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Endocannabinoids Mediate Muscarinic Acetylcholine Receptor-Dependent Long-Term Depression in the Adult Medial Prefrontal Cortex.

Martin HG, Bernabeu A, Lassalle O, Bouille C, Beurrier C, Pelissier-Alicot AL, Manzoni OJ - Front Cell Neurosci (2015)

Bottom Line: Cholinergic inputs into the prefrontal cortex (PFC) are associated with attention and cognition; however there is evidence that acetylcholine also has a role in PFC dependent learning and memory.Yet, when endogenous acetylcholine was released from local cholinergic afferents in the PFC using optogenetics, it failed to trigger eCB-LTD.Together these results shed new light on the mechanisms of synaptic plasticity in the adult PFC and expand on the actions of endogenous cholinergic signaling.

View Article: PubMed Central - PubMed

Affiliation: Aix-Marseille Université Marseille, France ; Institut de Neurobiologie de la Méditerranée UMR_S 901 Marseille, France ; INMED UMR_S 901 Marseille, France.

ABSTRACT
Cholinergic inputs into the prefrontal cortex (PFC) are associated with attention and cognition; however there is evidence that acetylcholine also has a role in PFC dependent learning and memory. Muscarinic acetylcholine receptors (mAChR) in the PFC can induce synaptic plasticity, but the underlying mechanisms remain either opaque or unresolved. We have characterized a form of mAChR mediated long-term depression (LTD) at glutamatergic synapses of layer 5 principal neurons in the adult medial PFC. This mAChR LTD is induced with the mAChR agonist carbachol and inhibited by selective M1 mAChR antagonists. In contrast to other cortical regions, we find that this M1 mAChR mediated LTD is coupled to endogenous cannabinoid (eCB) signaling. Inhibition of the principal eCB CB1 receptor blocked carbachol induced LTD in both rats and mice. Furthermore, when challenged with a sub-threshold carbachol application, LTD was induced in slices pretreated with the monoacylglycerol lipase (MAGL) inhibitor JZL184, suggesting that the eCB 2-arachidonylglyerol (2-AG) mediates M1 mAChR LTD. Yet, when endogenous acetylcholine was released from local cholinergic afferents in the PFC using optogenetics, it failed to trigger eCB-LTD. However coupling patterned optical and electrical stimulation to generate local synaptic signaling allowed the reliable induction of LTD. The light-electrical pairing induced LTD was M1 mAChR and CB1 receptor mediated. This shows for the first time that connecting excitatory synaptic activity with coincident endogenously released acetylcholine controls synaptic gain via eCB signaling. Together these results shed new light on the mechanisms of synaptic plasticity in the adult PFC and expand on the actions of endogenous cholinergic signaling.

No MeSH data available.


Related in: MedlinePlus

M1 muscarinic acetlycholine receptor (mAChR) dependent long-term depression (LTD) is CB1 receptor (CB1R) mediated in adult rat mPFC. (A) Time course of normalized field EPSPs during acute carbachol (10 μM, 10 min) stimulation in presence of M1 receptor antagonist VU0255035 (10 μM, n = 5; control, n = 17). (B) Individual experiments from control group (gray), pre (baseline) and post (40 min washout) carbachol treatment and in black group average (**P < 0.01). Below, example traces from baseline (black) and 40 min post (orange) carbachol treatment (scale bar: 5 ms, 0.1 mV). (C) Time course of normalized field EPSPs in presence of CB1R antagonist AM251 (4 μM, n = 8) during carbachol induced LTD. (D) Pre and post carbachol field EPSPs for individual experiments (gray) and group average (green) in presence of AM251; pre and post carbachol example traces below. (E) Time course of normalized field EPSPs during carbachol induced LTD in presence of transient receptor potential vanilloid type 1 (TRPV1) receptor antagonist AMG 9810 (3 μM, n = 9). (F) Summary bar chart of percent LTD 40 min after carbachol washout (*P < 0.05).
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Figure 2: M1 muscarinic acetlycholine receptor (mAChR) dependent long-term depression (LTD) is CB1 receptor (CB1R) mediated in adult rat mPFC. (A) Time course of normalized field EPSPs during acute carbachol (10 μM, 10 min) stimulation in presence of M1 receptor antagonist VU0255035 (10 μM, n = 5; control, n = 17). (B) Individual experiments from control group (gray), pre (baseline) and post (40 min washout) carbachol treatment and in black group average (**P < 0.01). Below, example traces from baseline (black) and 40 min post (orange) carbachol treatment (scale bar: 5 ms, 0.1 mV). (C) Time course of normalized field EPSPs in presence of CB1R antagonist AM251 (4 μM, n = 8) during carbachol induced LTD. (D) Pre and post carbachol field EPSPs for individual experiments (gray) and group average (green) in presence of AM251; pre and post carbachol example traces below. (E) Time course of normalized field EPSPs during carbachol induced LTD in presence of transient receptor potential vanilloid type 1 (TRPV1) receptor antagonist AMG 9810 (3 μM, n = 9). (F) Summary bar chart of percent LTD 40 min after carbachol washout (*P < 0.05).

