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. 2017 Jan 19;8:327.
doi: 10.3389/fnagi.2016.00327. eCollection 2016.

Phenotypic Alterations in Hippocampal NPY- And PV-Expressing Interneurons in a Presymptomatic Transgenic Mouse Model of Alzheimer's Disease

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Free PMC article

Phenotypic Alterations in Hippocampal NPY- And PV-Expressing Interneurons in a Presymptomatic Transgenic Mouse Model of Alzheimer's Disease

Ian Mahar et al. Front Aging Neurosci. .
Free PMC article

Abstract

Interneurons, key regulators of hippocampal neuronal network excitability and synchronization, are lost in advanced stages of Alzheimer's disease (AD). Given that network changes occur at early (presymptomatic) stages, we explored whether alterations of interneurons also occur before amyloid-beta (Aβ) accumulation. Numbers of neuropeptide Y (NPY) and parvalbumin (PV) immunoreactive (IR) cells were decreased in the hippocampus of 1 month-old TgCRND8 mouse AD model in a sub-regionally specific manner. The most prominent change observed was a decrease in the number of PV-IR cells that selectively affected CA1/2 and subiculum, with the pyramidal layer (PY) of CA1/2 accounting almost entirely for the reduction in number of hippocampal PV-IR cells. As PV neurons were decreased selectively in CA1/2 and subiculum, and given that they are critically involved in the control of hippocampal theta oscillations, we then assessed intrinsic theta oscillations in these regions after a 4-aminopyridine (4AP) challenge. This revealed increased theta power and population bursts in TgCRND8 mice compared to non-transgenic (nTg) controls, suggesting a hyperexcitability network state. Taken together, our results identify for the first time AD-related alterations in hippocampal interneuron function as early as at 1 month of age. These early functional alterations occurring before amyloid deposition may contribute to cognitive dysfunction in AD.

Keywords: Alzheimer’s disease; hippocampal sub-regions; neuropeptide Y; parvalbumin; pre-plaque.

Figures

Figure 1
Figure 1
Expression of neuronal markers and amyloid-beta precursor protein (APP) cleavage products in the hippocampus of 1 month-old TgCRND8 mice. (A) Micrographs of immunohistochemical labeling of hippocampal neurons for NeuN, neuropeptide Y (NPY) and parvalbumin (PV) in CA1 and 2, CA3, dentate gyrus (DG) and subiculum (SUB) hippocampal regions. Scale bar = 50 μm. (B) Amyloid-beta (Aβ) and C-terminal fragment/Amyloid precursor protein intracellular domain (CTF/AICD) expression as assessed by FCA3340 and CT20 antibodies, respectively. Anatomically matched hippocampal sections of CA1/2 sub-region of 11 month-old TgCRND8 mice were used as a positive control. Scale bar = 100 μm.
Figure 2
Figure 2
Quantification of NeuN-immunoreactive neurons in the hippocampus of 1 month-old TgCRND8 mice. Number of neurons (A), average layer volume (B) and neuronal density (C) in the studied hippocampal sub-regions (CA1/2, CA3 and DG) were examined. nTg, non-transgenic; Tg, transgenic. *p < 0.05.
Figure 3
Figure 3
Quantification of NPY- (A), and PV-immunoreactive (IR; B) cells in the overall hippocampus for nTg and Tg animals. *p < 0.05.
Figure 4
Figure 4
Quantification of NPY-IR cells in CA1/2 (A), CA3 (B), dentate gyrus (DG; C) and subiculum (D), as well as sub-regions within CA1/2 (E), CA3 (F) and DG (G). nTg, non-transgenic; PO, polymorphic layer; SO, stratum oriens; SR, stratum radiatum; Tg, transgenic. *p < 0.05; **p < 0.01.
Figure 5
Figure 5
Quantification of PV-IR cells in CA1/2 (A), CA3 (B), dentate gyrus (DG; C) and subiculum (D), as well as sub-regions within CA1/2 (E), CA3 (F) and DG (G). nTg, non-transgenic; PO, polymorphic layer; SO, stratum oriens; SR, stratum radiatum; Tg, transgenic. *p < 0.05; ***p < 0.001.
Figure 6
Figure 6
Analysis of the co-expression of APP cleavage products and PV-IR in CA1 hippocampal neurons of 1 month-old TgCRND8 mice. (A) Micrographs of immunohistochemical labeling of hippocampal neurons for PV and Aβ; anatomically matched sections from 11 month-old mice were used as a positive control. Note that in contrast to the absence of Aβ-IR in 1 month-old TgCRND8 mice, intracytoplasmic Aβ is clearly detectable in the pyramidal layer (PY) of the CA1 region of 11 month-old TgCRND8 mice. (B) Analysis of Aβ/CTF expression in CA1 hippocampal PV neurons in 1 month-old TgCRND8 mice. As Aβ was undetectable when assessed with the selective FCA3340 Aβ antibody, and enzyme-linked immunoabsorbent assay (ELISA) detected a substantial amount of βCTF, this immunoreactivity reveals likely the expression of βCTF. However, no PV-IR neurons co-expressing βCTF were observed. Scale bar = 10 μm.
Figure 7
Figure 7
Electrophysiological monitoring of CA1/subiculum neurons in response to 4AP challenge. Raw traces of theta oscillations recorded in CA1/subiculum area using septo-hippocampal preparations from non-transgenic (nTg; A) and transgenic (Tg) mice (D). In nTg mice, 150 μM-4AP treatments did not change theta amplitude (A, red square). Conversely, in TgCRND8 mice 4AP treatments altered theta amplitude (D, red square). Magnification of raw theta activity before, during and after 4AP treatment in nTg (B) and TgCRND8 mice (E). Power spectrum analysis of theta power and frequency in nTg (C) and TgCRND8 mice (F). Theta frequency did not show statistically significant changes in TgCRND8 4AP-treated animals (G,H, different colors correspond to individual TgCRND8 samples). TgCRND8 mice reveal theta power increase during and after 4AP treatment (I,J, red circles denote averages, black circles denote individual TgCRND8 traces). Under 4AP challenge, elevated number of burst events was observed in TgCRND8 mice (L) compared to nTg (K). Relative change of burst events is higher in TgCRND8 mice (N, representative trace of burst events after 4AP in L) compared to nTg mice (M, representative trace of burst events after 4AP in K). Burst events were significantly increased for TgCRND8 mice (see inset in N). *p < 0.05.

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