Elsevier

Neuroscience

Volume 418, 15 October 2019, Pages 149-156
Neuroscience

Research Article
Nitric Oxide-Dependent LTD at Infralimbic Cortex

https://doi.org/10.1016/j.neuroscience.2019.08.029Get rights and content

Highlights

  • Activity dependent nitric oxide release induces presynaptic LTD of the excitatory synaptic transmission in infralimbic cortex.

  • The LTD is dependent on calcium spikes mediated by the activation of NMDARs and L-type VGCCs.

  • An LTD may be involved in fear-conditioned memories.

Abstract

Dendritic calcium (Ca2+) spikes play a key role in the genesis of long-term synaptic plasticity. Although synaptic plasticity in the infralimbic cortex is critical for the extinction of fear-conditioned memory, the role of Ca2+-spikes in the induction of synaptic plasticity at this cortex has not been explored in depth. Here we show that Ca2+-spikes in layer 5 pyramidal neurons (L5 PNs) of the rat infralimbic cortex are crucial in the induction of long-term depression of the excitatory postsynaptic currents (EPSCs). The lack of effect on the postsynaptic currents evoked by puffing glutamate and the changes in the variance of the EPSC amplitude that paralleled its inhibition suggest that this LTD of the EPSCs is mediated presynaptically. However, its induction requires cytosolic calcium elevations because it is prevented when the recorded L5 PN is loaded with BAPTA. Moreover, it depends on the synthesis of nitric oxide (NO) because it is absent on slices incubated with nitric oxidase synthase inhibitor L-NAME. Therefore, Ca2+-spikes can trigger LTD of the ESPCs through the NO dependent presynaptic form of synaptic plasticity, thus providing a novel form of inducing synaptic plasticity at L5 PNs of the rat infralimbic cortex.

Section snippets

INTRODUCTION

The infralimbic cortex (IL) is a portion of ventromedial prefrontal cortex (mPFC) that receives projection from the basolateral complex of the amygdala and play an essential role in the extinction of fear-conditioning responses (Little and Carter, 2012, Little and Carter, 2013, Do-Monte et al., 2015). The amygdala projects to layer 2/3 of IL (Little and Carter, 2012, Little and Carter, 2013) and most subcortical projection pathways originated predominantly from layer 5 of the IL (Gabbott et

Ethics statement

All animal procedures were approved by the Ethical Committee of the Universidad Autónoma de Madrid (CEI72–1286-A156) and in accordance with European Community Council Directive 2010/63/UE. All effort was made to minimize animal suffering and to promote the animal welfare.

Slice preparation

Sprague–Dawley rats (12–18 days old) were decapitated, and brains were removed and submerged in cold (4 °C) cutting solution containing (in mM): 189.0 sucrose, 10.0 glucose, 26.0 NaHCO3, 3.0 KCl, 5.0 Mg2SO4, 0.1 CaCl2, and 1.25

The Ca2+-spikes induce LTD of the postsynaptic currents

Recordings were obtained from the soma of L5 PNs of the IL (Fig. 1A). In control ACSF, basal stimulation induced an PSP followed by a single AP when the depolarization reached a threshold level. Indeed, The AP rode on a slow depolarization wave (peak amplitude 24.91 ± 2.28 mV; duration 176.24 ± 14.23 ms; Fig. 1C) that exhibit the all-or-none behavior of a calcium spike (Ca2+-spike) because it was not modified when stimulation intensity was increased. Indeed, the Ca2+-spike was absent in the

DISCUSSION

In this work we show a LTD of excitatory synaptic transmission induced by low frequency stimulation at basal dendrites of L5 PNs in IL. We demonstrate that this stimulation generates an PSP followed by an AP and a Ca2+-spike. The PSP followed by the Ca2+-spikes produce the necessary calcium influx through the NMDARs and L-type VGCCs for the induction of the LTD of the EPSCs. We show that this LTD is mediated by a decrease in the probability of release of glutamate and requires the activation of

Acknowledgements

This work was supported by grants from Ministerio de Ciencia e innovación, Spain (MICINN; BFU2011-23522) and Ministerio de Economía y Competitividad, Spain (MINECO; BFU2013-43668-P and BFU2016-80802-P AEI/FEDER, UE) to Dr. D. Fernández de Sevilla, professor at the Departamento de Anatomía, Histología y Neurociencia, Facultad de Medicina, Universidad Autónoma de Madrid.

References (23)

  • J.E. Brenman et al.

    Synaptic signaling by nitric oxide

    Curr Opin Neurobiol

    (1997)
  • H. Luo et al.

    Effect of nitric oxide synthase inhibitor l-NAME on fear extinction in rats: a task-dependent effect

    Neurosci Lett

    (2014)
  • Y. Andrade-Talavera et al.

    Presynaptic spike timing-dependent long-term depression in the mouse Hippocampus

    Cereb Cortex

    (2016)
  • J.D. Baker et al.

    The NMDA antagonist MK-801 blocks the extinction of Pavlovian fear conditioning

    Behav Neurosci

    (1996)
  • C.K. Cain et al.

    L-type voltage-gated calcium channels are required for extinction, but not for acquisition or expression, of conditional fear in mice

    J Neurosci

    (2002)
  • J. Dachtler et al.

    Experience-dependent plasticity acts via GluR1 and a novel neuronal nitric oxide synthase-dependent synaptic mechanism in adult cortex

    J Neurosci

    (2011)
  • A. Díez-García

    Corrigendum: bidirectional Hebbian plasticity induced by low-frequency stimulation in basal dendrites of rat barrel cortex layer 5 pyramidal neurons

    Front Cell Neurosci

    (2017)
  • F.H. Do-Monte et al.

    Revisiting the role of Infralimbic cortex in fear extinction with optogenetics

    J Neurosci

    (2015)
  • D.F. Fernandez de Sevilla et al.

    Selective muscarinic regulation of functional glutamatergic Schaffer collateral synapses in rat CA1 pyramidal neurons

    J Physiol

    (2002)
  • P.L.A. Gabbott et al.

    Prefrontal cortex in the rat: projections to subcortical autonomic, motor, and limbic centers

    J Comp Neurol

    (2005)
  • M.R. Gilmartin et al.

    Trace and contextual fear conditioning require neural activity and NMDA receptor-dependent transmission in the medial prefrontal cortex

    Learning and Memory

    (2010)
  • View full text