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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 mAChR dependent LTD is expressed in the presynapse and is mediated by the endogenous cannabinoid (eCB) 2-AG. (A) Time course of normalized EPSC in response to carbachol (10 μM, 10 min) from layer 5 principal neurons (y-axis: left; clear data points), co-plotted with paired-pulse ratio (PPR; 50 ms interval) at indicated time points (y-axis: right; filled data points). (B) Plot of PPR from individual neurons (gray), before (baseline) and 20 min after (LTD) carbachol challenge; group averages superimposed (filled data points, n = 7, *P < 0.05). Example traces taken at the indicated time points (A) during baseline (†) and after LTD (#) shown above (scale bar: 20 ms, 50 pA). (C) Time—response plot of percent LTD resulting from 10 μM carbachol challenge for varying time periods. (D) Time course of normalized field EPSPs during sub-threshold carbachol challenge (10 μM, 5 min) in presence of MAG lipase inhibitor JZL184 (1 μM, n = 4; control, n = 6). Insert: fEPSPs expressed as percent LTD 40 min after challenge. (E) Before-after responses from individual experiments (gray) of baseline (Pre) and 40 min after sub-threshold carbachol challenge (Post) in presence of JZL184; in yellow group average. Example traces below, pre carbachol (black) and post (orange; scale bar: 10 ms, 0.1 mV).
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Figure 3: M1 mAChR dependent LTD is expressed in the presynapse and is mediated by the endogenous cannabinoid (eCB) 2-AG. (A) Time course of normalized EPSC in response to carbachol (10 μM, 10 min) from layer 5 principal neurons (y-axis: left; clear data points), co-plotted with paired-pulse ratio (PPR; 50 ms interval) at indicated time points (y-axis: right; filled data points). (B) Plot of PPR from individual neurons (gray), before (baseline) and 20 min after (LTD) carbachol challenge; group averages superimposed (filled data points, n = 7, *P < 0.05). Example traces taken at the indicated time points (A) during baseline (†) and after LTD (#) shown above (scale bar: 20 ms, 50 pA). (C) Time—response plot of percent LTD resulting from 10 μM carbachol challenge for varying time periods. (D) Time course of normalized field EPSPs during sub-threshold carbachol challenge (10 μM, 5 min) in presence of MAG lipase inhibitor JZL184 (1 μM, n = 4; control, n = 6). Insert: fEPSPs expressed as percent LTD 40 min after challenge. (E) Before-after responses from individual experiments (gray) of baseline (Pre) and 40 min after sub-threshold carbachol challenge (Post) in presence of JZL184; in yellow group average. Example traces below, pre carbachol (black) and post (orange; scale bar: 10 ms, 0.1 mV).

Mentions: If M1 mAChR LTD follows the classic model of CB1R mediated LTD it is expected that the resultant synaptic depression will have a presynaptic loci. To test this prediction we recorded the PPR from patched neurons during the induction of M1 mAChR LTD; any change in this measure would suggest the LTD involves a presynaptic component. Similar to field EPSP recordings, we found that patch-clamped neurons also undergo a robust LTD in response to carbachol challenge (10 min, 10 μM) resulting in a sustained depression in EPSC (67.2 ± 4.8% of baseline, n = 7; Figure 3A). Initial responses from these neurons showed a weak paired-pulse facilitation in response to closely spaced EPSCs (1.66 ± 0.09, n = 9). However carbachol induced LTD resulted in sharp increase in the PPR that persisted and was concomitant to M1 mAChR LTD (Figure 3A). Comparing the PPR from individual neurons before and after M1 mAChR LTD, we found a significant increase in the PPR (Figure 3B; t(6) = 2.519, P = 0.045). Such an increase in paired-pulse facilitation is consistent with a reduction in neurotransmitter release probability and the expression of M1 mAChR LTD in the presynapse.


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 mAChR dependent LTD is expressed in the presynapse and is mediated by the endogenous cannabinoid (eCB) 2-AG. (A) Time course of normalized EPSC in response to carbachol (10 μM, 10 min) from layer 5 principal neurons (y-axis: left; clear data points), co-plotted with paired-pulse ratio (PPR; 50 ms interval) at indicated time points (y-axis: right; filled data points). (B) Plot of PPR from individual neurons (gray), before (baseline) and 20 min after (LTD) carbachol challenge; group averages superimposed (filled data points, n = 7, *P < 0.05). Example traces taken at the indicated time points (A) during baseline (†) and after LTD (#) shown above (scale bar: 20 ms, 50 pA). (C) Time—response plot of percent LTD resulting from 10 μM carbachol challenge for varying time periods. (D) Time course of normalized field EPSPs during sub-threshold carbachol challenge (10 μM, 5 min) in presence of MAG lipase inhibitor JZL184 (1 μM, n = 4; control, n = 6). Insert: fEPSPs expressed as percent LTD 40 min after challenge. (E) Before-after responses from individual experiments (gray) of baseline (Pre) and 40 min after sub-threshold carbachol challenge (Post) in presence of JZL184; in yellow group average. Example traces below, pre carbachol (black) and post (orange; scale bar: 10 ms, 0.1 mV).
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Figure 3: M1 mAChR dependent LTD is expressed in the presynapse and is mediated by the endogenous cannabinoid (eCB) 2-AG. (A) Time course of normalized EPSC in response to carbachol (10 μM, 10 min) from layer 5 principal neurons (y-axis: left; clear data points), co-plotted with paired-pulse ratio (PPR; 50 ms interval) at indicated time points (y-axis: right; filled data points). (B) Plot of PPR from individual neurons (gray), before (baseline) and 20 min after (LTD) carbachol challenge; group averages superimposed (filled data points, n = 7, *P < 0.05). Example traces taken at the indicated time points (A) during baseline (†) and after LTD (#) shown above (scale bar: 20 ms, 50 pA). (C) Time—response plot of percent LTD resulting from 10 μM carbachol challenge for varying time periods. (D) Time course of normalized field EPSPs during sub-threshold carbachol challenge (10 μM, 5 min) in presence of MAG lipase inhibitor JZL184 (1 μM, n = 4; control, n = 6). Insert: fEPSPs expressed as percent LTD 40 min after challenge. (E) Before-after responses from individual experiments (gray) of baseline (Pre) and 40 min after sub-threshold carbachol challenge (Post) in presence of JZL184; in yellow group average. Example traces below, pre carbachol (black) and post (orange; scale bar: 10 ms, 0.1 mV).
Mentions: If M1 mAChR LTD follows the classic model of CB1R mediated LTD it is expected that the resultant synaptic depression will have a presynaptic loci. To test this prediction we recorded the PPR from patched neurons during the induction of M1 mAChR LTD; any change in this measure would suggest the LTD involves a presynaptic component. Similar to field EPSP recordings, we found that patch-clamped neurons also undergo a robust LTD in response to carbachol challenge (10 min, 10 μM) resulting in a sustained depression in EPSC (67.2 ± 4.8% of baseline, n = 7; Figure 3A). Initial responses from these neurons showed a weak paired-pulse facilitation in response to closely spaced EPSCs (1.66 ± 0.09, n = 9). However carbachol induced LTD resulted in sharp increase in the PPR that persisted and was concomitant to M1 mAChR LTD (Figure 3A). Comparing the PPR from individual neurons before and after M1 mAChR LTD, we found a significant increase in the PPR (Figure 3B; t(6) = 2.519, P = 0.045). Such an increase in paired-pulse facilitation is consistent with a reduction in neurotransmitter release probability and the expression of M1 mAChR LTD in the presynapse.

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