Discrete subicular circuits control generalization of hippocampal seizures

Abstract

Epilepsy is considered a circuit-level dysfunction associated with imbalanced excitation-inhibition, it is therapeutically necessary to identify key brain regions and related circuits in epilepsy. The subiculum is an essential participant in epileptic seizures, but the circuit mechanism underlying its role remains largely elusive. Here we deconstruct the diversity of subicular circuits in a mouse model of epilepsy. We find that excitatory subicular pyramidal neurons heterogeneously control the generalization of hippocampal seizures by projecting to different downstream regions. Notably, anterior thalamus-projecting subicular neurons bidirectionally mediate seizures, while entorhinal cortex-projecting subicular neurons act oppositely in seizure modulation. These two subpopulations are structurally and functionally dissociable. An intrinsically enhanced hyperpolarization-activated current and robust bursting intensity in anterior thalamus-projecting neurons facilitate synaptic transmission, thus contributing to the generalization of hippocampal seizures. These results demonstrate that subicular circuits have diverse roles in epilepsy, suggesting the necessity to precisely target specific subicular circuits for effective treatment of epilepsy.

Commissural dentate granule cell projections and their rapid formation in the adult brain

“…Here, we showed that commissural GCs contribute to an inter-hippocampal excitatory-to-excitatory circuit. By directly targeting pyramidal cells in the contralateral hippocampus, commissural GCs bypass several feedback and feedforward inhibitory microcircuits which could control seizures ( 47 ), suggesting that excessive activation of this cell type may facilitate the generation and/or generalization of seizures ( 48 ).…”

From the Subiculum to the Anterior Nuclei of the Thalamus: The Key to Hippocampal Seizure Generalization?

“…Then, using a retrograde tracer, they showed that deep subicular pyramidal cells project to the ANT while superficial subicular neurons project to the EC. 5 To assess the impact of the deep subicular projections to the ANT versus superficial projections to the EC, the authors used an optogenetic strategy. Activation of the subicular afferents that terminate in the ANT produced a proseizure effect, and inhibition of these terminals had an anti-seizure effect.…”

“…These findings were paralleled with a chemogenetic strategy in a chronic intrahippocampal CA1 kainic acid model of TLE. 5 Next, the authors explored whether the firing characteristics of deep versus superficial neurons also played a part. Using axonal calcium imaging they showed that the timing of the inputs to the ANT and EC differ.…”

“…In their concluding experiments, Fei and colleagues showed, in the kindling model, using both pharmacological and genetic strategies, that HCN channel conductance in deep subicular pyramidal cells specifically is proconvulsive. 5 Fei and colleagues' study elegantly showed the importance of the projections from the deep subicular pyramidal layer to the ANT for secondary seizure generalization, including a potential proepileptic role of HCN-1 channel expression in these neurons. 5 This study illustrates that there is functional heterogeneity in subicular pyramidal neurons, as has been previously reported in CA1 6,7 and CA3.…”

“…5 Fei and colleagues' study elegantly showed the importance of the projections from the deep subicular pyramidal layer to the ANT for secondary seizure generalization, including a potential proepileptic role of HCN-1 channel expression in these neurons. 5 This study illustrates that there is functional heterogeneity in subicular pyramidal neurons, as has been previously reported in CA1 6,7 and CA3. 8 Targeting only the deep subicular pyramidal neurons projecting to ANT with a viral gene therapy could be a therapeutic strategy.…”