(898.7) nTS Glutamate Signaling in the Chemoreflex Axis of an Alzheimers Disease Rat Model

Poster Board Number: E410

Robert Tipton (A.T. Still University), Chuma Humphrey (A.T. Still University), Dorothy Scales (A.T. Still University), Daniela Ostrowski (Truman State University), Tim Ostrowski (A.T. Still University)

Respiratory dysfunction is commonly observed in Alzheimer’s disease (AD) and likely due to neuronal alterations of the respiratory network in the brain. The streptozotocin (STZ) -induced AD model mimics respiratory problems seen in humans and exhibits neuronal hyperactivity in the nucleus tractus solitarii (nTS), the central integration site for respiratory afferents in the brainstem. This ongoing study looks at the changes of glutamate signaling within the chemoreflex axis as a possible mechanism for nTS hyperactivity and respiratory dysfunction in STZ-AD.

AD was induced by intracerebroventricular injection of 2 mg/kg STZ in 6-week old male Sprague Dawley rats. After 14 days, caudal nTS neurons within close proximity of DiI-labeled chemoafferent terminals were recorded using the patch clamp technique. Electrical stimulation of the tractus solitarii (TS) generated glutamatergic excitatory postsynaptic currents (EPSCs) that were compared between experimental groups. Consistent with enhanced glutamatergic signaling, TS-EPSC amplitude was increased in STZ-AD. High TS stimulation frequency induced a time and frequency dependent depression that was similar between groups, indicating no change in presynaptic vesicle turnover or postsynaptic receptor desensitization. On the other hand, asynchronous EPSCs following high frequency stimulation seemed enhanced in STZ-AD, supporting an increased excitatory tone in the nTS. Immunohistochemical analysis of the caudal nTS revealed no change in neuron number but showed a reduced synaptic density in the AD model. Astrocyte number and morphology were unchanged between groups. However, microglia, which are able to influence glutamate-handling of astrocytes, showed an activated phenotype.

Overall, our data show enhanced glutamatergic signaling in the chemoreflex axis contributing to nTS hyperactivity of the STZ-AD model. nTS hyperactivity may lead to the observed respiratory dysfunction in this model and potentially constitutes a mechanism for sleep disordered breathing in AD patients.

KCOM Biomedical Graduate Program (RKT amp;amp;TDO); Truman State University TruScholar Research Program (CMH); A.T. Still University Warner/Fermaturo Grant (TDO); NIH R15AG065927 (TDO amp;amp; DO)