Altered synaptic physiology clearly contributes to memory loss and other CNS symptoms in Alzheimer's disease. A new paper in this issue of the Journal of Alzheimer's Disease, from Zhe Jin's group in Uppsala, Sweden, adds important new information to help us understand how. A powerful, yet largely uncharacterized form of neuronal inhibition—GABAA, slow synaptic current—was studied using whole-cell recordings in hippocampal brain slices from AD model mice (tg-APPSwe). The investigators found that GABAA, slow inhibition was significantly reduced in dentate granule neurons from aged AD mice, compared to both wild type and adult non-aged AD mice. This reduction would nicely explain the change in excitatory-inhibitory balance previously reported in this and other AD model animals, as well as impairments in pattern separation and theta-gamma cross-frequency coupling that are early manifestations of AD.
PearceRA. Physiological evidence for two distinct GABAA responses in rat hippocampus. Neuron1993; 10: 189–200.
2.
FigueroaAGBenkwitzCSurgesG, et al.Hippocampal β2-GABAA receptors mediate LTP suppression by etomidate and contribute to long-lasting feedback but not feedforward inhibition of pyramidal neurons. J Neurophysiol2021; 126: 1090–1100.
3.
BanksMIWhiteJAPearceRA. Interactions between distinct GABA(A) circuits in hippocampus. Neuron2000; 25: 449–457.
4.
CapognaMPearceRA. GABA A,slow: causes and consequences. Trends Neurosci2011; 34: 101–112.
5.
SceniakMPMaciverMB. Slow GABA(A) mediated synaptic transmission in rat visual cortex. BMC Neurosci2008; 9: 8.
6.
IsidroF. Brain aging and Alzheimer’s disease, a perspective from non-human primates. Aging (Albany NY)2024; 16: 13145–13171.
7.
HunsakerMRKesnerRP. Unfolding the cognitive map: the role of hippocampal and extra-hippocampal substrates based on a systems analysis of spatial processing. Neurobiol Learn Mem2018; 147: 90–119.
8.
LaczóMLerchOMartinkovicL, et al.Spatial pattern separation testing differentiates Alzheimer’s disease biomarker-positive and biomarker-negative older adults with amnestic mild cognitive impairment. Front Aging Neurosci2021; 13: 774600.
9.
NetsykOKorolSVLiJP, et al.GABA-activated slow spontaneous inhibitory postsynaptic currents are decreased in dorsal hippocampal dentate gyrus granule cells in an aged mouse model of Alzheimer's disease. J Alzheimers Dis2025; 104.
10.
RuiterMHerstelLJWierengaCJ. Reduction of dendritic inhibition in CA1 pyramidal neurons in amyloidosis models of early Alzheimer’s disease. J Alzheimers Dis2020; 78: 951–964.
11.
Jiménez-BaladoJEichTS. GABAergic dysfunction, neural network hyperactivity and memory impairments in human aging and Alzheimer’s disease. Semin Cell Dev Biol2021; 116: 146–159.
12.
YaoZvan VelthovenCTJNguyenTN, et al.A taxonomy of transcriptomic cell types across the isocortex and hippocampal formation. Cell2021; 184: 3222–3241.e26.
13.
KangY-JLewisHESYoungMW, et al.Cell type-specific intrinsic perithreshold oscillations in hippocampal GABAergic interneurons. Neuroscience2018; 376: 80–93.
14.
MusaeusCSNielsenMSMusaeusJS, et al.Electroencephalographic cross-frequency coupling as a sign of disease progression in patients with mild cognitive impairment: a pilot study. Front Neurosci2020; 14: 790.
15.
GoodmanMSKumarSZomorrodiR, et al.Theta-gamma coupling and working memory in Alzheimer’s dementia and mild cognitive impairment. Front Aging Neurosci2018; 10: 101.
16.
VictorinoDBFaberJPinheiroDJLL, et al.Toward the identification of neurophysiological biomarkers for Alzheimer’s disease in down syndrome: a potential role for cross-frequency phase-amplitude coupling analysis. Aging Dis2023; 14: 428–449.
17.
DengYBiMDelerueF, et al.Loss of LAMP5 interneurons drives neuronal network dysfunction in Alzheimer’s disease. Acta Neuropathol2022; 144: 637–650.
18.
BernardoAMMarcotteMWongK, et al.Procognitive and neurotrophic benefits of α5-GABA-A receptor positive allosteric modulation in a β-amyloid deposition mouse model of Alzheimer’s disease pathology. Neurobiol Aging2024; 147: 49–59.
19.
MaciverMBMcCarrenHSEaglemanSL, et al.Comparative electroencephalographic profile of a new anesthetic and anticonvulsant that is selective for the GABA A R slow receptor subtype. Anesth Analg2024. Epub ahead of print 4 October 2024. DOI: https://doi.org/10.1213/ANE.0000000000007178.
20.
RodgersFCZarnowskaEDLahaKT, et al.Etomidate impairs long-term potentiation in vitro by targeting α5-subunit containing GABAA receptors on nonpyramidal cells. J Neurosci2015; 35: 9707–9716.
21.
HammoudHNetsykOTafreshihaAS, et al.Insulin differentially modulates GABA signalling in hippocampal neurons and, in an age-dependent manner, normalizes GABA-activated currents in the tg-APPSwe mouse model of Alzheimer’s disease. Acta Physiol (Oxf)2021; 232: e13623.
22.
Kazmierska-GrebowskaPSiwiecMSowaJE, et al.Lamotrigine attenuates neuronal excitability, depresses GABA synaptic inhibition, and modulates theta rhythms in rat hippocampus. Int J Mol Sci2021; 22: 13604.
23.
MossDEPerezRG. The phospho-tau cascade, basal forebrain neurodegeneration, and dementia in Alzheimer’s disease: anti-neurodegenerative benefits of acetylcholinesterase inhibitors. J Alzheimers Dis2024; 102: 617–626.
