Frequency-Tuned Distribution of Inhibition in the Dentate Gyrus

Abstract

Granule cells (GCs) of the dentate gyrus use sparse encoding to perform redundancy reduction, pattern separation, and novelty detection. One likely candidate mechanism to enforce low spiking activity is feedforward inhibition, in which the cortical excitatory drive from the perforant path (PP) recruits GABAergic interneurons that then inhibit GCs. Little is known, however, about how PP drive is balanced between GCs versus inhibitory neurons. In simultaneous recordings of GCs and fast-spiking (FS) interneurons from C57BL/6 mice, we find that focal PP stimulation preferentially recruits spiking in FS interneurons over GCs, because GCs require a larger excitatory synaptic current density to reach spike threshold. Blocking inhibition reversed this relationship, revealing a stronger intrinsic coupling between the PP and GCs versus FS interneurons and showing that inhibition can sparsify the output of the dentate gyrus by tightly regulating GC spike probability. Moreover, this regulation is dynamic, because the spiking profile of FS interneurons was frequency tuned, displaying bursting behavior in response to PP stimulation near theta rhythm frequency (ϳ10 Hz). The later spikes in the bursts were part of the feedback inhibitory pathway because they were driven by late EPSCs, were blocked by an inhibitor of synaptic output from GCs, and shared the same frequency dependence as GC spiking. Therefore, the temporal content of signals arriving via the PP determines whether a FS interneuron participates in only feedforward (one spike) or both feedforward and feedback (burst) inhibition.

Distinct Determinants of Sparse Activation during Granule Cell Maturation

“…Dendritic (slow) and somatic (fast) inhibition typically control synaptic integration and spike output, respectively, and both contribute to oscillatory behavior and patterned spike activity (Freund and Buzsáki, 1996;Stokes and Isaacson, 2010;Royer et al, 2012). Fast and slow IPSCs develop during the first 4 weeks following GC birth (Espó sito et al, 2005;Marín-Burgin et al, 2012) and synaptic inhibition within the DG is robust (Ewell and Jones, 2010;Yu et al, 2013); thus, we predicted that GABAergic inhibition restricts spiking even at early stages of GC development.…”

“…To address whether the I/E ratio was causally related to spiking probability, we altered the I/E ratio using 10 Hz train stimulation (Ewell and Jones, 2010). Although the action potential probability of most nonspiking cells remained zero (n ϭ 7 of 17 cells), a subset of nonspiking cells began to fire during the train (Fig.…”

Adult neurogenesis in the mammalian hippocampus: Why the dentate gyrus?

“…Mossy cells also innervate local inhibitory INs that target GCs (Scharfman 1995;Jinde et al 2012). Although significant progress has been made in unraveling the dynamics of hippocampal microcircuits in CA1 (e.g., Pouille and Scanziani 2004;Lovett-Barron et al 2012), similarly detailed analyses of DG microcircuits are only beginning (Ewell and Jones 2010).…”

Updating hippocampal representations: CA2 joins the circuit

“…For example, in addition to synapsing onto apical dendrites of granule cells, the PP-DG projection from MEC also drives fast-spiking, GABAergic interneurons in DG [110]. Granule cells and their surrounding interneurons are tuned to respond differentially to particular oscillatory frequencies of input from EC [110], hence the net impact of PP input on GC firing could be adaptively filtered according to its pattern and does not depend solely on excitation. Models suggest that filtering of this kind by dynamically tuned inhibition may be used to divert information via different routes during different behavioral states [111,112].…”