Chloride homeostasis, the main determinant factor for the dynamic tuning of GABAergic inhibition during development, has emerged as a key element altered in a wide variety of brain disorders. Accordingly, developmental disorders such as schizophrenia, Autism Spectrum Disorder, Down syndrome, epilepsy, and tuberous sclerosis complex (TSC) have been associated with alterations in the expression of genes codifying for either of the two cotransporters involved in the excitatory-to-inhibitory GABA switch, KCC2 and NKCC1. These alterations can result from environmental insults, including prenatal stress and maternal separation which share, as common molecular denominator, the elevation of pro-inflammatory cytokines. In this review we report and systemize recent research articles indicating that different perinatal environmental perturbations affect the expression of chloride transporters, delaying the developmental switch of GABA signaling, and that inflammatory cytokines, in particular interleukin 1β, may represent a key causal factor for this phenomenon. Based on literature data, we provide therefore a unifying conceptual framework, linking environmental hits with the excitatory-to-inhibitory GABA switch in the context of brain developmental disorders.

Environmental regulation of the chloride transporter KCC2: switching inflammation off to switch the GABA on?

Pozzi, Davide;Rasile, Marco;Matteoli, Michela
2020

Abstract

Chloride homeostasis, the main determinant factor for the dynamic tuning of GABAergic inhibition during development, has emerged as a key element altered in a wide variety of brain disorders. Accordingly, developmental disorders such as schizophrenia, Autism Spectrum Disorder, Down syndrome, epilepsy, and tuberous sclerosis complex (TSC) have been associated with alterations in the expression of genes codifying for either of the two cotransporters involved in the excitatory-to-inhibitory GABA switch, KCC2 and NKCC1. These alterations can result from environmental insults, including prenatal stress and maternal separation which share, as common molecular denominator, the elevation of pro-inflammatory cytokines. In this review we report and systemize recent research articles indicating that different perinatal environmental perturbations affect the expression of chloride transporters, delaying the developmental switch of GABA signaling, and that inflammatory cytokines, in particular interleukin 1β, may represent a key causal factor for this phenomenon. Based on literature data, we provide therefore a unifying conceptual framework, linking environmental hits with the excitatory-to-inhibitory GABA switch in the context of brain developmental disorders.
File in questo prodotto:
File Dimensione Formato  
41398_2020_Article_1027.pdf

non disponibili

Tipologia: Versione Editoriale (PDF)
Licenza: Copyright dell'editore
Dimensione 689.5 kB
Formato Adobe PDF
689.5 kB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11699/54353
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 17
  • ???jsp.display-item.citation.isi??? 15
social impact