Mentions: Layer 5 mPFC pyramidal neurons in adult rodents are notable for expressing a prominent eCB mediated LTD in response to direct mGluR5 activation or patterned glutamatergic stimuli (Lafourcade et al., 2007; Jung et al., 2012). This population of neurons also express M1 mAChRs that may couple to the same set of secondary messengers as the mGluR5 (Yamasaki et al., 2010). Given the role of acetylcholine in mPFC mediated tasks throughout life, we asked if M1 mAChR activation might also result in eCB-LTD in the adult rat mPFC. Recording field EPSPs from layer 5 of the mPFC, we first challenged acute brain slices with a brief (10 min, 10 μM) carbachol stimulation to test whether M1 mAChR LTD is expressed in these neurons (Figure 2A). As reported in juvenile rats (Huang and Hsu, 2010; Caruana et al., 2011), carbachol induced a rapid depression of responses that following washout incompletely recovered and stabilized at 76.8 ± 3.3% (n = 17) of the baseline response. Notably, incubating the slices in the highly selective M1 mAChR antagonist VU0255035 had no effect on the acute carbachol induced depression of responses, however after washout of carbachol responses recovered to baseline values (93.9 ± 6.4%, n = 5). We compared individual field EPSPs before and 40 min after carbachol washout in control animals (Figure 2B). Carbachol treatment resulted in a highly significant depression of field EPSP responses (t(16) = 6.60, P < 0.001).


Endocannabinoids Mediate Muscarinic Acetylcholine Receptor-Dependent Long-Term Depression in the Adult Medial Prefrontal Cortex.

Martin HG, Bernabeu A, Lassalle O, Bouille C, Beurrier C, Pelissier-Alicot AL, Manzoni OJ - Front Cell Neurosci (2015)

M1 muscarinic acetlycholine receptor (mAChR) dependent long-term depression (LTD) is CB1 receptor (CB1R) mediated in adult rat mPFC. (A) Time course of normalized field EPSPs during acute carbachol (10 μM, 10 min) stimulation in presence of M1 receptor antagonist VU0255035 (10 μM, n = 5; control, n = 17). (B) Individual experiments from control group (gray), pre (baseline) and post (40 min washout) carbachol treatment and in black group average (**P < 0.01). Below, example traces from baseline (black) and 40 min post (orange) carbachol treatment (scale bar: 5 ms, 0.1 mV). (C) Time course of normalized field EPSPs in presence of CB1R antagonist AM251 (4 μM, n = 8) during carbachol induced LTD. (D) Pre and post carbachol field EPSPs for individual experiments (gray) and group average (green) in presence of AM251; pre and post carbachol example traces below. (E) Time course of normalized field EPSPs during carbachol induced LTD in presence of transient receptor potential vanilloid type 1 (TRPV1) receptor antagonist AMG 9810 (3 μM, n = 9). (F) Summary bar chart of percent LTD 40 min after carbachol washout (*P < 0.05).
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4664641&req=5

