The CO2/pH Chemosensitivity of Locus Coeruleus Neurons Is Increased in the Streptozotocin‐Model of Alzheimer's Disease

Abstract

Patients with Alzheimer's disease (AD) develop pathological changes in the Locus Coeruleus (LC), an important pontine nucleus involved in respiratory control and central chemoreception. In addition, AD patients have breathing disturbances that may be related to LC dysfunction. Here, we tested the electrophysiological properties of LC neurons in a model for AD. Sporadic AD was induced in rats (6–7 weeks) by intracerebroventricular injection of streptozotocin (STZ; 2 mg/kg). After 14 days following injection, LC neurons were recorded using the patch clamp technique and tested for CO2 chemosensitivity (10% CO2, pH = 7.0).Hypercapnic exposure lowered current‐evoked spike discharge in the majority of LC neurons (~60%) when compared to baseline responses. The remaining cells either increased spiking (~20%) or did not respond (~20%) to CO2. Within the cell group that was inhibited by hypercapnia, baseline spike discharge to current injection was similar between control and STZ rats. These responses decreased significantly in both groups when exposed to 10% CO2 (bsl vs. 10% CO2: CTL, p=0.003, n=8 and STZ, p=0.001, n=9). The CO2‐induced decrease in spike discharge of the STZ group was significantly lower when compared to control (CTL vs. STZ, p=0.038), indicating greater sensitivity to hypercapnia. However, we observed no difference in resting membrane potential and input resistance (Ri, resistance across the cell membrane) between groups at baseline and CO2. Despite lack of difference between groups, within the STZ group Ri decreased significantly with hypercapnia (bsl, 126.5 ± 14.9 MΩ vs. 10% CO2, 98.4 ± 8.2 MΩ; p=0.01), indicating ion channel opening when exposed to CO2. Analysis of the current‐voltage relationship only showed a significant decrease in the steady state current under CO2 (bsl vs. 10% CO2: CTL, p=0.002, and STZ, p=0.001,), which had a similar magnitude in both groups. Close analysis of action potential (AP) shape (spike threshold, peak, slope, peak to anti‐peak) showed no difference between groups. Within the STZ rats, however, spike threshold was significantly shifted to more positive potentials when exposed to CO2 (−39.6 ± 1.9 mV vs −34.8 ± 2.2 mV, p=0.01). This shift in spike threshold likely contributes to the pronounced decrease in spike discharge in the STZ group during hypercapnic conditions.In summary, our data suggest that the majority of LC neurons in adult rats are inhibited by CO2. Further, the STZ‐treated group exhibits a greater sensitivity to CO2, possibly due to an increased spike threshold and opening of additional, yet unidentified membrane channels. A decreased excitability of LC neurons may play a role in the respiratory dysfunction observed in patients with AD.Support or Funding InformationFAPESP 2017/21750‐9 (MCV); ATSU seed money (TDO)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.