Abstract
GABAergic parvalbumin-expressing (PV+) interneurons provide powerful inhibitory modulation of grid cells in layer II of the medial entorhinal cortex (MEC LII). However, the molecular machinery through which PV+ cells regulate grid cell activity is poorly defined. PV+ interneurons impart inhibitory modulation primarily via GABA-A receptors (GABAARs). GABAARs are pentameric ion channels assembled from a repertoire of 19 subunits. Multiple subunit combinations result in a variety of receptor subtypes mediating functionally diverse postsynaptic inhibitory currents. Whilst the broad expression patterns of GABAAR subunits within the EC have been reported, those expressed by individual MEC LII cell types, in particular grid cells candidates, stellate and pyramidal cells, are less well described. Stellate and pyramidal cells are distinguished by their selective expression of reelin (RE+) and calbindin (CB+) respectively. Thus, the overall aim of this study was to provide a high resolution analysis of the major (α and γ) GABAAR subunits expressed in proximity to somato-dendritic PV+ boutons, on RE+ and CB+ cells, using immunohistochemistry, confocal microscopy and quantitative RT-PCR (qPCR). Clusters immunoreactive for the α1 and γ2 subunits decorated the somatic membranes of both RE+ and CB+ cells and were predominantly located in apposition to clusters immunoreactive for PV and vesicular GABA transporter (VGAT), suggesting expression in GABAergic synapses innervated by PV interneurons. Although intense α2 subunit-immunopositive clusters were evident in hippocampal fields located in close proximity to the EC, no specific signal was detected in MEC LII RE+ and CB+ profiles. Immunoreactivity for the α3 subunit was detected in all RE+ somata. In contrast, only a sub-population of CB+ cells was α3 immunopositive. These included CB-α3 cells which were both PV+ and PV−. Furthermore, α3 subunit mRNA and immunofluorescence decreased significantly between P 15 and P 25, a period implicated in the functional maturation of grid cells. Finally, α5 subunit immunoreactivity was detectable only on CB+ cells, not on RE+ cells. The present data demonstrates that physiologically distinct GABAAR subtypes are selectively expressed by CB+ and RE+ cells. This suggests that PV+ interneurons could utilize distinct postsynaptic signaling mechanisms to regulate the excitability of these different, candidate grid cell sub-populations.
Highlights
The internal representation of space is generated from a complex interplay between functionally distinct cell types within the hippocampal formation
The overall aim of the study was to: (1) determine the spatiotemporal expression patterns of specific GABAA receptors (GABAARs) subunits on MEC LII RE+ stellate and CB+ pyramidal cells, in relation to PV immunoreactive boutons, in the adult mouse; and (2) investigate possible subunit plasticity during a period implicated in grid cell pattern maturation, namely P 15 to P 25
PV+ interneurons were greatly outnumbered by principal cells, PV immunoreactivity was prominent throughout LII and appeared strongly associated with CB+ and RE+ profiles (Figure 1B1)
Summary
The internal representation of space is generated from a complex interplay between functionally distinct cell types within the hippocampal formation. While the exact mechanisms underlying the striking activity pattern are yet to be understood, recent evidence suggests that grid cells include both stellate cells and pyramidal cells, which are the two main principal cell types in MEC LII (Domnisoru et al, 2013; Tang et al, 2014; Sun et al, 2015). These cell types can be chemically distinguished by their respective expression of reelin (RE+) and calbindin (CB+; Fuchs et al, 2015; Donato et al, 2017; Witter et al, 2017). Studies have shown that principal cells within this layer to a large degree communicate via GABAergic interneurons (Couey et al, 2013; Fuchs et al, 2015), and that in particular parvalbumin-expressing (PV+) interneurons play a crucial role in maintaining the periodic firing pattern in grid cells (Buetfering et al, 2014; Miao et al, 2017)
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