Medial and Lateral Entorhinal Cortex Differentially Excite Deep versus Superficial CA1 Pyramidal Neurons

Abstract

SUMMARY Although hippocampal CA1 pyramidal neurons (PNs) were thought to comprise a uniform population, recent evidence supports two distinct sublayers along the radial axis, with deep neurons more likely to form place cells than superficial neurons. CA1 PNs also differ along the transverse axis with regard to direct inputs from entorhinal cortex (EC), with medial EC (MEC) providing spatial information to PNs toward CA2 (proximal CA1) and lateral EC (LEC) providing non-spatial information to PNs toward subiculum (distal CA1). We demonstrate that the two inputs differentially activate the radial sublayers and that this difference reverses along the transverse axis, with MEC preferentially targeting deep PNs in proximal CA1 and LEC preferentially exciting superficial PNs in distal CA1. This differential excitation reflects differences in dendritic spine numbers. Our results reveal a heterogeneity in EC-CA1 connectivity that may help explain differential roles of CA1 PNs in spatial and non-spatial learning and memory.

CA1 pyramidal cell diversity enabling parallel information processing in the hippocampus

“…CA3 Schaffer collateral excitation is stronger in calbindin-positive, superficially located CA1PCs. Note that proximodistal differences in cortical innervation between radial sublayers have also been reported 93,94 (not shown). PVBCs (green) provide stronger perisomatic inhibition onto deep CA1PCs and receive stronger excitation from superficial CA1PCs.…”

“…In this pathway, MEC and LEC project to different parts of CA1 along the proximodistal axis, leading to differential recruitment of PCs along this axis during spatial and nonspatial tasks 47,75,76,78,80,91,92 . A recent study 93 found that these two inputs also activate the radial CA1PC sublayers differentially (Fig. 3a) and that this differential innervation varies as a function along the proximodistal axis.…”

“…43 ). Note that Li et al 93 reported that calbindin-expressing CA1PCs, primarily located in the superficial sublayer, have more complex apical dendritic arborizations (not shown). Middle: superficial CA1PCs exhibit a more strongly depolarized somatic resting membrane potential ( V rest ) and a larger somatic h- current that mediates a depolarizing sag (indicated by arrow) during hyperpolarizing current pulses.…”

Heterogeneity in hippocampal place coding

“…For example, dorsal and ventral entorhinal cortex (EC) predominately innervate dorsal and ventral CA1, respectively, and via the EC, dorsal hippocampus receives more input from anterior cingulate and retrosplential cortex, while ventral hippocampus receives more input from infralimbic and prelimbic cortices [52]. Modified with permission from [58]. (c) Illustration highlighting experiments in which changes in grid cell representations were associated with altered place cell activity.…”

“…Differences in afferent connectivity likely contribute: deep CA1 place cells receive stronger excitation from CA2, superficial CA1 place cells receive stronger excitation from CA3 [53 • ], and the extent of MEC and LEC drive to CA1 varies across both the radial and transverse axes (Figure 1) [58,59]. However, it is also possible that differences in single-cell intrinsic biophysical properties and the genetic expression profiles that underlie such biophysics contribute.…”