Chemogenetic modulation of the rat locus coeruleus alters hippocampal noradrenaline release and modulates perforant path-evoked responses.

Abstract

Introduction: The locus coeruleus (LC)-noradrenaline (NA) system plays a crucial role in modulating neuronal excitability and plasticity. In epilepsy, the LC-NA system plays an important role in regulating seizure thresholds and severity, with elevated NA release mediating the seizure-suppressing effects of vagus nerve stimulation (VNS). We investigated whether chemogenetic LC activation is able to increase hippocampal NA release and affect hippocampal electrophysiology in anesthetized rats.

Methods: 22 male Sprague-Dawley rats were injected with the viral vector AAV9-hSyn-NE2m in the hippocampus to induce expression of the GRAB_NE2m biosensor to locally measure changes in extracellular NA. 15/22 rats were injected with the CAV2-PRSx8-hM3Dq hSyn-mCherry viral vector in the LC to express the excitatory DREADD hM3Dq, allowing LC activation with deschloroclozapine (DCZ), and 7/22 with CAV2-PRSx8-GtACR2 as a control. A perforant path stimulation electrode and a dentate gyrus (DG) recording electrode were implanted for local field potential (LFP) and evoked potential (EP) recording as well as a DG optical fiber for GRAB_NE2m fluorescence measurement.

Results: In a significant number of rats (7/15) we found an increase in hippocampal NA release, field excitatory post synaptic potential (fEPSP) slope and population spike (PS) amplitude, indicating an increase in excitatory neurotransmission and neuronal output. 4/15 rats showed a decrease in NA release without changes in fEPSP slope or PS amplitude, and 4/15 showed no change in NA release.

Discussion: These findings indicate that chemogenetic activation of the LC-NA system can modulate hippocampal evoked responses, supporting further exploration of its role in health and disease, such as in epilepsy.