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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

Cholinergic terminals expressing ChR2-EYFP richly innervate the mPFC in ChR2:ACh mice. (A) Fluorescent image of a projected confocal z-stack 20 μm thick from the prelimbic cortex of the ChR2:ACh mouse. Approximate cortical layer boundaries are indicated to the right. Insert: similar image from a control C57Bl/6J mouse mPFC section acquired with identical settings. (B) Example of a presumed bipolar local cholinergic interneuron in mPFC from ChR2:ACh mouse. Image represents projected confocal image of YFP signal from prelimbic cortex coronal section. Approximate layer boundaries are indicated to the left. Orientation markers: D, dorsal; V, ventral; M, medial; L, lateral; scale bar: 30 μm.
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Figure 1: Cholinergic terminals expressing ChR2-EYFP richly innervate the mPFC in ChR2:ACh mice. (A) Fluorescent image of a projected confocal z-stack 20 μm thick from the prelimbic cortex of the ChR2:ACh mouse. Approximate cortical layer boundaries are indicated to the right. Insert: similar image from a control C57Bl/6J mouse mPFC section acquired with identical settings. (B) Example of a presumed bipolar local cholinergic interneuron in mPFC from ChR2:ACh mouse. Image represents projected confocal image of YFP signal from prelimbic cortex coronal section. Approximate layer boundaries are indicated to the left. Orientation markers: D, dorsal; V, ventral; M, medial; L, lateral; scale bar: 30 μm.

Mentions: Medial PFC expression of channelrhodopsin 2 in ChR2:ACh mice was confirmed by confocal microscopy. Direct fluorescent microscopy of the ChR2(H134R)-EYFP fusion protein showed that cholinergic afferents richly innervate the mPFC with corresponding channelrhodpsin expression in all cortical layers (Figure 1A). Furthermore we were able to identify a sparse population of bipolar cells that expressed channelrhodpsin locally (Figure 1B). These cells situated in layer 5 project neurites perpendicular to the cortical layer boundaries into both superficial and deep layers. We hypothesize these are previously reported cholinergic interneurons (Houser et al., 1985; Van der Zee and Keijser, 2011).


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)

Cholinergic terminals expressing ChR2-EYFP richly innervate the mPFC in ChR2:ACh mice. (A) Fluorescent image of a projected confocal z-stack 20 μm thick from the prelimbic cortex of the ChR2:ACh mouse. Approximate cortical layer boundaries are indicated to the right. Insert: similar image from a control C57Bl/6J mouse mPFC section acquired with identical settings. (B) Example of a presumed bipolar local cholinergic interneuron in mPFC from ChR2:ACh mouse. Image represents projected confocal image of YFP signal from prelimbic cortex coronal section. Approximate layer boundaries are indicated to the left. Orientation markers: D, dorsal; V, ventral; M, medial; L, lateral; scale bar: 30 μm.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 1: Cholinergic terminals expressing ChR2-EYFP richly innervate the mPFC in ChR2:ACh mice. (A) Fluorescent image of a projected confocal z-stack 20 μm thick from the prelimbic cortex of the ChR2:ACh mouse. Approximate cortical layer boundaries are indicated to the right. Insert: similar image from a control C57Bl/6J mouse mPFC section acquired with identical settings. (B) Example of a presumed bipolar local cholinergic interneuron in mPFC from ChR2:ACh mouse. Image represents projected confocal image of YFP signal from prelimbic cortex coronal section. Approximate layer boundaries are indicated to the left. Orientation markers: D, dorsal; V, ventral; M, medial; L, lateral; scale bar: 30 μm.
Mentions: Medial PFC expression of channelrhodopsin 2 in ChR2:ACh mice was confirmed by confocal microscopy. Direct fluorescent microscopy of the ChR2(H134R)-EYFP fusion protein showed that cholinergic afferents richly innervate the mPFC with corresponding channelrhodpsin expression in all cortical layers (Figure 1A). Furthermore we were able to identify a sparse population of bipolar cells that expressed channelrhodpsin locally (Figure 1B). These cells situated in layer 5 project neurites perpendicular to the cortical layer boundaries into both superficial and deep layers. We hypothesize these are previously reported cholinergic interneurons (Houser et al., 1985; Van der Zee and Keijser, 2011).

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