The Dendrites of CA2 and CA1 Pyramidal Neurons Differentially Regulate Information Flow in the Cortico-Hippocampal Circuit

Abstract

The impact of a given neuronal pathway depends on the number of synapses it makes with its postsynaptic target, the strength of each individual synapse, and the integrative properties of the postsynaptic dendrites. Here we explore the cellular and synaptic mechanisms responsible for the differential excitatory drive from the entorhinal cortical pathway onto mouse CA2 compared with CA1 pyramidal neurons (PNs). Although both types of neurons receive direct input from entorhinal cortex onto their distal dendrites, these inputs produce a 5- to 6-fold larger EPSP at the soma of CA2 compared with CA1 PNs, which is sufficient to drive action potential output from CA2 but not CA1. Experimental and computational approaches reveal that dendritic propagation is more efficient in CA2 than CA1 as a result of differences in dendritic morphology and dendritic expression of the hyperpolarization-activated cation current (). Furthermore, there are three times as many cortical inputs onto CA2 compared with CA1 PN distal dendrites. Using a computational model, we demonstrate that the differences in dendritic properties of CA2 compared with CA1 PNs are necessary to enable the CA2 PNs to generate their characteristically large EPSPs in response to their cortical inputs; in contrast, CA1 dendritic properties limit the size of the EPSPs they generate, even to a similar number of cortical inputs. Thus, the matching of dendritic integrative properties with the density of innervation is crucial for the differential processing of information from the direct cortical inputs by CA2 compared with CA1 PNs. Recent discoveries have shown that the long-neglected hippocampal CA2 region has distinct synaptic properties and plays a prominent role in social memory and schizophrenia. This study addresses the puzzling finding that the direct entorhinal cortical inputs to hippocampus, which target the very distal pyramidal neuron dendrites, provide an unusually strong excitatory drive at the soma of CA2 pyramidal neurons, with EPSPs that are 5-6 times larger than those in CA1 pyramidal neurons. We here elucidate synaptic and dendritic mechanisms that account quantitatively for the marked difference in EPSP size. Our findings further demonstrate the general importance of fine-tuning the integrative properties of neuronal dendrites to their density of synaptic innervation.

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

“…We previously found that CA2 receives a much greater excitatory drive from PP inputs than does CA1 or CA3 (Chevaleyre and Siegelbaum, 2010; Srinivas et al, 2017; Sun et al, 2014). Here we examined the heterogeneity of direct cortical excitation of CA3 across the transverse axis.…”

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

“…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.…”

“…CA2 pyramidal neurons have been shown to receive excitatory input from mossy fibers from the dentate gyrus (DG) and SCs from CA3 that form synapses primarily onto proximal apical dendrites in the stratum radiatum (Lorente de Nó, 1934). CA2 neurons also receive excitatory synaptic input on more distal apical dendrites localized in the SLM from Cajal–Retzius cells originating within the hippocampal formation (Anstotz et al, ; Anstotz, Lee, Neblett, Rune, & Maccaferri, ) as well as outside the hippocampus from hypothalamic SuM (Borhegyi & Leranth, ; Kocsis & Vertes, ; Magloczky et al, ) and EC layer II neurons (Chevaleyre & Siegelbaum, ; Kohara et al, ; Srinivas et al, ). Activation of SC or EC inputs onto CA2 pyramidal neuron apical dendrites via stimulating electrodes placed in either the SR or SLM, respectively, revealed differences in relative effectiveness of synaptic input in Mb‐like cells.…”

“…Pyramidal neurons in CA2 differ from those in CA1 and CA3 in excitatory input circuitry, synaptic plasticity, and protein expression (Cui, Gerfen, & Young, ; Dudek, Alexander, & Farris, ). They receive selective and prominent excitatory inputs from the supramammillary nucleus of the hypothalamus (SuM) (Borhegyi & Leranth, ; Kocsis & Vertes, ; Magloczky, Acsady, & Freund, ), and like CA3, a direct excitatory drive from the entorhinal cortex (EC), primarily from cells in layer II (Chevaleyre & Siegelbaum, ; Kohara et al, ; Srinivas et al, ). Interestingly, CA2 pyramidal neurons were reported to have an atypically strong excitation response to ECII stimulation compared with ECIII inputs to CA1 (Sun, Srinivas, Sotayo, & Siegelbaum, ).…”

Three brain states in the hippocampus and cortex

“…EC sends exceptionally strong input to CA2. See (Bartesaghi & Gessi, ; Chevaleyre & Siegelbaum, ; Srinivas et al, ; Sun et al, ). (d) Illustration of generalizing spatial representation in EC.…”