SummaryVoltage-dependent Ca2+ channels (VGCC) represent the principal source of Ca2+ ions driving evoked neurotransmitter release at presynaptic boutons. In mammals, presynaptic Ca2+ influx is mediated mainly via P/Q-type and N-type VGCC, which differ in their properties. Changes in their relative contributions tune neurotransmission both during development and in Hebbian plasticity. However, whether this represents a functional motif also present in other forms of activity-dependent regulation is unknown. Here, we study the role of VGCC in homeostatic plasticity (HSP) in mammalian hippocampal neurons using optical techniques. We find that changes in evoked Ca2+ currents specifically through P/Q-type, but not N-type, VGCC mediate bidirectional homeostatic regulation of both neurotransmitter release efficacy and the size of the major synaptic vesicle pools. Selective dependence of HSP on P/Q-type VGCC in mammalian terminals has important implications for phenotypes associated with P/Q-type channelopathies, including migraine and epilepsy.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, with a long preclinical and prodromal phase. To enable the study of disease mechanisms, AD has been modeled in many transgenic animal lines and cognitive functioning has been tested using several widely used behavioral tasks. These tasks, however, are not always suited for repeated longitudinal testing and are often associated with acute stress such as animal transfer, handling, novelty, or stress related to the task itself. This makes it challenging to relate cognitive dysfunction in animal models to cognitive decline observed in AD patients. Here, we designed an automated figure-8-maze (F8M) to test mice in a delayed alternation task (DAT) in a longitudinal manner. Mice were rewarded when they entered alternate sides of the maze on subsequent trials. Automation as well as connection of the F8M set-up with a home cage reduces experimenter interference and minimizes acute stress, thus making it suitable for longitudinal testing and facilitating clinical translation. In the present study, we monitored cognitive functioning of 2-month-old APPswe/PSEN1dE9 (APP/PS1) mice over a period of 4 months. The percentage of correct responses in the DAT did not differ between wild-type and transgenic mice from 2 to 6 months of age. However, 6-month-old mice displayed an increase in the number of consecutive incorrect responses. These results demonstrate the feasibility of longitudinal testing using an automated F8M and suggest that APP/PS1 mice are not impaired at delayed spatial alternation until 6 months of age under the current experimental conditions.

BackgroundAlzheimer’s disease (AD) mouse models allow for the identification of cellular and molecular processes underlying neuronal network imbalance. In order to interpret these processes in a disease context, we need to link network changes in AD animals to those in human patients. Brain oscillations reflect neuronal network (im)balance and offer a tool to translate findings from mice to men. In this preliminary study, we investigate and compare cortical and hippocampal oscillatory activity using magnetoencephalography (MEG) in human patients and longitudinal electrophysiology recordings in AD mice.MethodsSource reconstructed resting state whole‐brain MEG of ten APP and PSEN1 mutation carriers and ten age‐ and gender‐matched control subjects were acquired. Carriers did not show objectively impaired cognitive functioning on any of the composite scores after extensive neuropsychological testing. Longitudinal local field potential recordings were obtained by implanted electrodes in APP/PS1 transgenic and wildtype controls from 3 until 10 months of age in different brain regions of the left hemisphere: hippocampus, prefrontal and parietal cortex. MEG analyses were constrained to similar brain regions. We estimated peak frequency, total (absolute broadband) and relative power across canonical frequency bands and compared these between human or mice mutation carriers and controls.ResultsHuman APP and PSEN1 mutation carriers showed lower peak frequency in the hippocampus and lower relative alpha 2 power in the precuneus and frontal cortex compared to controls (Fig1.). APP/PS1 mice also showed specific network alterations compared to wildtype control mice, but these seem to have more faster oscillations instead.ConclusionIn cognitively unimpaired human APP and PS1 mutation carriers we find oscillatory activity changes in the cortex and hippocampus, indicating network imbalance. However, opposite network changes are observed in the APP/PS1 AD mouse model compared to human mutation carriers using spectral measures. Future studies should explore other measures of network imbalance to identify potential cross‐species mechanistic links of early stage AD.