and depression-like measures. Disruption of Drd1 activity also blocked the rapid antidepressant effects of ketamine. Finally, we demonstrate that stimulation of mPFC Drd1 terminals in the BLA recapitulates the antidepressant effects of somatic stimulation. These findings aid in understanding the cellular target neurons in the mPFC and the downstream circuitry involved in rapid antidepressant responses.

SUBMITTER: Hare BD

PROVIDER: S-EPMC6333924 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Optogenetic stimulation of medial prefrontal cortex Drd1 neurons produces rapid and long-lasting antidepressant effects.

Hare Brendan D BD Shinohara Ryota R Liu Rong Jian RJ Pothula Santosh S DiLeone Ralph J RJ Duman Ronald S RS

Nature communications 20190115 1

Impaired function in the medial prefrontal cortex (mPFC) contributes to depression, and the therapeutic response produced by novel rapid-acting antidepressants such as ketamine are mediated by mPFC activity. The mPFC contains multiple types of pyramidal cells, but it is unclear whether a particular subtype mediates the rapid antidepressant actions of ketamine. Here we tested two major subtypes, Drd1 and Drd2 dopamine receptor expressing pyramidal neurons and found that activating Drd1 expressing ...[more]

PMID: 30644390

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Project description:Background:We previously reported that serotonergic transmission plays an important role in antidepressant effects of ketamine. However, detailed mechanisms have not been elucidated. Among the serotonin receptor subtypes, the serotonin1A receptor in the medial prefrontal cortex has an important role in depression. Here, we investigated the role of the medial prefrontal cortex serotonin1A receptor and its signaling mechanism in the antidepressant effects of ketamine. Methods:The role of serotonin1A receptor-mediated signaling mechanism (phosphoinositide-3 kinase/Akt) in the medial prefrontal cortex was examined in the mouse forced swimming test and western blotting. Results:Ketamine exerted antidepressant effects that lasted for 24 hours, and the sustained antidepressant effects were attenuated by intra-medial prefrontal cortex injection of a serotonin1A receptor antagonist, WAY100635. The sustained antidepressant effects were mimicked by intra- medial prefrontal cortex, but not systemic, administration of a serotonin1A receptor agonist, (±)-8-hydroxy-2-dipropylaminotetralin hydrobromide (8-OH-DPAT). The sustained antidepressant effects of ketamine and 8-OH-DPAT were abrogated by intra- medial prefrontal cortex injection of a phosphoinositide-3 kinase inhibitor. Ketamine increased the phosphorylation of Akt in the medial prefrontal cortex at 60 minutes after administration, which was blocked by a serotonin1A receptor antagonist and a phosphoinositide-3 kinase inhibitor. Furthermore, the sustained antidepressant effects of ketamine and 8-OH-DPAT were attenuated by pretreatment of intra-medial prefrontal cortex injection of a mechanistic target of rapamycin complex-1 inhibitor. Conclusions:These results indicate that selective stimulation of the medial prefrontal cortex serotonin1A receptor and subsequent activation of the phosphoinositide-3 kinase/Akt/mechanistic target of rapamycin complex-1 pathway may be necessary for ketamine to exert the sustained antidepressant effects, and that this mechanism could be targeted to develop a novel and effective approach for treating depression.

Project description:Rapastinel (GLYX-13) is an N-methyl-d-aspartate receptor (NMDAR) modulator that has characteristics of a glycine site partial agonist. Rapastinel is a robust cognitive enhancer and facilitates hippocampal long-term potentiation (LTP) of synaptic transmission in slices. In human clinical trials, rapastinel has been shown to produce marked antidepressant properties that last for at least one week following a single dose. The long-lasting antidepressant effect of a single dose of rapastinel (3mg/kg IV) was assessed in rats using the Porsolt, open field and ultrasonic vocalization assays. Cognitive enhancement was examined using the Morris water maze, positive emotional learning, and contextual fear extinction tests. LTP was assessed in hippocampal slices. Dendritic spine morphology was measured in the dentate gyrus and the medial prefrontal cortex. Significant antidepressant-like or cognitive enhancing effects were observed that lasted for at least one week in each model. Rapastinel facilitated LTP 1day-2weeks but not 4weeks post-dosing. Biweekly dosing with rapastinel sustained this effect for at least 8weeks. A single dose of rapastinel increased the proportion of whole-cell NMDAR current contributed by NR2B-containing NMDARs in the hippocampus 1week post-dosing, that returned to baseline by 4weeks post-dosing. The NMDAR antagonist 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) blocked the antidepressant-like effect of rapastinel 1week post dosing. A single injection of rapastinel also increased mature spine density in both brain regions 24h post-dosing. These data demonstrate that rapastinel produces its long-lasting antidepressant effects via triggering NMDAR-dependent processes that lead to increased sensitivity to LTP that persist for up to two weeks. These data also suggest that these processes led to the alterations in dendritic spine morphologies associated with the maintenance of long-term changes in synaptic plasticity associated with learning and memory.

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Optogenetic stimulation of medial prefrontal cortex Drd1 neurons produces rapid and long-lasting antidepressant effects.

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Optogenetic stimulation of medial prefrontal cortex Drd1 neurons produces rapid and long-lasting antidepressant effects.

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