Calcium-Permeable AMPA Receptors Promote Endocannabinoid Signaling at Parvalbumin Interneuron Synapses in the Nucleus Accumbens Core

Cell Rep. 2020 Jul 28;32(4):107971. doi: 10.1016/j.celrep.2020.107971.


Synaptic plasticity is a key mechanism of learning and memory. Synaptic plasticity mechanisms within the nucleus accumbens (NAc) mediate differential behavioral adaptations. Feedforward inhibition in the NAc occurs when glutamatergic afferents onto medium spiny neurons (MSNs) collateralize onto fast-spiking parvalbumin (PV)-expressing interneurons (PV-INs), which exert GABAergic control over MSN action potential generation. Here, we find that feedforward glutamatergic synapses onto PV-INs in the NAc core selectively express Ca2+-permeable AMPA receptors (CP-AMPARs). Ca2+ influx by CP-AMPARs on PV-INs triggers long-term depression (LTD) mediated by endocannabinoid (eCB) signaling at presynaptic cannabinoid type-1 (CB1) receptors (CB1Rs). Moreover, CP-AMPARs authorize tonic eCB signaling to negatively regulate glutamate release probability. Blockade of CP-AMPARs in the NAc core in vivo is sufficient to disinhibit locomotor output. These findings elucidate mechanisms by which PV-IN-embedded microcircuits in the NAc undergo activity-dependent shifts in synaptic strength.

Keywords: CB(1) receptor; CP-AMPA receptors; endocannabinoids; feedforward inhibition; nucleus accumbens; plasticity.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Action Potentials / physiology
  • Animals
  • Calcium / metabolism
  • Endocannabinoids / metabolism*
  • Endocannabinoids / physiology
  • Glutamic Acid / metabolism
  • Interneurons / metabolism
  • Long-Term Synaptic Depression / physiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neuronal Plasticity / physiology
  • Neurons / metabolism
  • Nucleus Accumbens / metabolism*
  • Parvalbumins
  • Receptors, AMPA / metabolism*
  • Receptors, Calcium-Sensing / metabolism
  • Signal Transduction / physiology
  • Synapses / metabolism
  • Synaptic Transmission / physiology


  • Endocannabinoids
  • Parvalbumins
  • Receptors, AMPA
  • Receptors, Calcium-Sensing
  • Glutamic Acid
  • Calcium