Parvalbumin+ interneurons obey unique connectivity rules and establish a powerful lateral-inhibition microcircuit in dentate gyrus

Abstract

Parvalbumin-positive (PV+) GABAergic interneurons in hippocampal microcircuits are thought to play a key role in several higher network functions, such as feedforward and feedback inhibition, network oscillations, and pattern separation. Fast lateral inhibition mediated by GABAergic interneurons may implement a winner-takes-all mechanism in the hippocampal input layer. However, it is not clear whether the functional connectivity rules of granule cells (GCs) and interneurons in the dentate gyrus are consistent with such a mechanism. Using simultaneous patch-clamp recordings from up to seven GCs and up to four PV+ interneurons in the dentate gyrus, we find that connectivity is structured in space, synapse-specific, and enriched in specific disynaptic motifs. In contrast to the neocortex, lateral inhibition in the dentate gyrus (in which a GC inhibits neighboring GCs via a PV+ interneuron) is ~ 10-times more abundant than recurrent inhibition (in which a GC inhibits itself). Thus, unique connectivity rules may enable the dentate gyrus to perform specific higher-order computations.

Quantitative properties of a feedback circuit predict frequency-dependent pattern separation

“…However, in contrast to the neocortex 50,52 and area CA3 51 , we did not find single GCinduced feedback inhibition in any of these experiments, consistent with a recent large scale study reporting that such connections are extremely sparse (0.124%) 22 .…”

“…Recent evidence indicates that inhibition by individual PV + fast spiking hilar border interneurons is non-uniformly distributed over space, with decreasing connectivity and inhibition at greater distances from the interneuron 22,54 . To test whether feedback inhibition by the entire ensemble of feedback inhibitory interneurons also displays a spatial gradient we activated cell populations at 100 µm intervals along the GC layer while recording inhibition in individual GCs (Fig.…”

“…the relation between the number of active principal cells and the resulting feedback inhibition. This property of the feedback circuit is determined by complex, mainly hilar cellular connectivity patterns 21,22 ( Supplementary Table 1). While delving into detailed cell-cell connectivities is clearly important, such studies do not allow the quantitative determination of the gain and dynamic range of net feedback inhibition 50,52 .…”

“…The DG is thought to subserve this task by converting different types of inputs to sparse, nonoverlapping activity patterns of granule cells (GCs). However, in contrast to the insect olfactory system, the DG feedback circuit is extremely complex, comprising numerous interconnected interneuron types (Supplementary Table 1) [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39] . For instance, interneurons subserving feedback inhibition are also incorporated into circuits mediating feedforward inhibition 32,35,40 and disinhibition 21,29 .…”

Differential coupling of adult-born granule cells to parvalbumin and somatostatin interneurons

“…Activation of mature GCs recruit feedback loops that limit activation of the GCL through lateral inhibition (Espinoza et al, 2018;Temprana et al, 2015). They also recruit mossy cells that activate a range of interneuron cell types, with a preference for basket cells (Scharfman, 2018).…”