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. 2023 Apr 13;24(8):7196.
doi: 10.3390/ijms24087196.

Aberrant Dopamine System Function in the Ferrous Amyloid Buthionine (FAB) Rat Model of Alzheimer's Disease

Stephanie M Perez  1   2 , Angela M Boley  1   2 , Alexandra M McCoy  1   2 , Daniel J Lodge  1   2
Affiliations

Aberrant Dopamine System Function in the Ferrous Amyloid Buthionine (FAB) Rat Model of Alzheimer's Disease

Stephanie M Perez et al. Int J Mol Sci. .

Abstract

Antipsychotics increase the risk of death in elderly patients with Alzheimer's disease (AD). Thus, there is an immediate need for novel therapies to treat comorbid psychosis in AD. Psychosis has been attributed to a dysregulation of the dopamine system and is associated with aberrant regulation by the hippocampus. Given that the hippocampus is a key site of pathology in AD, we posit that aberrant regulation of the dopamine system may contribute to comorbid psychosis in AD. A ferrous amyloid buthionine (FAB) rodent model was used to model a sporadic form of AD. FAB rats displayed functional hippocampal alterations, which were accompanied by decreases in spontaneous, low-frequency oscillations and increases in the firing rates of putative pyramidal neurons. Additionally, FAB rats exhibited increases in dopamine neuron population activity and augmented responses to the locomotor-inducing effects of MK-801, as is consistent with rodent models of psychosis-like symptomatology. Further, working memory deficits in the Y-maze, consistent with an AD-like phenotype, were observed in FAB rats. These data suggest that the aberrant hippocampal activity observed in AD may contribute to dopamine-dependent psychosis, and that the FAB model may be useful for the investigation of comorbid psychosis related to AD. Understanding the pathophysiology that leads to comorbid psychosis in AD will ultimately lead to the discovery of novel targets for the treatment of this disease.

Keywords: Alzheimer’s disease; FAB; dopamine; in vivo electrophysiology; psychosis; ventral hippocampus.

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Conflict of interest statement

Lodge has received research funding from Heptares Therapeutics Ltd. and consulting fees from Alkermes, Inc., and is co-inventor of a patent (US 2019/0117637). All of these are unrelated to the work described in this manuscript.

Figures

Figure 1
Figure 1
The average firing rate of spontaneously active putative pyramidal neurons in the ventral hippocampus (vHipp) was significantly higher in FAB rats, indicative of regional hyperactivity (A). Representative trace of spontaneous local field potential oscillations (filtered for <4 Hz; dark line) throughout the vHipp of a control (top) and FAB (bottom) rat (B). FAB rats displayed significant decreases in power in lower-frequency oscillations (C), specifically in the delta and theta frequency bands, as summarized in (D). * p < 0.05.
Figure 2
Figure 2
FAB rats exhibited increased ventral tegmental area (VTA) dopamine neuron population activity (A). No changes were observed in the percent burst firing (B) or the average firing rates (C) of dopamine neurons. Representative dopamine neuron trace and action potential from a control (left) and FAB (right) rat. *** p = 0.001.
Figure 3
Figure 3
FAB rats displayed a baseline locomotor activity level higher than that of controls, which persisted after systemic MK-801 administration (A). No differences were observed in pre-pulse inhibition of startle (PPI) (B). A significant decrease in the percentage of spontaneous alternations in the Y-maze was observed in FAB rats (C). No differences were observed in the time spent interacting socially (D). * p = 0.033. ** denotes a main effect of strain p < 0.001. The icons used were adapted from BioRender.com (2021), retrieved from https://app.biorender.com/illustrations (accessed on 18 August 2021).
Figure 4
Figure 4
FAB rats displayed decreased levels of ventral hippocampal (vHipp) parvalbumin (PV). Representative Western blot films demonstrating PV and GAPDH levels in control and FAB rats. * p = 0.008.
Figure 5
Figure 5
The ventral hippocampus (vHipp) can modulate activity in the ventral tegmental area (VTA) via a multi-synaptic pathway that includes the nucleus accumbens (NAc) and ventral pallidum (VP, left). In the case of psychosis, hyperactivity in hippocampal subfields can drive aberrant dopamine neuron activity by causing a disinhibition of the VTA by the VP, therefore modulating dopamine neurotransmission (right).
Figure 6
Figure 6
Schematic representation of the experimental timeline (A). Representative coronal brain slice displaying a cannula track into the lateral ventricles, indicated by a black arrow (B). Representative dark field image of a silver-stained brain from a control (left) and FAB (right) rat, with the brighter areas depicting areas of pathological deposits (C). 40× magnification. The icons used were adapted from BioRender.com (2021), retrieved from https://app.biorender.com/illustrations (accessed on 18 August 2021).
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References

    1. Ballard C., Walker M. Neuropsychiatric aspects of Alzheimer’s disease. Curr. Psychiatry Rep. 1999;1:49–60. doi: 10.1007/s11920-999-0010-4. - DOI - PubMed
    1. Haupt M., Kurz A., Janner M. A 2-year follow-up of behavioural and psychological symptoms in Alzheimer’s disease. Dement. Geriatr. Cogn. Disord. 2000;11:147–152. doi: 10.1159/000017228. - DOI - PubMed
    1. Ropacki S.A., Jeste D.V. Epidemiology of and risk factors for psychosis of Alzheimer’s disease: A review of 55 studies published from 1990 to 2003. Am. J. Psychiatry. 2005;162:2022–2030. doi: 10.1176/appi.ajp.162.11.2022. - DOI - PubMed
    1. Emanuel J.E., Lopez O.L., Houck P.R., Becker J.T., Weamer E.A., Demichele-Sweet M.A., Kuller L., Sweet R.A. Trajectory of cognitive decline as a predictor of psychosis in early Alzheimer disease in the cardiovascular health study. Am. J. Geriatr. Psychiatry. 2011;19:160–168. doi: 10.1097/JGP.0b013e3181e446c8. - DOI - PMC - PubMed
    1. Ballard C., Kales H.C., Lyketsos C., Aarsland D., Creese B., Mills R., Williams H., Sweet R.A. Psychosis in Alzheimer’s Disease. Curr. Neurol. Neurosci. Rep. 2020;20:57. doi: 10.1007/s11910-020-01074-y. - DOI - PMC - PubMed