Neurophysiological alterations in mice and humans carrying mutations in APP and PSEN1 genes.

BACKGROUND: Studies in animal models of Alzheimer's disease (AD) have provided valuable insights into the molecular and cellular processes underlying neuronal network dysfunction. Whether and how AD-related neurophysiological alterations translate between mice and humans remains however uncertain. METHODS: We characterized neurophysiological alterations in mice and humans carrying AD mutations in the APP and/or PSEN1 genes, focusing on early pre-symptomatic changes. Longitudinal local field potential recordings were performed in APP/PS1 mice and cross-sectional magnetoencephalography recordings in human APP and/or PSEN1 mutation carriers. All recordings were acquired in the left frontal cortex, parietal cortex, and hippocampus. Spectral power and functional connectivity were analyzed and compared with wildtype control mice and healthy age-matched human subjects. RESULTS: APP/PS1 mice showed increased absolute power, especially at higher frequencies (beta and gamma) and predominantly between 3 and 6 moa. Relative power showed an overall shift from lower to higher frequencies over almost the entire recording period and across all three brain regions. Human mutation carriers, on the other hand, did not show changes in power except for an increase in relative theta power in the hippocampus. Mouse parietal cortex and hippocampal power spectra showed a characteristic peak at around 8 Hz which was not significantly altered in transgenic mice. Human power spectra showed a characteristic peak at around 9 Hz, the frequency of which was significantly reduced in mutation carriers. Significant alterations in functional connectivity were detected in theta, alpha, beta, and gamma frequency bands, but the exact frequency range and direction of change differed for APP/PS1 mice and human mutation carriers. CONCLUSIONS: Both mice and humans carrying APP and/or PSEN1 mutations show abnormal neurophysiological activity, but several measures do not translate one-to-one between species. Alterations in absolute and relative power in mice should be interpreted with care and may be due to overexpression of amyloid in combination with the absence of tau pathology and cholinergic degeneration. Future studies should explore whether changes in brain activity in other AD mouse models, for instance, those also including tau pathology, provide better translation to the human AD continuum.

Longitudinal Assessment of Working Memory Performance in the APPswe/PSEN1dE9 Mouse Model of Alzheimer's Disease Using an Automated Figure-8-Maze.

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.

Homeostatic Presynaptic Plasticity Is Specifically Regulated by P/Q-type Ca2+ Channels at Mammalian Hippocampal Synapses.

Voltage-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.