TY - JOUR
T1 - Localized chemogenetic silencing of inhibitory neurons
T2 - a novel mouse model of focal cortical epileptic activity
AU - Goldenberg, Adi Miriam
AU - Schmidt, Sarah
AU - Mitelman, Rea
AU - Levy, Dana Rubi
AU - Prigge, Matthias
AU - Katz, Yonatan
AU - Yizhar, Ofer
AU - Beck, Heinz
AU - Lampl, Ilan
N1 - This work was supported by Deutsche Forschungsgemeinschaft (DFG), Sonderforschungsbereiche (SFB 1089) to HB and IL; The DFG (BE 1822/11) to HB; EraNet (DeCipher Neuron 01EW1606) to HB and IL; The Israel Science Foundation (ISF 1539/17) to IL. This research was also supported by Marianne Manoville Beck Laboratory for Research.
PY - 2022/7/4
Y1 - 2022/7/4
N2 - Focal cortical epilepsies are frequently refractory to available anticonvulsant drug therapies. One key factor contributing to this state is the limited availability of animal models that allow to reliably study focal cortical seizures and how they recruit surrounding brain areas in vivo. In this study, we selectively expressed the inhibitory chemogenetic receptor, hM4D, in GABAergic neurons in focal cortical areas using viral gene transfer. GABAergic silencing using Clozapine-N-Oxide (CNO) demonstrated reliable induction of local epileptiform events in the electroencephalogram signal of awake freely moving mice. Anesthetized mice experiments showed consistent induction of focal epileptiform-events in both the barrel cortex (BC) and the medial prefrontal cortex (mPFC), accompanied by high-frequency oscillations, a known characteristic of human seizures. Epileptiform-events showed propagation indication with favored propagation pathways: from the BC on 1 hemisphere to its counterpart and from the BC to the mPFC, but not vice-versa. Lastly, sensory whisker-pad stimulation evoked BC epileptiform events post-CNO, highlighting the potential use of this model in studying sensory-evoked seizures. Combined, our results show that targeted chemogenetic inhibition of GABAergic neurons using hM4D can serve as a novel, versatile, and reliable model of focal cortical epileptic activity suitable for systematically studying cortical ictogenesis in different cortical areas.
AB - Focal cortical epilepsies are frequently refractory to available anticonvulsant drug therapies. One key factor contributing to this state is the limited availability of animal models that allow to reliably study focal cortical seizures and how they recruit surrounding brain areas in vivo. In this study, we selectively expressed the inhibitory chemogenetic receptor, hM4D, in GABAergic neurons in focal cortical areas using viral gene transfer. GABAergic silencing using Clozapine-N-Oxide (CNO) demonstrated reliable induction of local epileptiform events in the electroencephalogram signal of awake freely moving mice. Anesthetized mice experiments showed consistent induction of focal epileptiform-events in both the barrel cortex (BC) and the medial prefrontal cortex (mPFC), accompanied by high-frequency oscillations, a known characteristic of human seizures. Epileptiform-events showed propagation indication with favored propagation pathways: from the BC on 1 hemisphere to its counterpart and from the BC to the mPFC, but not vice-versa. Lastly, sensory whisker-pad stimulation evoked BC epileptiform events post-CNO, highlighting the potential use of this model in studying sensory-evoked seizures. Combined, our results show that targeted chemogenetic inhibition of GABAergic neurons using hM4D can serve as a novel, versatile, and reliable model of focal cortical epileptic activity suitable for systematically studying cortical ictogenesis in different cortical areas.
UR - http://www.scopus.com/inward/record.url?scp=85138322351&partnerID=8YFLogxK
U2 - 10.1093/cercor/bhac245
DO - 10.1093/cercor/bhac245
M3 - مقالة
SN - 1047-3211
VL - 33
SP - 2838
EP - 2856
JO - Cerebral cortex (New York, N.Y. 1991)
JF - Cerebral cortex (New York, N.Y. 1991)
IS - 6
M1 - bhac245
ER -