Interplay of Entorhinal Input and Local Inhibitory Network in the Hippocampus at the Origin of Slow Inhibition in Granule Cells

Abstract

Neuronal activity from the entorhinal cortex propagates through the perforant path (PP) to the molecular layer 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 A -R or metabotropic GABA B -R. Although postsynaptic GABA A and GABA B -R differ in their location at the synapse, mixed GABA A/B -R IPSPs can also occur. Here we describe a slow inhibition mechanism in mouse GCs recorded from either sex, mediated by GABA A/B -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 B -R IPSPs. As a result, LLH alters GC firing patterns and the responses to concomitant excitatory signals are also affected. Synaptic recruitment of feedforward inhibition and subsequent GABA release from interneurons, also successfully trigger mixed GABA responses in GCs. 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. Significance StatementOur 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 the 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.

Density of GABAB Receptors Is Reduced in Granule Cells of the Hippocampus in a Mouse Model of Alzheimer’s Disease

“…Using the SDS-FRL technique, we detected the majority of postsynaptic GABA B1 immunoparticles along the extrasynaptic membrane of dendritic spines and shafts of granule cells, consistent with our immunoreactions at the light microscopic level. GABA B receptors localised to postsynaptic sites activate G protein-gated inwardly rectifying K+ (GIRK) channels and are responsible for the slow inhibitory postsynaptic potentials IPSP [47,48], and GABA B receptor-mediated slow inhibitory responses have been found in granule cells [31,[49][50][51][52]. The prevalent localisation of GABA B1 in spines and dendrites we revealed here is in agreement with those electrophysiological observations showing the postsynaptic role of GABA B receptors in granule cells.…”

Neuroligin-3 Regulates Excitatory Synaptic Transmission and EPSP-Spike Coupling in the Dentate Gyrus In Vivo

“…Nlgn3 was shown to regulate inhibitory synaptic transmission from dendrite-targeting somatostatin (SOM) expressing interneurons in hippocampal subregion CA1 [ 28 ]. Feedforward inhibition from molecular layer interneurons decreases the granule cell excitability during entorhinal input integration [ 55 ], so changes in dendritic inhibition might alter the granule cell excitability without affecting PPI (cf. [ 56 ]).…”

Circuit-based intervention corrects excessive dentate gyrus output in the Fragile X mouse model

“…Considering that granule cells are the only output neurons in the dentate gyrus and thus integrate all dentate circuit operations, these results indicate that loss of FMRP causes abnormal dentate information processing, leading to excessive dentate output. The dentate GABAergic system plays a critical role in the above gamma-suppression of granule cell output (Mircheva, Peralta & Toth 2019). Based on our findings, we hypothesized that the compromised dentate inhibitory pathway in the Fmr1 KO mice weakens gammasuppression through enhancing the EPSP summation in granule cells.…”

“…The power of theta-gamma oscillations is particularly high in the dentate gyrus (Csicsvari et al 2003), and plays a critical role in many dentate functions, such as pattern separation (Leutgeb et al 2007), information coding (Mizuseki et al 2009, Pernia-Andrade & Jonas 2014), and thus learning/memory (Bott et al 2016, Lisman & Jensen 2013, Neves et al 2022). In order to evaluate the contribution of MC defects in Fmr1 KO mice to this critical dentate function, we used a protocol of double-oscillation interplay at the single-cell level (Hasselmo, Giocomo & Zilli 2007, Mircheva, Peralta & Toth 2019). In this paradigm, gamma (∼50Hz) frequency stimulation of PP suppresses granule cell output driven by PP stimulation at the theta (∼5Hz) frequency range (gamma-suppression, for brevity).…”