Proximodistal Heterogeneity of Hippocampal CA3 Pyramidal Neuron Intrinsic Properties, Connectivity, and Reactivation during Memory Recall

Abstract

Summary The hippocampal CA3 region is classically viewed as a homogeneous autoassociative network critical for associative memory and pattern completion. However, recent evidence has demonstrated a striking heterogeneity along the transverse, or proximodistal, axis of CA3 in spatial encoding and memory. Here we report the presence of striking proximodistal gradients in intrinsic membrane properties and synaptic connectivity for dorsal CA3. A decreasing gradient of mossy fiber synaptic strength along the proximodistal axis is mirrored by an increasing gradient of direct synaptic excitation from entorhinal cortex. Furthermore, we uncovered a nonuniform pattern of reactivation of fear memory traces, with the most robust reactivation during memory retrieval occurring in mid-CA3 (CA3b), the region showing the strongest net recurrent excitation. Our results suggest that heterogeneity in both intrinsic properties and synaptic connectivity may contribute to the distinct spatial encoding and behavioral role of CA3 subregions along the proximodistal axis.

Diversity of dendritic morphology and entorhinal cortex synaptic effectiveness in mouse CA2 pyramidal neurons

“…Mouse pyramidal neurons differ in their electrophysiological properties across CA1, CA2, and CA3 hippocampal sub‐regions, and also vary within each sub‐region (Mercer, Trigg, & Thomson, ; Sun et al, ). The cytological features we observed from CA2 pyramidal neuron apical dendrites suggest that different cell types may have different electrophysiological properties and be engaged differently by excitatory inputs from intra‐ and extra‐hippocampal regions of the mouse brain.…”

“…As early as 1934, Lorente de Nó observed significant pyramidal cell dendritic heterogeneity in mouse, monkey, and human brain (Lorente de Nó, 1934). More recent studies further describe hippocampal pyramidal neuron subtype morphological and electrophysiological differences based on hippocampal subregion (Ishizuka et al, ; Mercer et al, ; Srinivas et al, ) and within hippocampal subregions (Bartesaghi & Ravasi, ; Li et al, ; Sun et al, ). In this study, we attempted to determine if a heterogeneous population of pyramidal neurons exists in mouse CA2 similar to that in guinea pig, and if so, whether the heterogeneity can result in any consequential physiological properties.…”

“…In the late 20th century, a comprehensive morphometric analysis of dendritic organization of rat hippocampal pyramidal cells by Ishizuka et al noted a number of characteristics that differentiated CA1, CA2, and CA3 pyramidal neurons, including total dendritic length, cell body size, 1° and 2° apical dendritic branching, and the absence of thorny excrescences in CA1 and CA2 (Ishizuka, Cowan, & Amaral, ). More recent findings by Li et al () and Sun et al () have shown that CA1 and CA3, respectively, display a heterogeneous dendritic structure. Interestingly, nearly two decades earlier, Bartesaghi & Ravasi () identified four distinct subtypes of CA2 pyramidal cells (Ma, Mb, Mc, and B cells) in guinea pig CA2 based on 1° apical dendrite morphology, indicating that a particularly heterogeneous population of pyramidal neuron morphologies also exists in CA2.…”

Immunohistochemical Analysis of Activin Receptor-Like Kinase 1 (ACVRL1/ALK1) Expression in the Rat and Human Hippocampus: Decline in CA3 During Progression of Alzheimer’s Disease

“…CA3 participates in short-term spatial memory, associative memory recall, and pattern completion processes [46–48]. CA3 receives septal GABA-ergic afferents [49] synapsing on GABAergic interneurons in the hippocampal subfields (CA1, CA3, and DG) [50].…”

CA1 pyramidal cell diversity enabling parallel information processing in the hippocampus

“…For example, subicular pyramidal neurons can be divided into two classes based on morphological, electrophysiological, extrahippocampal projection, and plasticity properties 125 , and deep CA2PCs play distinct roles in initiating SPWRs 126 . Gene expression in CA3PCs displays prominent laminar specificities 127 , and CA3PC morphological and intrinsic physiological properties vary along the main axes 128,129 , as well as with regard to the extent of mossy fiber innervation of individual CA3PCs 130 . The identification of a subpopulation of early-generated, deep CA3PCs with ability to synchronize adult network activity 110 is consistent with developmentally derived radial differences.…”