TY - JOUR
T1 - In vivo evaluation of the dentate gate theory in epilepsy
AU - Krook-Magnuson, Esther
AU - Armstrong, Caren
AU - Bui, Anh
AU - Lew, Sean
AU - Oijala, Mikko
AU - Soltesz, Ivan
N1 - Publisher Copyright:
© 2015 The Physiological Society.
PY - 2015/5/15
Y1 - 2015/5/15
N2 - The dentate gyrus is a region subject to intense study in epilepsy because of its posited role as a 'gate', acting to inhibit overexcitation in the hippocampal circuitry through its unique synaptic, cellular and network properties that result in relatively low excitability. Numerous changes predicted to produce dentate hyperexcitability are seen in epileptic patients and animal models. However, recent findings question whether changes are causative or reactive, as well as the pathophysiological relevance of the dentate in epilepsy. Critically, direct in vivo modulation of dentate 'gate' function during spontaneous seizure activity has not been explored. Therefore, using a mouse model of temporal lobe epilepsy with hippocampal sclerosis, a closed-loop system and selective optogenetic manipulation of granule cells during seizures, we directly tested the dentate 'gate' hypothesis in vivo. Consistent with the dentate gate theory, optogenetic gate restoration through granule cell hyperpolarization efficiently stopped spontaneous seizures. By contrast, optogenetic activation of granule cells exacerbated spontaneous seizures. Furthermore, activating granule cells in non-epileptic animals evoked acute seizures of increasing severity. These data indicate that the dentate gyrus is a critical node in the temporal lobe seizure network, and provide the first in vivo support for the dentate 'gate' hypothesis.
AB - The dentate gyrus is a region subject to intense study in epilepsy because of its posited role as a 'gate', acting to inhibit overexcitation in the hippocampal circuitry through its unique synaptic, cellular and network properties that result in relatively low excitability. Numerous changes predicted to produce dentate hyperexcitability are seen in epileptic patients and animal models. However, recent findings question whether changes are causative or reactive, as well as the pathophysiological relevance of the dentate in epilepsy. Critically, direct in vivo modulation of dentate 'gate' function during spontaneous seizure activity has not been explored. Therefore, using a mouse model of temporal lobe epilepsy with hippocampal sclerosis, a closed-loop system and selective optogenetic manipulation of granule cells during seizures, we directly tested the dentate 'gate' hypothesis in vivo. Consistent with the dentate gate theory, optogenetic gate restoration through granule cell hyperpolarization efficiently stopped spontaneous seizures. By contrast, optogenetic activation of granule cells exacerbated spontaneous seizures. Furthermore, activating granule cells in non-epileptic animals evoked acute seizures of increasing severity. These data indicate that the dentate gyrus is a critical node in the temporal lobe seizure network, and provide the first in vivo support for the dentate 'gate' hypothesis.
UR - http://www.scopus.com/inward/record.url?scp=84929510035&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84929510035&partnerID=8YFLogxK
U2 - 10.1113/JP270056
DO - 10.1113/JP270056
M3 - Article
C2 - 25752305
AN - SCOPUS:84929510035
SN - 0022-3751
VL - 593
SP - 2379
EP - 2388
JO - Journal of Physiology
JF - Journal of Physiology
IS - 10
ER -