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Maturation of silent synapses in amygdala-accumbens projection contributes to incubation of cocaine craving.

Lee BR, Ma YY, Huang YH, Wang X, Otaka M, Ishikawa M, Neumann PA, Graziane NM, Brown TE, Suska A, Guo C, Lobo MK, Sesack SR, Wolf ME, Nestler EJ, Shaham Y, Schlüter OM, Dong Y - Nat. Neurosci. (2013)

Bottom Line: However, the circuit-level adaptations mediating this plasticity remain elusive.We studied silent synapses, often regarded as immature synapses that express stable NMDA receptors with AMPA receptors being either absent or labile, in the projection from the basolateral amygdala to the NAc in incubation of cocaine craving.As the withdrawal period progressed, these silent synapses became unsilenced, a process that involved synaptic insertion of calcium-permeable AMPA receptors (CP-AMPARs).

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Molecular Therapeutics, Scripps Research Institute, Jupiter, Florida, USA. [2] Program in Neuroscience, Washington State University, Pullman, Washington, USA. [3].

ABSTRACT
In rat models of drug relapse and craving, cue-induced cocaine seeking progressively increases after withdrawal from the drug. This 'incubation of cocaine craving' is partially mediated by time-dependent adaptations at glutamatergic synapses in nucleus accumbens (NAc). However, the circuit-level adaptations mediating this plasticity remain elusive. We studied silent synapses, often regarded as immature synapses that express stable NMDA receptors with AMPA receptors being either absent or labile, in the projection from the basolateral amygdala to the NAc in incubation of cocaine craving. Silent synapses were detected in this projection during early withdrawal from cocaine. As the withdrawal period progressed, these silent synapses became unsilenced, a process that involved synaptic insertion of calcium-permeable AMPA receptors (CP-AMPARs). In vivo optogenetic stimulation-induced downregulation of CP-AMPARs at amygdala-to-NAc synapses, which re-silenced some of the previously silent synapses after prolonged withdrawal, decreased incubation of cocaine craving. Our findings indicate that silent synapse-based reorganization of the amygdala-to-NAc projection is critical for persistent cocaine craving and relapse after withdrawal.

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Blockade of CP-AMPARs resilences silent synapses in BLA-to-NAc shell projection on withdrawal day 45EPSCs elicited by minimal stimulations (recorded at −70 and +50 mV) from BLA-to-NAc synapses 45 days after withdrawal from cocaine self-administration. A–C. Example (A) and trials (B, C) of EPSCs from a cocaine-experienced rat before and during perfusion of Naspm. (D). Summary showing that blockade of CP-AMPARs on withdrawal day 45 caused a re-emergence of silent synapses in the BLA-to-NAc shell projection, suggesting that a large portion of cocaine-generated silent synapses was unsilenced by recruiting CP-AMPARs. Error bar, s.e.m. * p<0.05.
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Figure 5: Blockade of CP-AMPARs resilences silent synapses in BLA-to-NAc shell projection on withdrawal day 45EPSCs elicited by minimal stimulations (recorded at −70 and +50 mV) from BLA-to-NAc synapses 45 days after withdrawal from cocaine self-administration. A–C. Example (A) and trials (B, C) of EPSCs from a cocaine-experienced rat before and during perfusion of Naspm. (D). Summary showing that blockade of CP-AMPARs on withdrawal day 45 caused a re-emergence of silent synapses in the BLA-to-NAc shell projection, suggesting that a large portion of cocaine-generated silent synapses was unsilenced by recruiting CP-AMPARs. Error bar, s.e.m. * p<0.05.

Mentions: Under our experimental conditions, the time courses for the incubation of cocaine craving, disappearance of silent synapses, and accumulation of CP-AMPARs exhibit parallel changes during the withdrawal period (Fig. 4J), suggesting that disappearance of silent synapses is mediated in part by an un-silencing process involving CP-AMPAR synaptic insertion. If this speculation is correct, selective inhibition of CP-AMPARs after prolonged withdrawal (day 45) should at least partially re-silence those previously silent synapses. Accordingly, we accessed silent synapses within the BLA-to-NAc projection (Fig. S1) on withdrawal day 45. In cocaine-experienced rats, inhibiting CP-AMPARs with Naspm significantly increased the failure rate of minimal stimulation-induced synaptic responses at −70 mV [t(14)=2.72, p=0.01], but not at +50 mV [t(15)=0.29, p=0.78] within the BLA-to-NAc projection (Fig. 5D). In saline-experienced rats, perfusion of Naspm did not affect the failure rate at either −70 [t(8)=1.0, p=0.33] or +50 mV [t(8)=1.7, p=0.13]. Consequently, inhibition of CP-AMPARs with Naspm caused the reemergence of silent synapses in cocaine-experienced rats [t(16)=2.4, p=0.028; Fig. 5E], but not in saline-experienced rats [t(17)=0.14, p=0.89; Fig. S2]. Note that perfusion of Naspm did not fully recover cocaine-generated silent synapses to the level observed on withdrawal day 1, suggesting that other mechanisms are involved in silent synapse maturation (see Discussion). Nonetheless, these results suggest that a significant portion of cocaine-generated silent synapses within the BLA-to-NAc projection are un-silenced after withdrawal from cocaine by recruiting CP-AMPARs.


