Regulation of Neuronal Chloride Homeostasis by Pro- and Mature Brain-Derived Neurotrophic Factor (BDNF) Via KCC2 Cation-Chloride Cotransporters in Rat Cortical Neurons

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2024 Jun 19

PMID 38892438

Authors

Mira Hamze

Cathy Brier

Emmanuelle Buhler

Jinwei Zhang

Igor Medina

Christophe Porcher

Affiliations

Soon will be listed here.

Abstract

The strength of inhibitory neurotransmission depends on intracellular neuronal chloride concentration, primarily regulated by the activity of cation-chloride cotransporters NKCC1 (Sodium-Potassium-Chloride Cotransporter 1) and KCC2 (Potassium-Chloride Cotransporter 2). Brain-derived neurotrophic factor (BDNF) influences the functioning of these co-transporters. BDNF is synthesized from precursor proteins (proBDNF), which undergo proteolytic cleavage to yield mature BDNF (mBDNF). While previous studies have indicated the involvement of BDNF signaling in the activity of KCC2, its specific mechanisms are unclear. We investigated the interplay between both forms of BDNF and chloride homeostasis in rat hippocampal neurons and in utero electroporated cortices of rat pups, spanning the behavioral, cellular, and molecular levels. We found that both pro- and mBDNF play a comparable role in immature neurons by inhibiting the capacity of neurons to extrude chloride. Additionally, proBDNF increases the endocytosis of KCC2 while maintaining a depolarizing shift of E in maturing neurons. Behaviorally, proBDNF-electroporated rat pups in the somatosensory cortex exhibit sensory deficits, delayed huddling, and cliff avoidance. These findings emphasize the role of BDNF signaling in regulating chloride transport through the modulation of KCC2. In summary, this study provides valuable insights into the intricate interplay between BDNF, chloride homeostasis, and inhibitory synaptic transmission, shedding light on the underlying cellular mechanisms involved.

References

Blaesse P, Airaksinen M, Rivera C, Kaila K . Cation-chloride cotransporters and neuronal function. Neuron. 2009; 61(6):820-38. DOI: 10.1016/j.neuron.2009.03.003. View

Ben-Ari Y . NKCC1 Chloride Importer Antagonists Attenuate Many Neurological and Psychiatric Disorders. Trends Neurosci. 2017; 40(9):536-554. DOI: 10.1016/j.tins.2017.07.001. View

Kirmse K, Kummer M, Kovalchuk Y, Witte O, Garaschuk O, Holthoff K . GABA depolarizes immature neurons and inhibits network activity in the neonatal neocortex in vivo. Nat Commun. 2015; 6:7750. DOI: 10.1038/ncomms8750. View

Menshanov P, Lanshakov D, Dygalo N . proBDNF is a major product of bdnf gene expressed in the perinatal rat cortex. Physiol Res. 2015; 64(6):925-34. DOI: 10.33549/physiolres.932996. View

Ernfors P, Lee K, Jaenisch R . Mice lacking brain-derived neurotrophic factor develop with sensory deficits. Nature. 1994; 368(6467):147-50. DOI: 10.1038/368147a0. View

Kourdougli N, Varpula S, Chazal G, Rivera C . Detrimental effect of post Status Epilepticus treatment with ROCK inhibitor Y-27632 in a pilocarpine model of temporal lobe epilepsy. Front Cell Neurosci. 2015; 9:413. PMC: 4615811. DOI: 10.3389/fncel.2015.00413. View

Kourdougli N, Pellegrino C, Renko J, Khirug S, Chazal G, Kukko-Lukjanov T . Depolarizing γ-aminobutyric acid contributes to glutamatergic network rewiring in epilepsy. Ann Neurol. 2017; 81(2):251-265. DOI: 10.1002/ana.24870. View

Eftekhari S, Mehrabi S, Soleimani M, Hassanzadeh G, Shahrokhi A, Mostafavi H . BDNF modifies hippocampal KCC2 and NKCC1 expression in a temporal lobe epilepsy model. Acta Neurobiol Exp (Wars). 2014; 74(3):276-87. DOI: 10.55782/ane-2014-1993. View

Buerli T, Pellegrino C, Baer K, Lardi-Studler B, Chudotvorova I, Fritschy J . Efficient transfection of DNA or shRNA vectors into neurons using magnetofection. Nat Protoc. 2007; 2(12):3090-101. DOI: 10.1038/nprot.2007.445. View

10.

Aguado F, Carmona M, Pozas E, Aguilo A, Martinez-Guijarro F, Alcantara S . BDNF regulates spontaneous correlated activity at early developmental stages by increasing synaptogenesis and expression of the K+/Cl- co-transporter KCC2. Development. 2003; 130(7):1267-80. DOI: 10.1242/dev.00351. View

11.

Ben-Ari Y, Gaiarsa J, Tyzio R, Khazipov R . GABA: a pioneer transmitter that excites immature neurons and generates primitive oscillations. Physiol Rev. 2007; 87(4):1215-84. DOI: 10.1152/physrev.00017.2006. View

12.

Wilson S . Modelling the emergence of rodent filial huddling from physiological huddling. R Soc Open Sci. 2018; 4(11):170885. PMC: 5717655. DOI: 10.1098/rsos.170885. View

13.

Hubner C, Holthoff K . Anion transport and GABA signaling. Front Cell Neurosci. 2013; 7:177. PMC: 3807543. DOI: 10.3389/fncel.2013.00177. View

14.

Miesenbock G, De Angelis D, Rothman J . Visualizing secretion and synaptic transmission with pH-sensitive green fluorescent proteins. Nature. 1998; 394(6689):192-5. DOI: 10.1038/28190. View

15.

Lam P, Newland J, Faull R, Kwakowsky A . Cation-Chloride Cotransporters KCC2 and NKCC1 as Therapeutic Targets in Neurological and Neuropsychiatric Disorders. Molecules. 2023; 28(3). PMC: 9920462. DOI: 10.3390/molecules28031344. View

16.

Keramidis I, McAllister B, Bourbonnais J, Wang F, Isabel D, Rezaei E . Restoring neuronal chloride extrusion reverses cognitive decline linked to Alzheimer's disease mutations. Brain. 2023; 146(12):4903-4915. PMC: 10690023. DOI: 10.1093/brain/awad250. View

17.

Dincheva I, Lynch N, Lee F . The Role of BDNF in the Development of Fear Learning. Depress Anxiety. 2016; 33(10):907-916. PMC: 5089164. DOI: 10.1002/da.22497. View

18.

Inoue K, Furukawa T, Kumada T, Yamada J, Wang T, Inoue R . Taurine inhibits K+-Cl- cotransporter KCC2 to regulate embryonic Cl- homeostasis via with-no-lysine (WNK) protein kinase signaling pathway. J Biol Chem. 2012; 287(25):20839-50. PMC: 3375508. DOI: 10.1074/jbc.M111.319418. View

19.

Friedel P, Kahle K, Zhang J, Hertz N, Pisella L, Buhler E . WNK1-regulated inhibitory phosphorylation of the KCC2 cotransporter maintains the depolarizing action of GABA in immature neurons. Sci Signal. 2015; 8(383):ra65. DOI: 10.1126/scisignal.aaa0354. View

20.

Rivera C, Voipio J, Kaila K . Two developmental switches in GABAergic signalling: the K+-Cl- cotransporter KCC2 and carbonic anhydrase CAVII. J Physiol. 2004; 562(Pt 1):27-36. PMC: 1665491. DOI: 10.1113/jphysiol.2004.077495. View