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

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Publicated to:European Neuropsychopharmacology. 29 (11): 1288-1294 - 2019-11-01 29(11), DOI: 10.1016/j.euroneuro.2019.09.004

Authors: Neus Fullana, Ma; Covelo, Ana; Bortolozzi, Analia; Araque, Alfonso; Artigas, Francesc

Affiliations

Centro de Investigacion Biomedica en Red de Salud Mental - Author

Consejo Superior de Investigaciones Científicas - Author

CSIC, Inst Invest Biomed Barcelona, Dept Neurochem & Neuropharmacol, Barcelona, Spain - Author

Inst Invest Biomed August Pi & Sunyer IDIBAPS, Syst Neuropharmacol Grp, Barcelona, Spain - Author

Inst Salud Carlos III, Ctr Invest Biomed Red Salud Mental, Madrid, Spain - Author

Institut d'Investigacions Biomèdiques August Pi i Sunyer - IDIBAPS - Author

Neuroctr Magendie, Team Marsicano Endocannabinoids & Neuroadaptat, Bordeaux, France - Author

Univ Minnesota, Dept Neurosci, Minneapolis, MN USA - Author

University of Minnesota Twin Cities - Author

Abstract

© 2019 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.

Keywords

braincurrentsexcitatory synapsesglastglt-1infralimbic cortexinvolvementlayer v pyramidal neuronsmodulationpathologyratAnimalsAstrocytesBdnf protein, mouseBrainBrain-derived neurotrophic factorCurrentsDepressive disorder, majorExcitatory amino acid transporter 1Excitatory amino acid transporter 2Excitatory postsynaptic potentialsExcitatory synapsesGene knockdown techniquesGlastGlt-1Gyrus cinguliInfralimbic cortexInvolvementLayer v pyramidal neuronsLimbic lobeMiceMicroinjectionsModulationPathologyPrefrontal cortexProsencephalonPyramidal cellsRatRna, small interferingSlc1a3 protein, mouseSynaptic transmission

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Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal European Neuropsychopharmacology due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2019, it was in position 67/271, thus managing to position itself as a Q1 (Primer Cuartil), in the category Psychiatry.

From a relative perspective, and based on the normalized impact indicator calculated from World Citations provided by WoS (ESI, Clarivate), it yields a value for the citation normalization relative to the expected citation rate of: 1.38. This indicates that, compared to works in the same discipline and in the same year of publication, it ranks as a work cited above average. (source consulted: ESI Nov 14, 2024)

This information is reinforced by other indicators of the same type, which, although dynamic over time and dependent on the set of average global citations at the time of their calculation, consistently position the work at some point among the top 50% most cited in its field:

Weighted Average of Normalized Impact by the Scopus agency: 1.44 (source consulted: FECYT Feb 2024)
Field Citation Ratio (FCR) from Dimensions: 8.49 (source consulted: Dimensions May 2025)

Specifically, and according to different indexing agencies, this work has accumulated citations as of 2025-05-11, the following number of citations:

WoS: 29
Scopus: 32
Europe PMC: 9
Google Scholar: 26

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Leadership analysis of institutional authors

This work has been carried out with international collaboration, specifically with researchers from: France; United States of America.

There is a significant leadership presence as some of the institution’s authors appear as the first or last signer, detailed as follows: First Author (Fullana Rivas, Miquel Àngel) and Last Author (Artigas Perez, Francesc).

the author responsible for correspondence tasks has been Artigas Perez, Francesc.

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