Abnormal glutamatergic neurotransmission and cognitive impairment in male APPNL-F/NL-F mice.

Abstract

It is well established that glutamatergic neurotransmission plays an essential role in learning and memory. In Alzheimer's disease (AD), previous studies indicate that glutamate dynamics shift with disease progression, inciting cognitive impairment and further perpetuating disease pathology. Here, we build upon previous work by utilizing a novel knock-in mouse model of AD (APPNL-F/NL-F ) to characterize hippocampal glutamate signaling and cognition during late stage AD. At 18-24 months old, male APPNL-F/NL-F and genetic background control (C57BL/6) mice underwent cognitive assessment through a Morris water maze (MWM) task. Following MWM, basal and 70 mM KCl stimulus-evoked glutamate release was measured in the CA1 region of the hippocampus using a glutamate-selective microelectrode in isoflurane anesthetized mice. Briefly, microelectrodes were coated with L-glutamate oxidase for the detection of glutamate at the electrode surface. A layer of 1,3-phenylenediamine was applied to prevent detection of electroactive compounds at the recording potential (+0.7 volts). A micropipette (diameter = ∼20 µm) was attached 50-100 µm from the recording surface for local application of KCl). Calibration and recordings are taken using the FAST-16 recording software. Preliminary MWM data indicates no significant differences in spatial learning performance (corrected integrated path length and cumulative distance from the platform) between C57BL/6 and APPNL-F/NL-F mice. We observed a trend of decreased platform entries during the probe trial, supporting long-term spatial memory impairment in APPNL-F/NL-F mice. Preliminary in vivo CA1 data support a trend of decreased basal and stimulus-evoked glutamate levels in APPNL-F/NL-F mice compared to control mice. Preliminary findings support impaired long-term spatial memory and hypoactive glutamatergic neurotransmission in aged male APPNL-F/NL-F mice compared to age-matched C57BL/6 mice. Lack of glutamate activity in late-stage AD may underlie cognitive decline in APPNL-F/NL-F mice. Our laboratory previously observed similar findings in a transgenic AD model. However, unlike APPNL-F/NL-F mice, those mice also displayed increased basal glutamate levels. This divergence could be attributed to possible differences in glutamate transporter expression or activity with disease progression. Together, these data support loss of glutamate excitation with amyloid accumulation. Studies are ongoing.