Firing Alterations of Neurons in Alzheimer's Disease: Are They Merely a Consequence of Pathogenesis or a Pivotal Component of Disease Progression?

Abstract

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, yet its underlying causes remain elusive. The conventional perspective on disease pathogenesis attributes alterations in neuronal excitability to molecular changes resulting in synaptic dysfunction. Early hyperexcitability is succeeded by a progressive cessation of electrical activity in neurons, with amyloid beta (Aβ) oligomers and tau protein hyperphosphorylation identified as the initial events leading to hyperactivity. In addition to these key proteins, voltage-gated sodium and potassium channels play a decisive role in the altered electrical properties of neurons in AD. Impaired synaptic function and reduced neuronal plasticity contribute to a vicious cycle, resulting in a reduction in the number of synapses and synaptic proteins, impacting their transportation inside the neuron. An understanding of these neurophysiological alterations, combined with abnormalities in the morphology of brain cells, emerges as a crucial avenue for new treatment investigations. This review aims to delve into the detailed exploration of electrical neuronal alterations observed in different AD models affecting single neurons and neuronal networks.

Keywords: Alzheimer’s disease; LTP; dendritic spine; interneurons; neuronal firing properties; neurophysiology; pyramidal neurons.

Figure 1

Illustration of pyramidal neurons and their electrophysiological activity pattern. (A) Schematic representation of a pyramidal neuron in the CA1 area of the hippocampus. (B) Electrophysiological pattern of regular spiking pyramidal neuron. (C) Electrophysiological pattern of bursting pyramidal neuron. (D) Schematic representation of a pyramidal neuron with reduced dendritic spines in AD. (E) Electrophysiological model of a pyramidal neuron in AD.

Figure 2

Excitatory (PCs) and inhibitory (Ints) neurons recorded in the CA1 region of the hippocampus. (A) CA1 PCs and Ints were patch-clamped with a pipette solution containing Lucifer Yellow (2 mM). The location of neurons in the slices was visualized by superimposition of the reflected light image of the hippocampal slice and of the Lucifer Yellow fluorescence signal (left panel). The right panel shows reconstructed confocal images of two PCs (yellow) and three Ints (green) recorded in the CA1 sp and sr, respectively. (B,C) Confocal images of one PC (B) and one Int (C) of CA1 pyramidal layer and stratum radiatum, respectively. (B) Right and (C) right expanded confocal images of dendritic spines. Note the spiny dendritic segment of the PC (B) in contrast with the a-spiny (C) one of the Int. The arrowheads indicate dendritic spines. (D,E) Voltage responses of one PC and one Int (top), to a series of intracellular current pulses (bottom) are shown. The current was applied at rest (−70 and −56 mV for PC and Int, respectively). Inset, action potentials from a PC and Int are superimposed. Note the larger Iahp in Int compared to PC. Abbreviations: so, stratum oriens; sp, stratum pyramidale; sr, stratum radiatum; slm, stratus lacunosum moleculare. Scale bar: 200 μm. (Reproduced with permission from Martina, M., Comas, T., & Mealing, G.A. (2013). Selective Pharmacological Modulation of Pyramidal Neurons and Interneurons in the CA1 Region of the Rat Hippocampus. Frontiers in pharmacology, 4, 24. https://doi.org/10.3389/fphar.2013.00024 [30]. This content is licensed under the Creative Commons Attribution License).

Figure 3

Firing properties of inhibitory interneurons in 5–6-month-old non-Tg and rTg4510 mice. (A,B) Input–output (I–O) relationship in fast-spiking (FS) neurons. Representative traces evoked by +300 pA injection are shown in (A). (C,D) Single action potentials (APs) and phase plots of FS neurons. A representative single AP is shown in (C). (E,F) I–O relationship in non-FS neurons. Representative traces evoked by +300 pA injection are shown in (F). (G,H) Single APs and phase plots of non-FS neurons. A representative single AP is shown in (H). (I–L) Parameters of single APs: threshold (I), AP amplitude (J), maximum rising slope (K), and maximum repolarizing slope (L). Data are shown as mean ± S.E.M. FS, N = 7 cells from seven slices (7 non-Tg mice), N = 13 cells from 12 slices (eight rTg4510 mice); non-FS, N = 11 cells from 6 slices (7 non-Tg mice), N = 7 cells from 7 slices (6 rTg4510 mice). p value (* p < 0.05) by two-way ANOVA (B), or by the Student’s t test (I,L) (Reproduced from Kudo, T., Takuwa, H., Takahashi, M., Urushihata, T., Shimojo, M., Sampei, K., Yamanaka, M., Tomita, Y., Sahara, N., Suhara, T., & Higuchi, M. (2023). Selective dysfunction of fast-spiking inhibitory interneurons and disruption of perineuronal nets in a tauopathy mouse model. iScience, 26(4), 106342. https://doi.org/10.1016/j.isci.2023.106342 [54] with permission from Elsevier).

Figure 4

Extracellular recording of the response of CA1 pyramidal neurons to stimulation of afferent Schaffer collaterals. The stimulation evokes an afferent volley) and a field EPSP. After a tetanus (two trains of 100 Hz, 1 s duration, 30 s interval) applied through the same stimulating electrode, the field EPSP is recorded. Note the increased initial slop after the tetanus.

Figure 5

(A) Representative field potential responses recorded extracellularly in NTG mouse tissue. A 40 Hz, 10-pulse stimulation evoked depressive (decreasing amplitude) responses in the NTG animals. APdE9 mice showed sustained field potential responses with little decrease in the amplitude throughout the stimulation train. (B) Average and S.E.M. for APdE9and NTG fEPSP amplitudes during the 40 Hz stimulation. Note significant differences for the fEPSP amplitudes produced by pulse stimulations 4–10 (marked with *) (pulse to pulse comparison, unpaired t-test, p < 0.05). (Reproduced with permission from Hazra, A., Gu, F., Aulakh, A., Berridge, C., Eriksen, J. L., & Ziburkus, J. (2013). Inhibitory neuron and hippocampal circuit dysfunction in an aged mouse model of Alzheimer’s disease. PLoS ONE, 8(5), e64318. https://doi.org/10.1371/journal.pone.0064318 [118]. This content is licensed under the Creative Commons Attribution License).