Novel object and social interaction tasks allow assessments of rodent cognition and social behavior. Here, we combined these tasks and defined unequivocal locations of interest. Our procedure, termed OF-NO-SI, comprised habituation to the open field (OF), novel object (NO) and social interaction (SI) stages. Habituation was measured within- and between-trials (10 minutes each, two per stage). Ambulation emerged as the appropriate proxy during the OF stage, but NO and SI trials were best quantified via direct exploration measures. We pharmacologically validated the paradigm using 5-month old C57BL/6J male mice, treated intraperitoneally with (1) 0.5 mg/kg scopolamine, (2) 0.05 mg/kg MK-801 and (3) 0.05 mg/kg SCH-23390 to block muscarinic (M1), NMDA, and D1 receptors, respectively, or (4) vehicle (distilled water). Activity and gross exploratory behavior were affected by all compounds cf. vehicle: scopolamine and MK-801 cohorts were hyperactive, while SCH-23390 caused hypo-locomotion throughout. Vehicle treated mice showed reliable habituation to all stages for time in interaction zone, directed exploration and number of visits. Exploration was severely impaired by scopolamine. MK-801 mostly affected within-session exploration but also increased exploration of the conspecific compared to the object. Interestingly, even though within-trial habituation was lacking in the SCH-23390 cohort, between-trial habituation was largely intact, despite reduced locomotion. Our data suggest that the OF-NO-SI task is a convenient and robust paradigm to measure habituation to different experimental settings and stimuli. It allows the dissociation of proxies related to activity and non-associative learning/memory, as revealed by distinct pharmacological treatment effects within- vs. between-trials.

Combining infrared event-stamping and auto-regressive modelling enables rapid, automated and sensitive phenotyping of AD mouse models. Subtle alterations in brain signalling can be detected prior to overt behavioural impairments.

Synapse loss is associated with cognitive decline in Alzheimer’s disease, and owing to their plastic nature, synapses are an ideal target for therapeutic intervention. Oligomeric amyloid beta around amyloid plaques is known to contribute to synapse loss in mouse models and is associated with synapse loss in human Alzheimer’s disease brain tissue, but the mechanisms leading from Aβ to synapse loss remain unclear. Recent data suggest that the fast-activating and -inactivating voltage-gated potassium channel subtype 3.4 (Kv3.4) may play a role in Aβ-mediated neurotoxicity. Here, we tested whether this channel could also be involved in Aβ synaptotoxicity. Using adeno-associated virus and clustered regularly interspaced short palindromic repeats technology, we reduced Kv3.4 expression in neurons of the somatosensory cortex of APP/PS1 mice. These mice express human familial Alzheimer’s disease-associated mutations in amyloid precursor protein and presenilin-1 and develop amyloid plaques and plaque-associated synapse loss similar to that observed in Alzheimer’s disease brain. We observe that reducing Kv3.4 levels ameliorates dendritic spine loss and changes spine morphology compared to control virus. In support of translational relevance, Kv3.4 protein was observed in human Alzheimer’s disease and control brain and is associated with synapses in human induced pluripotent stem cell–derived cortical neurons. We also noted morphological changes in induced pluripotent stem cell neurones challenged with human Alzheimer’s disease-derived brain homogenate containing Aβ but, in this in vitro model, total mRNA levels of Kv3.4 were found to be reduced, perhaps as an early compensatory mechanism for Aβ-induced damage. Overall, our results suggest that approaches to reduce Kv3.4 expression and/or function in the Alzheimer’s disease brain could be protective against Aβ-induced synaptic alterations.

Gene mutations within amyloid precursor protein (APP or AβPP) and/or presenilin 1 (PS1) genes are determinants of familial Alzheimer's disease (fAD) and remain fundamental for experimental models. Here, we generated a neuronal knock-in mouse (PLB2APP) with mutated human APPSwe/Lon and investigated histopathology and behavioral phenotypes. Additionally, PLB2APP mice were cross-bred with a presenilin (PS1A246E) line to assess the impact of this gene combination. Immunohistochemistry determined amyloid-β (Aβ) pathology, astrogliosis (via GFAP labelling), and neuronal densities in hippocampal and cortical brain regions. One-year old PLB2APP mice showed higher levels of intracellular Aβ in CA1, dentate gyrus, and cortical regions compared to PLBWT controls. Co-expression of PS1 reduced hippocampal but elevated cortical Aβ build-up. Amyloid plaques were sparse in aged PLB2APP mice, and co-expression of PS1 promoted plaque formation. Heightened GFAP expression followed the region-specific pattern of Aβ in PLB2APP and PLB2APP/PS1 mice. Behaviorally, habituation to a novel environment was delayed in 6-month-old PLB2APP mice, and overall home-cage activity was reduced in both lines at 6 and 12 months, particularly during the dark phase. Spatial learning in the water maze was impaired in PLB2APP mice independent of PS1 expression and associated with reduced spatial navigation strategies. Memory retrieval was compromised in PLB2APP mice only. Our data demonstrate that low expression of APP is sufficient to drive histopathological and cognitive changes in mice without overexpression or excessive plaque deposition. AD-like phenotypes were altered by co-expression of PS1, including a shift from hippocampal to cortical Aβ pathology, alongside reduced deficits in spatial learning.