Perturbing cortical networks: in vivo electrophysiological consequences of pan-neuronal chemogenetic manipulations using deschloroclozapine

Péter Kovács; Lauren N Beloate; Nanyin Zhang

doi:10.3389/fnins.2024.1396978

Perturbing cortical networks: in vivo electrophysiological consequences of pan-neuronal chemogenetic manipulations using deschloroclozapine

Front Neurosci. 2024 Apr 25:18:1396978. doi: 10.3389/fnins.2024.1396978. eCollection 2024.

Authors

Péter Kovács^#¹, Lauren N Beloate¹, Nanyin Zhang^{1

2

3

4}

Affiliations

¹ Department of Biomedical Engineering, Pennsylvania State University, University Park, PA, United States.
² Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, PA, United States.
³ Center for Neural Engineering, Pennsylvania State University, University Park, PA, United States.
⁴ Center for Neurotechnology in Mental Health Research, Pennsylvania State University, University Park, PA, United States.

^# Contributed equally.

Abstract

Introduction: Chemogenetic techniques, specifically the use of Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), have become invaluable tools in neuroscience research. Yet, the understanding of how Gq- and Gicoupled DREADDs alter local field potential (LFP) oscillations in vivo remains incomplete.

Methods: This study investigates the in vivo electrophysiological effects of DREADD actuation by deschloroclozapine, on spontaneous firing rate and LFP oscillations recorded from the anterior cingulate cortex in lightly anesthetized male rats.

Results: Unexpectedly, in response to the administration of deschloroclozapine, we observed inhibitory effects with pan-neuronal hM3D(Gq) stimulation, and excitatory effects with pan-neuronal hM4D(Gi) stimulation in a significant portion of neurons. These results emphasize the need to account for indirect perturbation effects at the local neuronal network level in vivo, particularly when not all neurons express the chemogenetic receptors uniformly. In the current study, for instance, the majority of cells that were transduced with both hM3D(Gq) and hM4D(Gi) were GABAergic. Moreover, we found that panneuronal cortical chemogenetic modulation can profoundly alter oscillatory neuronal activity, presenting a potential research tool or therapeutic strategy in several neuropsychiatric models and diseases.

Discussion: These findings help to optimize the use of chemogenetic techniques in neuroscience research and open new possibilities for novel therapeutic strategies.

Keywords: DCZ; DREADD = designer receptor exclusively activated by designer drugs; GAD67; chemogenetics; deschloroclozapine; in vivo electrophysiology; neuronal oscillations; rat – brain.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. The present study was partially supported by the National Center for Complementary and Integrative Health (R01AT011665).