Targeting the Cation-Chloride Co-Transporter NKCC1 to Re-Establish GABAergic Inhibition and an Appropriate Excitatory/Inhibitory Balance in Selective Neuronal Circuits: A Novel Approach for the Treatment of Alzheimer's Disease

Simona Capsoni; Ivan Arisi; Francesca Malerba; Mara D'Onofrio; Antonino Cattaneo; Enrico Cherubini

doi:10.3390/brainsci12060783

Targeting the Cation-Chloride Co-Transporter NKCC1 to Re-Establish GABAergic Inhibition and an Appropriate Excitatory/Inhibitory Balance in Selective Neuronal Circuits: A Novel Approach for the Treatment of Alzheimer's Disease

Brain Sci. 2022 Jun 15;12(6):783. doi: 10.3390/brainsci12060783.

Authors

Simona Capsoni^{1

2}, Ivan Arisi³, Francesca Malerba³, Mara D'Onofrio³, Antonino Cattaneo^{1

3}, Enrico Cherubini³

Affiliations

¹ Bio@SNS Laboratory of Biology, Scuola Normale Superiore, 56126 Pisa, Italy.
² Section of Physiology, Department of Neuroscience and Rehabilitation, University of Ferrara, 44121 Ferrara, Italy.
³ Fondazione European Brain Research Institute (EBRI) Rita Levi-Montalcini, 00161 Rome, Italy.

Abstract

GABA, the main inhibitory neurotransmitter in the adult brain, depolarizes and excites immature neurons because of an initially higher intracellular chloride concentration [Cl^-]i due to the delayed expression of the chloride exporter KCC2 at birth. Depolarization-induced calcium rise via NMDA receptors and voltage-dependent calcium channels is instrumental in shaping neuronal circuits and in controlling the excitatory (E)/inhibitory (I) balance in selective brain areas. An E/I imbalance accounts for cognitive impairment observed in several neuropsychiatric disorders. The aim of this review is to summarize recent data on the mechanisms by which alterations of GABAergic signaling alter the E/I balance in cortical and hippocampal neurons in Alzheimer's disease (AD) and the role of cation-chloride co-transporters in this process. In particular, we discuss the NGF and AD relationship and how mice engineered to express recombinant neutralizing anti-NGF antibodies (AD11 mice), which develop a neurodegenerative pathology reminiscent of that observed in AD patients, exhibit a depolarizing action of GABA due to KCC2 impairment. Treating AD and other forms of dementia with bumetanide, a selective KCC2 antagonist, contributes to re-establishing a proper E/I balance in selective brain areas, leading to amelioration of AD symptoms and the slowing down of disease progression.

Keywords: AD11 transgenic mice; Alzheimer’s disease; KCC2 dysfunction; NGF; bumetanide treatment; cation-chloride co-transporters; depolarizing GABAA-mediated neurotransmission.

Publication types

Review

Grants and funding

This research was funded by the Telethon grant (GGP 16083) to EC; by Fondo Ordinario Enti (FOE D.M 865/2019) in the framework of a collaboration agreement between the Italian National Research Council and EBRI; by the European Commission (MADIA no. 732678); by Regione Lazio, Italy, POR (Operative Program Lazio Region, Italy) FESR (European Program Regional Development) 2014–2020, Public Notice “LIFE 2020”, MODIAG Project.