| First Author | Pati S | Year | 2019 |
| Journal | eNeuro | Volume | 6 |
| Issue | 6 | PubMed ID | 31645362 |
| Mgi Jnum | J:290864 | Mgi Id | MGI:6431913 |
| Doi | 10.1523/ENEURO.0124-19.2019 | Citation | Pati S, et al. (2019) Chemogenetic Activation of Excitatory Neurons Alters Hippocampal Neurotransmission in a Dose-Dependent Manner. eNeuro 6(6):ENEURO.0124-19.2019 |
| abstractText | Designer receptors exclusively activated by designer drugs (DREADD)-based chemogenetic tools are extensively used to manipulate neuronal activity in a cell type-specific manner. Whole-cell patch-clamp recordings indicate membrane depolarization, coupled with increased neuronal firing rate, following administration of the DREADD ligand, clozapine-N-oxide (CNO) to activate the Gq-coupled DREADD, hM3Dq. Although hM3Dq has been used to enhance neuronal firing in order to manipulate diverse behaviors, often within 30 min to 1 h after CNO administration, the physiological effects on excitatory neurotransmission remain poorly understood. We investigated the influence of CNO-mediated hM3Dq DREADD activation on distinct aspects of hippocampal excitatory neurotransmission at the Schaffer collateral-CA1 synapse in hippocampal slices derived from mice expressing hM3Dq in Ca(2+)/calmodulin-dependent protein kinase alpha (CamKIIalpha)-positive excitatory neurons. Our results indicate a clear dose-dependent effect on field EPSP (fEPSP) slope, with no change noted at the lower dose of CNO (1 microM) and a significant, long-term decline in fEPSP slope observed at higher doses (5-20 microM). Further, we noted a robust theta burst stimulus (TBS) induced long-term potentiation (LTP) in the presence of the lower CNO (1 microM) dose, which was significantly attenuated at the higher CNO (20 microM) dose. Whole-cell patch-clamp recording revealed both complex dose-dependent regulation of excitability, and spontaneous and evoked activity of CA1 pyramidal neurons in response to hM3Dq activation across CNO concentrations. Our data indicate that CNO-mediated activation of the hM3Dq DREADD results in dose-dependent regulation of excitatory hippocampal neurotransmission and highlight the importance of careful interpretation of behavioral experiments involving chemogenetic manipulation. |
