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- Title
α5-GABAA Receptor Modulation Reverses Behavioral and Neurophysiological Correlates of Psychosis in Rats with Ventral Hippocampal Alzheimer's Disease-like Pathology.
- Authors
Eassa, Nicole E.; Perez, Stephanie M.; Boley, Angela M.; Elam, Hannah B.; Sharmin, Dishary; Cook, James M.; Lodge, Daniel J.
- Abstract
Of the 35 million people in the world suffering from Alzheimer's Disease (AD), up to half experience comorbid psychosis. Antipsychotics, used to treat psychosis, are contraindicated in elderly patients because they increase the risk of premature death. Reports indicate that the hippocampus is hyperactive in patients with psychosis and those with AD. Preclinical studies have demonstrated that the ventral hippocampus (vHipp) can regulate dopamine system function, which is thought to underlie symptoms of psychosis. A viral-mediated approach was used to express mutated human genes known to contribute to AD pathology: the Swedish (K670N, M671L), Florida (I716V), and London (V717I) mutations of amyloid precursor protein and two mutations (M146L and L286V) of presenilin 1 specifically in the vHipp, to investigate the selective contribution of AD-like pathology in this region. We observed a significant increase in dopamine neuron population activity and behavioral deficits in this AD-AAV model that mimics observations in rodent models with psychosis-like symptomatologies. Further, systemic administration of MP-III-022 (α5-GABAA receptor selective positive allosteric modulator) was able to reverse aberrant dopamine system function in AD-AAV rats. This study provides evidence for the development of drugs that target α5-GABAA receptors for patients with AD and comorbid psychosis.
- Subjects
FLORIDA; LONDON (England); ALZHEIMER'S disease; PRESENILINS; DOPAMINE receptors; AMYLOID beta-protein precursor; PSYCHOSES; DOPAMINERGIC neurons; PATHOLOGY
- Publication
International Journal of Molecular Sciences, 2023, Vol 24, Issue 14, p11788
- ISSN
1661-6596
- Publication type
Article
- DOI
10.3390/ijms241411788