RT Journal Article
SR Electronic
T1 Level of hM4D(Gi) DREADD Expression Determines Inhibitory and Neurotoxic Effects in the Hippocampus
JF eneuro
JO eNeuro
FD Society for Neuroscience
SP ENEURO.0105-21.2021
DO 10.1523/ENEURO.0105-21.2021
VO 8
IS 6
A1 Marie-Gabrielle Goossens
A1 Lars Emil Larsen
A1 Marijke Vergaelen
A1 Wytse Wadman
A1 Chris Van den Haute
A1 Wayra Brackx
A1 Silke Proesmans
A1 Jana Desloovere
A1 Emma Christiaen
A1 Erine Craey
A1 Christian Vanhove
A1 Kristl Vonck
A1 Paul Boon
A1 Robrecht Raedt
YR 2021
UL http://www.eneuro.org/content/8/6/ENEURO.0105-21.2021.abstract
AB Selective neuromodulation using designer receptors exclusively activated by designer drugs (DREADDs) has become an increasingly important research tool, as well as an emerging therapeutic approach. However, the safety profile of DREADD expression is unknown. Here, different titers of adeno-associated viral (AAV) vector were administered in an attempt to vary total expression levels of the inhibitory DREADD hM4D(Gi) in excitatory hippocampal neurons. Male Sprague Dawley rats were injected with AAV2/7 encoding DREADD-mCherry, DREADD, or mCherry. Pronounced neuronal loss and neuroinflammatory reactions were observed after transduction with the high titer DREADD AAV, which also resulted in the highest DREADD expression levels. No such effects were observed in the mCherry control group, despite an equally high titer, nor in conditions where lower viral vector titers were injected. In the high titer DREADD conditions, dentate gyrus (DG) evoked potentials were inhibited on clozapine-induced activation of hM4D(Gi), while in low titer conditions DG evoked potentials were enhanced. Recordings of single neuronal activity nevertheless indicated a reduction in spontaneous firing of granule cell layer neurons. Our results indicate that prolonged, high levels of DREADD expression can have neurotoxic effects and that chemogenetic suppression of excitatory hippocampal neurons can paradoxically enhance DG evoked potentials.