Amyloid-Beta -Induced Increase in GABAergic Tonic Conductance in Mouse Hippocampal CA1 Pyramidal Cells

Overview

Journal Molecules

Publisher MDPI

Specialty Biology

Date 2020 Feb 12

PMID 32041202

Citations 9

Authors

Beatriz Calvo-Flores Guzman

Soohyun Kim

Bhavya Chawdhary

Katie Peppercorn

Warren P Tate

Henry J Waldvogel

Richard Lm Faull

Johanna Montgomery

Andrea Kwakowsky

Affiliations

Soon will be listed here.

Abstract

Alzheimer's disease (AD) is a complex and chronic neurodegenerative disorder that involves a progressive and severe decline in cognition and memory. During the last few decades a considerable amount of research has been done in order to better understand tau-pathology, inflammatory activity and neuronal synapse loss in AD, all of them contributing to cognitive decline. Early hippocampal network dysfunction is one of the main factors associated with cognitive decline in AD. Much has been published about amyloid-beta (Aβ)-mediated excitotoxicity in AD. However, increasing evidence demonstrates that the remodeling of the inhibitory gamma-aminobutyric acid (GABAergic) system contributes to the excitatory/inhibitory (E/I) disruption in the AD hippocampus, but the underlying mechanisms are not well understood. In the present study, we show that hippocampal injection of Aβ is sufficient to induce cognitive deficits 7 days post-injection. We demonstrate using whole-cell patch-clamping an increased inhibitory GABAergic tonic conductance mediated by extrasynaptic type A GABA receptors (GABARs), recorded in the CA1 region of the mouse hippocampus following Aβ micro injection. Such alterations in GABA neurotransmission and/or inhibitory GABARs could have a significant impact on both hippocampal structure and function, causing E/I balance disruption and potentially contributing to cognitive deficits in AD.

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References

Semyanov A, Walker M, Kullmann D . GABA uptake regulates cortical excitability via cell type-specific tonic inhibition. Nat Neurosci. 2003; 6(5):484-90. DOI: 10.1038/nn1043. View

Masurkar A . Towards a circuit-level understanding of hippocampal CA1 dysfunction in Alzheimer's disease across anatomical axes. J Alzheimers Dis Parkinsonism. 2018; 8(1). PMC: 6005196. View

Guzman B, Vinnakota C, Govindpani K, Waldvogel H, Faull R, Kwakowsky A . The GABAergic system as a therapeutic target for Alzheimer's disease. J Neurochem. 2018; 146(6):649-669. DOI: 10.1111/jnc.14345. View

Hillen H . The Beta Amyloid Dysfunction (BAD) Hypothesis for Alzheimer's Disease. Front Neurosci. 2019; 13:1154. PMC: 6853841. DOI: 10.3389/fnins.2019.01154. View

Yeung J, Palpagama T, Tate W, Peppercorn K, Waldvogel H, Faull R . The Acute Effects of Amyloid-Beta on Glutamatergic Receptor and Transporter Expression in the Mouse Hippocampus. Front Neurosci. 2020; 13:1427. PMC: 6978747. DOI: 10.3389/fnins.2019.01427. View

Madl J, Royer S . Glutamate dependence of GABA levels in neurons of hypoxic and hypoglycemic rat hippocampal slices. Neuroscience. 2000; 96(4):657-64. DOI: 10.1016/s0306-4522(99)00548-5. View

Marcade M, Bourdin J, Loiseau N, Peillon H, Rayer A, Drouin D . Etazolate, a neuroprotective drug linking GABA(A) receptor pharmacology to amyloid precursor protein processing. J Neurochem. 2008; 106(1):392-404. DOI: 10.1111/j.1471-4159.2008.05396.x. View

Martin L, Oh G, Orser B . Etomidate targets alpha5 gamma-aminobutyric acid subtype A receptors to regulate synaptic plasticity and memory blockade. Anesthesiology. 2009; 111(5):1025-35. DOI: 10.1097/ALN.0b013e3181bbc961. View

Crestani F, Keist R, Fritschy J, Benke D, Vogt K, Prut L . Trace fear conditioning involves hippocampal alpha5 GABA(A) receptors. Proc Natl Acad Sci U S A. 2002; 99(13):8980-5. PMC: 124409. DOI: 10.1073/pnas.142288699. View

10.

Kwakowsky A, Guzman B, Pandya M, Turner C, Waldvogel H, Faull R . GABA receptor subunit expression changes in the human Alzheimer's disease hippocampus, subiculum, entorhinal cortex and superior temporal gyrus. J Neurochem. 2018; 145(5):374-392. DOI: 10.1111/jnc.14325. View

11.

Fox N, Scahill R, Crum W, Rossor M . Correlation between rates of brain atrophy and cognitive decline in AD. Neurology. 1999; 52(8):1687-9. DOI: 10.1212/wnl.52.8.1687. View

12.

Limon A, Reyes-Ruiz J, Miledi R . GABAergic drugs and Alzheimer's disease. Future Med Chem. 2011; 3(2):149-53. DOI: 10.4155/fmc.10.291. View

13.

Louzada P, Paula Lima A, Mendonca-Silva D, Noel F, de Mello F, Ferreira S . Taurine prevents the neurotoxicity of beta-amyloid and glutamate receptor agonists: activation of GABA receptors and possible implications for Alzheimer's disease and other neurological disorders. FASEB J. 2004; 18(3):511-8. DOI: 10.1096/fj.03-0739com. View

14.

Palpagama T, Sagniez M, Kim S, Waldvogel H, Faull R, Kwakowsky A . GABA Receptors Are Well Preserved in the Hippocampus of Aged Mice. eNeuro. 2019; 6(4). PMC: 6709233. DOI: 10.1523/ENEURO.0496-18.2019. View

15.

Li Y, Sun H, Chen Z, Xu H, Bu G, Zheng H . Implications of GABAergic Neurotransmission in Alzheimer's Disease. Front Aging Neurosci. 2016; 8:31. PMC: 4763334. DOI: 10.3389/fnagi.2016.00031. View

16.

Bartos M, Vida I, Jonas P . Synaptic mechanisms of synchronized gamma oscillations in inhibitory interneuron networks. Nat Rev Neurosci. 2006; 8(1):45-56. DOI: 10.1038/nrn2044. View

17.

MARCZYNSKI T . GABAergic deafferentation hypothesis of brain aging and Alzheimer's disease revisited. Brain Res Bull. 1998; 45(4):341-79. DOI: 10.1016/s0361-9230(97)00347-x. View

18.

Chen X, Mobley W . Alzheimer Disease Pathogenesis: Insights From Molecular and Cellular Biology Studies of Oligomeric Aβ and Tau Species. Front Neurosci. 2019; 13:659. PMC: 6598402. DOI: 10.3389/fnins.2019.00659. View

19.

Ramos-Miguel A, Hercher C, Beasley C, Barr A, Bayer T, Falkai P . Loss of Munc18-1 long splice variant in GABAergic terminals is associated with cognitive decline and increased risk of dementia in a community sample. Mol Neurodegener. 2015; 10:65. PMC: 4667524. DOI: 10.1186/s13024-015-0061-4. View

20.

Kwakowsky A, Potapov K, Kim S, Peppercorn K, Tate W, Abraham I . Treatment of beta amyloid 1-42 (Aβ(1-42))-induced basal forebrain cholinergic damage by a non-classical estrogen signaling activator in vivo. Sci Rep. 2016; 6:21101. PMC: 4754683. DOI: 10.1038/srep21101. View