Maturation of silent synapses in amygdala-accumbens projection contributes to incubation of cocaine craving.

Lee BR, Ma YY, Huang YH, Wang X, Otaka M, Ishikawa M, Neumann PA, Graziane NM, Brown TE, Suska A, Guo C, Lobo MK, Sesack SR, Wolf ME, Nestler EJ, Shaham Y, Schlüter OM, Dong Y - Nat. Neurosci. (2013)

Blockade of CP-AMPARs resilences silent synapses in BLA-to-NAc shell projection on withdrawal day 45EPSCs elicited by minimal stimulations (recorded at −70 and +50 mV) from BLA-to-NAc synapses 45 days after withdrawal from cocaine self-administration. A–C. Example (A) and trials (B, C) of EPSCs from a cocaine-experienced rat before and during perfusion of Naspm. (D). Summary showing that blockade of CP-AMPARs on withdrawal day 45 caused a re-emergence of silent synapses in the BLA-to-NAc shell projection, suggesting that a large portion of cocaine-generated silent synapses was unsilenced by recruiting CP-AMPARs. Error bar, s.e.m. * p<0.05.
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Related In: Results  -  Collection

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Figure 5: Blockade of CP-AMPARs resilences silent synapses in BLA-to-NAc shell projection on withdrawal day 45EPSCs elicited by minimal stimulations (recorded at −70 and +50 mV) from BLA-to-NAc synapses 45 days after withdrawal from cocaine self-administration. A–C. Example (A) and trials (B, C) of EPSCs from a cocaine-experienced rat before and during perfusion of Naspm. (D). Summary showing that blockade of CP-AMPARs on withdrawal day 45 caused a re-emergence of silent synapses in the BLA-to-NAc shell projection, suggesting that a large portion of cocaine-generated silent synapses was unsilenced by recruiting CP-AMPARs. Error bar, s.e.m. * p<0.05.
Mentions: Under our experimental conditions, the time courses for the incubation of cocaine craving, disappearance of silent synapses, and accumulation of CP-AMPARs exhibit parallel changes during the withdrawal period (Fig. 4J), suggesting that disappearance of silent synapses is mediated in part by an un-silencing process involving CP-AMPAR synaptic insertion. If this speculation is correct, selective inhibition of CP-AMPARs after prolonged withdrawal (day 45) should at least partially re-silence those previously silent synapses. Accordingly, we accessed silent synapses within the BLA-to-NAc projection (Fig. S1) on withdrawal day 45. In cocaine-experienced rats, inhibiting CP-AMPARs with Naspm significantly increased the failure rate of minimal stimulation-induced synaptic responses at −70 mV [t(14)=2.72, p=0.01], but not at +50 mV [t(15)=0.29, p=0.78] within the BLA-to-NAc projection (Fig. 5D). In saline-experienced rats, perfusion of Naspm did not affect the failure rate at either −70 [t(8)=1.0, p=0.33] or +50 mV [t(8)=1.7, p=0.13]. Consequently, inhibition of CP-AMPARs with Naspm caused the reemergence of silent synapses in cocaine-experienced rats [t(16)=2.4, p=0.028; Fig. 5E], but not in saline-experienced rats [t(17)=0.14, p=0.89; Fig. S2]. Note that perfusion of Naspm did not fully recover cocaine-generated silent synapses to the level observed on withdrawal day 1, suggesting that other mechanisms are involved in silent synapse maturation (see Discussion). Nonetheless, these results suggest that a significant portion of cocaine-generated silent synapses within the BLA-to-NAc projection are un-silenced after withdrawal from cocaine by recruiting CP-AMPARs.

Bottom Line: However, the circuit-level adaptations mediating this plasticity remain elusive.We studied silent synapses, often regarded as immature synapses that express stable NMDA receptors with AMPA receptors being either absent or labile, in the projection from the basolateral amygdala to the NAc in incubation of cocaine craving.As the withdrawal period progressed, these silent synapses became unsilenced, a process that involved synaptic insertion of calcium-permeable AMPA receptors (CP-AMPARs).

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Molecular Therapeutics, Scripps Research Institute, Jupiter, Florida, USA. [2] Program in Neuroscience, Washington State University, Pullman, Washington, USA. [3].

ABSTRACT
In rat models of drug relapse and craving, cue-induced cocaine seeking progressively increases after withdrawal from the drug. This 'incubation of cocaine craving' is partially mediated by time-dependent adaptations at glutamatergic synapses in nucleus accumbens (NAc). However, the circuit-level adaptations mediating this plasticity remain elusive. We studied silent synapses, often regarded as immature synapses that express stable NMDA receptors with AMPA receptors being either absent or labile, in the projection from the basolateral amygdala to the NAc in incubation of cocaine craving. Silent synapses were detected in this projection during early withdrawal from cocaine. As the withdrawal period progressed, these silent synapses became unsilenced, a process that involved synaptic insertion of calcium-permeable AMPA receptors (CP-AMPARs). In vivo optogenetic stimulation-induced downregulation of CP-AMPARs at amygdala-to-NAc synapses, which re-silenced some of the previously silent synapses after prolonged withdrawal, decreased incubation of cocaine craving. Our findings indicate that silent synapse-based reorganization of the amygdala-to-NAc projection is critical for persistent cocaine craving and relapse after withdrawal.

Show MeSH
Related in: MedlinePlus