Early onset of hyperexcitability of medial mammillary body neurons in 5XFAD+ mice-an early target of Alzheimer's disease.

There are over seven million people in the United States living with Alzheimer's disease (AD), and two-thirds of these patients are postmenopausal women. In addition to neurodegenerative changes within the cortex and hippocampus, there are pronounced pathological changes in the mammillary bodies (MBs), which are thought to play a role in the development of AD. Currently, we documented in 5XFAD⁺ female mice that there was an early onset of Aβ immunostaining extracellularly that coincided with increased staining of vesicular glutamate transporter2 (vGlut2) intracellularly in medial MB neurons. We saw these changes at as early as 2 mo of age that reached a maximum by 3-4 mo. Using whole-cell current clamp and voltage clamp recordings from medial MB neurons of 4-mo-old females, we discovered that in 5XFAD⁺ ovariectomized females, the medial MB neurons were significantly depolarized and were hyperexcited based on their decreased rheobase and higher firing frequency (F-I curve) than their littermate controls. There was an increase in the persistent sodium current and the T-type calcium current that contributed to the pronounced increase in the excitability. Although medial MB neurons from 4-mo-old 5XFAD⁺ male mice did not show differences in their cellular properties, they did exhibit a pronounced increase in excitability (F-I curve) versus their littermate controls. Therefore, the hyperexcitability of medial MB neurons, which correlated with the high expression of vGlut2, could affect downstream targets in the anterior thalamic nuclei and beyond (e.g., entorhinal cortex), causing a clear cascading effect on the Papez circuitry excitability.NEW & NOTEWORTHY This study reveals early pathological changes in the medial mammillary bodies of female 5XFAD⁺ mice, an Alzheimer's disease model, with increased Aβ and vGlut2 expression beginning at 2 mo. Electrophysiological recordings show that female MB neurons are in a hyperexcitable state, driven by enhanced persistent sodium and T-type calcium currents. These changes suggest that MB dysfunction may contribute to Papez circuit hyperexcitability in AD, highlighting a previously underexplored site of pathology in postmenopausal females.