Decreased excitability of locus coeruleus neurons during hypercapnia is exaggerated in the streptozotocin-model of Alzheimer's disease

• Published in: Experimental neurology Vol. 328; p. 113250
• Main Authors: Vicente, Mariane C., Humphrey, Chuma M., Gargaglioni, Luciane H., Ostrowski, Tim D.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-06-2020
• Subjects: Alzheimer Disease - chemically induced; Alzheimer Disease - physiopathology; Animals; Brain slice; Brainstem; Carbon Dioxide - pharmacology; Chemosensitivity; CO2; Disease Models, Animal; Hypercapnia - physiopathology; Intracerebroventricular; Locus Coeruleus - drug effects; Locus Coeruleus - physiopathology; Male; Neurodegeneration; Neurons - drug effects; Neurons - physiology; Patch clamp; Potassium currents; Rats; Rats, Sprague-Dawley; Streptozocin - toxicity; STZ; Intracerebroventricular; Neurodegeneration; Brainstem; CO2; STZ; Patch clamp; Chemosensitivity; Brain slice; Potassium currents; CO
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1016/j.expneurol.2020.113250

The locus coeruleus (LC) is a pontine nucleus important for respiratory control and central chemoreception. It is affected in Alzheimer's disease (AD) and alteration of LC cell function may account for respiratory problems observed in AD patients. In the current study, we tested the electrophysiological properties and CO2/pH sensitivity of LC neurons in a model for AD. Sporadic AD was induced in rats by intracerebroventricular injection of 2 mg/kg streptozotocin (STZ), which induces behavioral and molecular impairments found in AD. LC neurons were recorded using the patch clamp technique and tested for responses to CO2 (10% CO2, pH = 7.0). The majority (~60%) of noradrenergic LC neurons in adult rats were inhibited by CO2 exposure as indicated by a significant decrease in action potential (AP) discharge to step depolarizations. The STZ-AD rat model had a greater sensitivity to CO2 than controls. The increased CO2-sensitivity was demonstrated by a significantly stronger inhibition of activity during hypercapnia that was in part due to hyperpolarization of the resting membrane potential. Reduction of AP discharge in both groups was generally accompanied by lower LC network activity, depolarized AP threshold, increased AP repolarization, and increased current through a subpopulation of voltage-gated K+ channels (KV). The latter was indicated by enhanced transient KV currents particularly in the STZ-AD group. Interestingly, steady-state KV currents were reduced under hypercapnia, a change that would favor enhanced AP discharge. However, the collective response of most LC neurons in adult rats, and particularly those in the STZ-AD group, was inhibited by CO2.
•The majority of Alzheimer’s disease (AD) patients suffer from disturbed respiratory function.•Chemosensitive Locus coeruleus neurons in adult rats are mainly inhibited by increased CO2.•The streptozotocin-induced model of AD (STZ-AD) had a significantly greater sensitivity to CO2.•CO2 hyperpolarized resting membrane potential, depolarized spike threshold, and reduced A-type K+ current in STZ-AD.