In vivo knockdown of astroglial glutamate transporters GLT-1 and GLAST increases excitatory neurotransmission in mouse infralimbic cortex: Relevance for depressive-like phenotypes

Mª Neus Fullana, Ana Covelo, Analía Bortolozzi, Alfonso Araque, Francesc Artigas

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Alterations of energy metabolism and of astrocyte number/function in ventral anterior cingulate cortex (vACC) have been reported in major depressive disorder (MDD) patients and may contribute to MDD pathophysiology. We recently developed a mouse model of MDD mimicking these alterations. We knocked down the astroglial glutamate transporters GLAST and GLT-1 in infralimbic cortex (IL, rodent equivalent of vACC) using small interfering RNA (siRNA). GLAST and GLT-1 siRNA microinfusion in IL evoked a depressive-like phenotype, associated with a reduced serotonergic function and reduced forebrain BDNF expression. Neither effect occurred after siRNA application in the adjacent prelimbic cortex (PrL), thus emphasizing the critical role of vACC/IL in MDD pathogenesis. Here we examined the cellular/network basis of the changes induced in IL using intracellular recordings of layer V pyramidal neurons from mice microinjected with siRNA 24 h before. We analyzed (i) the electrophysiological characteristics of neurons; (ii) the synaptic transmission properties, by monitoring miniature, spontaneous and evoked EPSCs, and (iii) the gliotransmission, by monitoring slow inward currents (SICs), mediated by astrocytic glutamate release and activation of extra-synaptic NMDA receptors. GLT-1 and GLAST knockdown led to a more depolarized membrane potential and increased action potential firing rate of layer V pyramidal neurons, and enhanced excitatory synaptic transmission, as shown by the enhanced amplitude/frequency of spontaneous EPSCs. Gliotransmission was also increased, as indicated by the enhanced SIC amplitude/frequency. Hence, the depressive-like phenotype is associated with IL hyperactivity, likely leading to an excessive top-down inhibitory control of serotonergic activity through IL-midbrain descending pathways.

Original languageEnglish (US)
Pages (from-to)1288-1294
Number of pages7
JournalEuropean Neuropsychopharmacology
Volume29
Issue number11
DOIs
StatePublished - Nov 2019

Bibliographical note

Funding Information:
This work was supported by the Spanish Ministry of Economy and Competitiveness (Grant numbers SAF2015-68346 to F.A., SAF2016-75797-R to A.B.), co-financed by European Regional Development Fund (ERDF) and NIH-NINDS (R01NS097312-01) and Human Frontier Science Program (Research Grant RGP0036/2014) to AA. The Centro de Investigaci?n Biom?dica en Red de Salud Mental (CIBERSAM) and CERCA Program/Generalitat de Catalunya are also acknowledged. N.F. is a recipient of a fellowship from Spanish Ministry of Education, Culture and Sport. The sponsors had no further role in the design of the review, in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

Funding Information:
This work was supported by the Spanish Ministry of Economy and Competitiveness (Grant numbers SAF2015-68346 to F.A., SAF2016-75797-R to A.B.), co-financed by European Regional Development Fund (ERDF) and NIH-NINDS ( R01NS097312-01 ) and Human Frontier Science Program (Research Grant RGP0036/2014 ) to AA. The Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM) and CERCA Program/Generalitat de Catalunya are also acknowledged. N.F. is a recipient of a fellowship from Spanish Ministry of Education, Culture and Sport. The sponsors had no further role in the design of the review, in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

Publisher Copyright:
© 2019

Keywords

  • Excitatory synapses
  • GLAST
  • GLT-1
  • Infralimbic cortex
  • Layer V pyramidal neurons

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