Interplay of entorhinal input and local inhibitory network in the hippocampus at the origin of slow inhibition in granule cells.

TitleInterplay of entorhinal input and local inhibitory network in the hippocampus at the origin of slow inhibition in granule cells.
Publication TypeJournal Article
Year of Publication2019
AuthorsMircheva, Y, Peralta, MR, Toth, K
JournalJ Neurosci
Date Published2019 Jun 10

Neuronal activity from the entorhinal cortex (EC) propagates through the perforant path (PP) to the molecular layer (ML) of the dentate gyrus (DG) where information is filtered and converted into sparse hippocampal code. Nearly simultaneous signaling to both granule cells (GC) and local interneurons (INs) engages network interactions that will modulate input integration and output generation. When triggered, GABA release from interneurons counteracts the glutamatergic signals of PP terminals, scaling down the overall DG activation. Inhibition occurs at fast or slow timescales depending on the activation of ionotropic GABA-R or metabotropic GABA-R. Although postsynaptic GABA and GABA-R differ in their location at the synapse, mixed GABA -R IPSPs can also occur. Here we describe a slow inhibition mechanism in mouse GCs recorded from either sex, mediated by GABA -R in combination with metabotropic glutamate receptors. Short burst PP stimulation in the gamma frequency range lead to a long-lasting hyperpolarization (LLH) of the GCs with a duration that exceeds GABA-R IPSPs. As a result, LLH alters GC firing patterns and the responses to concomitant excitatory signals are altered. Synaptic recruitment of feedforward inhibition and subsequent GABA release from interneurons, also successfully trigger mixed GABA responses in GCs. Taken together these results suggest that slow inhibition through LLH leads to reduced excitability of GCs during entorhinal input integration. The implication of LLH in regulation of neuronal excitability suggests it also contributes to the sparse population coding in DG. Our study describes a long-lasting hyperpolarization (LLH) in hippocampal granule cells. We used whole cell patch clamp recordings and an optogenetic approach to characterize this event. LLH is a slow inhibitory mechanism that occurs following the stimulation of perforant pathway in the molecular layer of the dentate gyrus. We found that it is mediated via postsynaptic ionotropic and metabotropic GABA and metabotropic glutamate receptors. The duration of LLH exceeds previously described IPSPs mediated by any of these receptors. The activation of LLH requires presynaptic gamma frequency bursts and recruitment of the local feedforward inhibition. LLH defines prolonged periods of low excitability of GCs and a restrained neuronal discharge. Our results suggest that LLH can contribute to sparse activation of GCs.

Alternate JournalJ. Neurosci.
PubMed ID31182636