Figure 2: M1 muscarinic acetlycholine receptor (mAChR) dependent long-term depression (LTD) is CB1 receptor (CB1R) mediated in adult rat mPFC. (A) Time course of normalized field EPSPs during acute carbachol (10 μM, 10 min) stimulation in presence of M1 receptor antagonist VU0255035 (10 μM, n = 5; control, n = 17). (B) Individual experiments from control group (gray), pre (baseline) and post (40 min washout) carbachol treatment and in black group average (**P < 0.01). Below, example traces from baseline (black) and 40 min post (orange) carbachol treatment (scale bar: 5 ms, 0.1 mV). (C) Time course of normalized field EPSPs in presence of CB1R antagonist AM251 (4 μM, n = 8) during carbachol induced LTD. (D) Pre and post carbachol field EPSPs for individual experiments (gray) and group average (green) in presence of AM251; pre and post carbachol example traces below. (E) Time course of normalized field EPSPs during carbachol induced LTD in presence of transient receptor potential vanilloid type 1 (TRPV1) receptor antagonist AMG 9810 (3 μM, n = 9). (F) Summary bar chart of percent LTD 40 min after carbachol washout (*P < 0.05).
Mentions: Layer 5 mPFC pyramidal neurons in adult rodents are notable for expressing a prominent eCB mediated LTD in response to direct mGluR5 activation or patterned glutamatergic stimuli (Lafourcade et al., 2007; Jung et al., 2012). This population of neurons also express M1 mAChRs that may couple to the same set of secondary messengers as the mGluR5 (Yamasaki et al., 2010). Given the role of acetylcholine in mPFC mediated tasks throughout life, we asked if M1 mAChR activation might also result in eCB-LTD in the adult rat mPFC. Recording field EPSPs from layer 5 of the mPFC, we first challenged acute brain slices with a brief (10 min, 10 μM) carbachol stimulation to test whether M1 mAChR LTD is expressed in these neurons (Figure 2A). As reported in juvenile rats (Huang and Hsu, 2010; Caruana et al., 2011), carbachol induced a rapid depression of responses that following washout incompletely recovered and stabilized at 76.8 ± 3.3% (n = 17) of the baseline response. Notably, incubating the slices in the highly selective M1 mAChR antagonist VU0255035 had no effect on the acute carbachol induced depression of responses, however after washout of carbachol responses recovered to baseline values (93.9 ± 6.4%, n = 5). We compared individual field EPSPs before and 40 min after carbachol washout in control animals (Figure 2B). Carbachol treatment resulted in a highly significant depression of field EPSP responses (t(16) = 6.60, P < 0.001).

Bottom Line: Cholinergic inputs into the prefrontal cortex (PFC) are associated with attention and cognition; however there is evidence that acetylcholine also has a role in PFC dependent learning and memory.Yet, when endogenous acetylcholine was released from local cholinergic afferents in the PFC using optogenetics, it failed to trigger eCB-LTD.Together these results shed new light on the mechanisms of synaptic plasticity in the adult PFC and expand on the actions of endogenous cholinergic signaling.

View Article: PubMed Central - PubMed

Affiliation: Aix-Marseille Université Marseille, France ; Institut de Neurobiologie de la Méditerranée UMR_S 901 Marseille, France ; INMED UMR_S 901 Marseille, France.

ABSTRACT
Cholinergic inputs into the prefrontal cortex (PFC) are associated with attention and cognition; however there is evidence that acetylcholine also has a role in PFC dependent learning and memory. Muscarinic acetylcholine receptors (mAChR) in the PFC can induce synaptic plasticity, but the underlying mechanisms remain either opaque or unresolved. We have characterized a form of mAChR mediated long-term depression (LTD) at glutamatergic synapses of layer 5 principal neurons in the adult medial PFC. This mAChR LTD is induced with the mAChR agonist carbachol and inhibited by selective M1 mAChR antagonists. In contrast to other cortical regions, we find that this M1 mAChR mediated LTD is coupled to endogenous cannabinoid (eCB) signaling. Inhibition of the principal eCB CB1 receptor blocked carbachol induced LTD in both rats and mice. Furthermore, when challenged with a sub-threshold carbachol application, LTD was induced in slices pretreated with the monoacylglycerol lipase (MAGL) inhibitor JZL184, suggesting that the eCB 2-arachidonylglyerol (2-AG) mediates M1 mAChR LTD. Yet, when endogenous acetylcholine was released from local cholinergic afferents in the PFC using optogenetics, it failed to trigger eCB-LTD. However coupling patterned optical and electrical stimulation to generate local synaptic signaling allowed the reliable induction of LTD. The light-electrical pairing induced LTD was M1 mAChR and CB1 receptor mediated. This shows for the first time that connecting excitatory synaptic activity with coincident endogenously released acetylcholine controls synaptic gain via eCB signaling. Together these results shed new light on the mechanisms of synaptic plasticity in the adult PFC and expand on the actions of endogenous cholinergic signaling.

No MeSH data available.


Related in: MedlinePlus