title: Age-dependent concomitant changes in synaptic dysfunction and GABAergic pathway in the APP/PS1 mouse model.
abstract: Synaptic dysfunction is a well-documented manifestation in animal models of Alzheimer's disease pathology. In this context, numerous studies have documented reduction in the functionality of synapses in various models. In addition, recent research has shed more light on increased excitability and its link to seizures and seizure-like activities in AD patients as well as in mouse models. These reports of hyperexcitability contradict the observed reduction in synaptic function and have been suggested to be as a result of the interplay between inhibitory and excitatory neuronal mechanism. The present study therefore investigates functional deficiency in the inhibitory system as complementary to the identified alterations in the glutamate excitatory pathway in AD. Since synaptic function deficit in AD is typically linked to progression/pathology of the disease, it is important to determine whether the deficits in the GABAergic system are functional and can be directly linked to the pattern of the disruption documented in the glutamate system. To build on previous research in this field, experiments were designed to determine if previously documented synaptic dysfunction in AD models is concomitantly observed with excitation/inhibition imbalance as suggested by observation of seizure and seizure-like pathology in such models. We report changes in synaptic function in aged APPPS1 mice not observable in the younger cohort. These changes in synaptic function are furthermore accompanied by alteration in the GABAergic neurotransmission. Thus, age-dependent alteration in the inhibitory/excitatory balance might underpin the symptomatic changes observed with the progression of Alzheimer's disease pathology including sleep disturbance and epileptic events.
authors.affiliation: Department of Neuroscience, Janssen Research and Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium; Institute of Neuroscience, Université Catholique de Louvain, Louvain-La-Neuve, Belgium.
authors.forename: Tutu
authors.initials: T
authors.lastname: Oyelami
authors.affiliation: Department of Computational Biology, Janssen Research and Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: An De
authors.initials: A
authors.lastname: Bondt
authors.affiliation: Department of Translational Sciences, Janssen Research and Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: Ilse Van
authors.initials: IV
authors.lastname: den Wyngaert
authors.affiliation: OpenAnalytics NV, Antwerp, Belgium, 5 Institute of Neuroscience, Université Catholique de Louvain, Louvain-La-Neuve, Belgium.
authors.forename: Kirsten Van
authors.initials: KV
authors.lastname: Hoorde
authors.affiliation: Department of Neuroscience, Janssen Research and Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: Luc
authors.initials: L
authors.lastname: Hoskens
authors.affiliation: Department of Neuroscience, Janssen Research and Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: Hamdy
authors.initials: H
authors.lastname: Shaban
authors.affiliation: Department of Neuroscience, Janssen Research and Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: John A
authors.initials: JA
authors.lastname: Kemp
authors.affiliation: Department of Neuroscience, Janssen Research and Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium, wdrinken@its.jnj.com.
authors.forename: Wilhelmus H
authors.initials: WH
authors.lastname: Drinkenburg
mesh_terms: D000375:Aging; D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D018682:GABA Agents / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology; D006801:Humans; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D053764:Presenilin-1 / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013569:Synapses / Q000187:drug effects / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D016564:Amyloid beta-Protein Precursor; D018682:GABA Agents; C508853:PSEN1 protein, human; D053764:Presenilin-1; D005680:gamma-Aminobutyric Acid