Phenotypic Alterations in Hippocampal NPY- and PV-Expressing Interneurons in a Presymptomatic Transgenic Mouse Model of Alzheimer's Disease.
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.
Douglas Mental Health University InstituteVerdun, QC, Canada; McGill Group for Suicide Studies, Douglas Mental Health University InstituteVerdun, QC, Canada; Integrated Program in Neuroscience, McGill UniversityMontreal, QC, Canada.
Ian
I
Mahar
Douglas Mental Health University InstituteVerdun, QC, Canada; Laboratory of Biomedicine and Biotechnology, School of Arts, Sciences and Humanities, Universidade de São PauloSão Paulo, Brazil; Graduation Course on Pharmacology, Institute of Biomedical Sciences, Universidade de São PauloSão Paulo, Brazil; Research Group on Neuropharmacology of AgingSão Paulo, Brazil.
Marilia Silva
MS
Albuquerque
Douglas Mental Health University InstituteVerdun, QC, Canada; CONACYT National Council for Science and TechnologyMéxico city, Mexico; UNAM Developmental Neurobiology and Neurophysiology, Institute of Neurobiology, National Autonomous University of MéxicoQuerétaro, Mexico.
Siddhartha
S
Mondragon-Rodriguez
Douglas Mental Health University InstituteVerdun, QC, Canada; Integrated Program in Neuroscience, McGill UniversityMontreal, QC, Canada.
Chelsea
C
Cavanagh
Douglas Mental Health University InstituteVerdun, QC, Canada; McGill Group for Suicide Studies, Douglas Mental Health University InstituteVerdun, QC, Canada.
Maria Antonietta
MA
Davoli
Douglas Mental Health University InstituteVerdun, QC, Canada; Integrated Program in Neuroscience, McGill UniversityMontreal, QC, Canada.
Jean-Guy
JG
Chabot
Douglas Mental Health University InstituteVerdun, QC, Canada; Integrated Program in Neuroscience, McGill UniversityMontreal, QC, Canada.
Sylvain
S
Williams
Douglas Mental Health University InstituteVerdun, QC, Canada; McGill Group for Suicide Studies, Douglas Mental Health University InstituteVerdun, QC, Canada; Integrated Program in Neuroscience, McGill UniversityMontreal, QC, Canada.
Naguib
N
Mechawar
Douglas Mental Health University InstituteVerdun, QC, Canada; Integrated Program in Neuroscience, McGill UniversityMontreal, QC, Canada.
Rémi
R
Quirion
Douglas Mental Health University InstituteVerdun, QC, Canada; Integrated Program in Neuroscience, McGill UniversityMontreal, QC, Canada; Centre de Recherche des Cordeliers, Sorbonne Universités, UPMC Univ Paris 06, INSERM, Université Paris Descartes, Sorbonne Paris Cité, UMR_S 1138Paris, France.
Slavica
S
Krantic
Alzheimer’s disease; hippocampal sub-regions; neuropeptide Y; parvalbumin; pre-plaque