Swietek, B. | Search bioRxiv

bioRxiv2021

Differential Activity-Dependent Scaling of Synaptic Inhibition and Parvalbumin Interneuron Recruitment in Dentate Projection Neuron Subtypes

Strong inhibitory synaptic gating of dentate gyrus granule cells (GCs), attributed largely to fast-spiking parvalbumin interneurons (PV-INs), is essential to maintain sparse network activity needed for dentate dependent behaviors. However, the contribution of PV-INs to basal and input driven sustained synaptic inhibition in GCs and semilunar granule cells (SGCs), a sparse morphologically distinct dentate projection neuron subtype are currently unknown. In studies conducted in hippocampal slices from mice, we find that although basal inhibitory postsynaptic currents (IPSCs) are more frequent in SGCs and optical activation of PV-INs elicited IPSCs in both GCs and SGCs, optical suppression of PV-INs failed to reduce IPSC frequency in either cell type. Amplitude and kinetics of IPSCs evoked by perforant path activation were not different between GCs and SGCs. However, the robust increase in sustained polysynaptic IPSCs elicited by paired afferent stimulation was lower in SGCs than in simultaneously recorded GCs. Optical suppression of PV-IN selectively reduced sustained IPSCs in SGCs but not in GCs. These results demonstrate that PV-INs, while contributing minimally to basal synaptic inhibition in both GCs and SGCs in slices, mediate sustained feedback inhibition selectively in SGCs. The temporally selective blunting of activity-driven sustained inhibitory gating of SGCs could support their preferential and persistent recruitment during behavioral tasks. Significance StatementOur study identifies that feedback inhibitory regulation of dentate semilunar granule cells, a sparse and functionally distinct class of projection neurons, differs from that of the classical projection neurons, granule cells. Notably, we demonstrate relatively lower activity dependent increase in sustained feedback inhibitory synaptic inputs to semilunar granule cells when compared to granule cells which would facilitate their persistent activity and preferential recruitment as part of memory ensembles. Since dentate granule cell activity levels during memory processing are heavily shaped by basal and feedback inhibition, the fundamental differences in basal and evoked sustained inhibition between semilunar granule cells and granule cells characterized here provide a framework to reorganize current understanding of the dentate circuit processing.

neuroscience↗

bioRxiv2019

Neuronal TLR4 signaling enhances AMPA currents and drives posttraumatic epileptogenesis

Traumatic brain injury is a major risk factor for acquired epilepsies and understanding the mechanisms underlying the early pathophysiology could yield viable therapeutic targets. Growing evidence indicates a role for inflammatory signaling in modifying neuronal excitability and promoting epileptogenesis. Here, we identify that signaling through an innate immune receptor, toll-like receptor 4 (TLR4), in neurons, augments calcium-permeable AMPA receptor (CP-AMPAR) currents in the hippocampal dentate gyrus after brain injury. Blocking TLR4 signaling in vivo shortly after brain injury reduced dentate network excitability and seizure susceptibility. When blocking of TLR4 signaling after injury was delayed, however, this treatment failed to reduce post-injury seizure susceptibility. Further, TLR4 signal blocking was less efficacious in limiting seizure susceptibility when AMPAR currents, downstream targets of TLR4 signaling, were transiently enhanced. Paradoxically, blocking TLR4 signaling augmented both network excitability and seizure susceptibility in uninjured controls. Despite the differential effect on seizure susceptibility, TLR4 antagonism suppressed cellular inflammatory responses after injury without impacting sham controls. These findings demonstrate that independently of glia, the immune receptor TLR4 directly regulates post-traumatic neuronal excitability. Moreover, the TLR4-dependent early increase in dentate excitability is causally associated with epileptogenesis. Identification and selective targeting of the mechanisms underlying the aberrant TLR4-mediated increase in CP-AMPAR signaling after injury may prevent epileptogenesis after traumatic brain injury. Graphical AbstractO_ST_ABSSummary of interactions between TLR4 signaling and brain injury on network excitability and epileptogenesisC_ST_ABSGraphic illustration of the effect of injury and early TLR4 antagonist treatment on early network excitability and the long-term network state. The schematic neurons include TLR4 and AMPAR subunit expression profiles in the acute phase of sham or brain injury. The corresponding early effects on network excitability are depicted by schematic population response traces (inset on upper left). Note the increase in excitability of the uninjured neuron after TLR4 antagonism without changes in AMPAR expression. Note also the increase in TLR4, calcium permeable AMPARs and population excitability after injury and its reduction by TLR4 antagonist treatment. Ampakine enhancement of excitability during TLR4 antagonism is illustrated. The early phase responses and manipulations (including injury, treatments, and molecular responses) are superimposed on a two-tone color-coded network state topology where green indicates low-normal network excitability, ensuring network stability and low risk for epilepsy (Inset on upper right). Note the correspondence between early excitability state (population response profile) and long-term seizure susceptibility and the effects of pharmacological manipulations.

neuroscience↗