Target-specific alterations in the VIP inhibitory drive to hippocampal GABAergic cells after status epilepticus

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Abstract

Status epilepticus (SE) is associated with complex reorganization of hippocampal circuits involving a significant loss of specific subtypes of GABAergic interneurons. While adaptive circuit plasticity may increase the chances for recruitment of surviving interneurons, the underlying mechanisms remain largely unknown. We studied the alterations in the inhibitory tone received by the hippocampal CA1 oriens/alveus (O/A) interneurons from the vasoactive intestinal peptide (VIP)- and calretinin (CR)-expressing interneurons using the pilocarpine-induced status epilepticus (SE) model of epilepsy. Our data showed that, while the overall density of the VIP/CR-co-expressing interneurons remained preserved, the number of axonal boutons made by these cells within the CA1 O/A was significantly lower after SE. Furthermore, VIP/CR interneurons exhibited significant alterations in their dendritic morphology and passive membrane properties. Subsequently, while all O/A interneuron types, including oriens-lacunosum moleculare (OLM), bistratified (Bis) and basket cells, exhibited decrease in spontaneous inhibitory drive, Bis and basket cells showed a smaller amplitude of light-evoked IPSCs mediated by the selective activation of VIP-positive interneurons. These data point to the target cell-specific changes in the inhibitory tone provided by the VIP cells to O/A interneurons following SE. Given that basket, Bis and OLM cells coordinate different subcellular domains of pyramidal neurons, significant disinhibition of basket and Bis cells along with a previously reported loss of the OLMs may result in a redistribution of inhibition converging onto pyramidal neurons, with a direct impact onto their recruitment to epileptiform network activity and seizure propagation.

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