Noncanonical connections between the subiculum and hippocampal CA1

Abstract

The hippocampal formation is traditionally viewed as having a feedforward, unidirectional circuit organization that promotes propagation of excitatory processes. While the substantial forward projection from hippocampal CA1 to the subiculum has been very well established, accumulating evidence supports the existence of a significant backprojection pathway comprised of both excitatory and inhibitory elements from the subiculum to CA1. Based on these recently updated anatomical connections, such a backprojection could serve to modulate information processing in hippocampal CA1. Here we review the published anatomical and physiological studies on the subiculum to CA1 backprojection, and present recent conclusive anatomical evidence for the presence of noncanonical subicular projections to CA1. New insights into this understudied pathway will improve our understanding of reciprocal CA1-subicular connections and guide future studies on how the subiculum interacts with CA1 to regulate hippocampal circuit activity and learning and memory behaviors. J. Comp. Neurol. 524:3666-3673, 2016. © 2016 The Authors The Journal of Comparative Neurology Published by Wiley Periodicals, Inc.

Keywords: back projection; genetic targeting; hippocampus; learning and memory; viral tracing.

Figure 1. Canonical hippocampal circuitry and the non-canonical subicular-CA1 pathway

The diagram depicts the non-canonical and canonical circuitry of the hippocampal formation. Evidence herein describes non-canonical back projections from the subiculum to CA1 (red line). Feed-forward and unidirectional canonical projections are depicted as black lines with large directional arrows. The trisynaptic circuit connections are made up of layer II (LII) entorhinal cortex (EC) projections to the dentate gyrus via the perforant pathway, projections of the dentate granule cells to area CA3 pyramidal neurons via mossy fibers, and CA3 projections to area CA1 pyramidal neurons via Schaffer collaterals. CA1 transfers excitatory information out of the hippocampus proper via direct projections to deep layers (layers V and VI, LV/VI) of the entorhinal cortex or to the subiculum. CA2 is described in the text but is not depicted in this diagram. Additional excitatory projections within the hippocampal formation include layer III (LII) entorhinal neurons projections to CA1 and the subiculum (the temporoammonic pathway), and local recurrent collaterals of CA3 pyramidal cells onto other CA3 pyramidal cells. Also the back-projection of CA3 pyramidal neurons to the dentate gyrus has been described.

Figure 2. New monosynaptic rabies tracing firmly demonstrates the non-canonical subicular projections to CA1

A–D. Example data images illustrating monosynaptic rabies tracing of presynaptic connections to excitatory neurons in hippocampal CA1 of the Camk2a-Cre; TVA mouse. A: Ipsilateral section image of the rabies injection site; mCherry labeling of excitatory neurons is seen throughout CA1. Note that much of the CA1 label is due to primary rabies infection as pyramidal neurons expressing TVA can be directly infected by local injection of EnvA- G rabies. The extent of the CA1 label under this experimental condition is not due to strong recurrent connections within CA1. B: Ipsilateral image of presynaptic retrograde tracing in the subiculum (Sub) showing non-canonical circuit connections between the subiculum and CA1. C and D: Enlarged views of the boxed areas in B showing the subicular neurons that project axons to CA1. E–F. Immunochemical analysis of subicular neurons projecting to CA1. E: Immunochemical characterization of rabies-labeled, CA1-projecting subicular neurons. The representative subicular section was from monosynaptic rabies tracing of CA1 excitatory pyramidal neurons in the Camk2a-Cre; TVA mouse. The section was stained immunochemically against excitatory amino acid transporter (EEAC1) with arrowheads indicating subicular excitatory neurons projecting to CA1, and against GABA with arrowheads indicating subicular inhibitory interneurons projecting to CA1. The CA1 projecting subicular neurons were labeled by mCherry-expressing rabies. F: Percentage quantification of glutamatergic versus GABAergic CA1 projecting subicular cells revealed by rabies tracing in Camk2a-Cre; TVA (targeting CA1 excitatory neurons) and Dlx5/6-Cre; TVA (targeting CA1 inhibitory neurons) mice. This figure is modified from data figures presented in Sun et al. (2014).