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Strong CA2 pyramidal neuron synapses define a powerful disynaptic cortico-hippocampal loop.

ABSTRACT: Neurons propagate information through circuits by integrating thousands of synaptic inputs to generate an action potential output. Inputs from different origins are often targeted to distinct regions of a neuron's dendritic tree, with synapses on more distal dendrites normally having a weaker influence on cellular output compared to synapses on more proximal dendrites. Here, we report that hippocampal CA2 pyramidal neurons, whose function has remained obscure for 75 years, have a reversed synaptic strength rule. Thus, CA2 neurons are strongly excited by their distal dendritic inputs from entorhinal cortex but only weakly activated by their more proximal dendritic inputs from hippocampal CA3 neurons. CA2 neurons in turn make strong excitatory synaptic contacts with CA1 neurons. In this manner, CA2 neurons form the nexus of a highly plastic disynaptic circuit linking the cortical input to the hippocampus to its CA1 neuronal output. This circuit is likely to mediate key aspects of hippocampal-dependent spatial memory.

SUBMITTER: Chevaleyre V

PROVIDER: S-EPMC2905041 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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Strong CA2 pyramidal neuron synapses define a powerful disynaptic cortico-hippocampal loop.

Chevaleyre Vivien V Siegelbaum Steven A SA

Neuron 20100501 4

Neurons propagate information through circuits by integrating thousands of synaptic inputs to generate an action potential output. Inputs from different origins are often targeted to distinct regions of a neuron's dendritic tree, with synapses on more distal dendrites normally having a weaker influence on cellular output compared to synapses on more proximal dendrites. Here, we report that hippocampal CA2 pyramidal neurons, whose function has remained obscure for 75 years, have a reversed synapt ...[more]

PMID: 20510860

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Project description: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 (Ih). 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.SIGNIFICANCE STATEMENT 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.

Project description:To evaluate molecular signatures of an individual cell type in comparison to the associated region relevant towards understanding the pathogenesis of Alzheimer's disease (AD), CA1 pyramidal neurons and the surrounding hippocampal formation were microaspirated via laser capture microdissection (LCM) from neuropathologically confirmed AD and age-matched control (CTR) subjects as well as from wild type mouse brain using single population RNA amplification methodology coupled with custom-designed microarray analysis with real-time quantitative polymerase-chain reaction (qPCR) validation. CA1 pyramidal neurons predominantly displayed downregulation of classes of transcripts related to synaptic transmission in AD versus CTR. Regional hippocampal dissections displayed downregulation of several overlapping genes found in the CA1 neuronal population related to neuronal expression, as well as upregulation of select transcripts indicative of admixed cell types including glial-associated markers and immediate-early and cell death genes. Gene level distributions observed in CA1 neurons and regional hippocampal dissections in wild type mice paralleled expression mosaics seen in postmortem human tissue. Microarray analysis was validated in qPCR studies using human postmortem brain tissue and CA1 sector and regional hippocampal dissections obtained from a mouse model of AD/Down syndrome (Ts65Dn mice) and normal disomic (2N) littermates. Classes of transcripts that have a greater percentage of the overall hybridization signal intensity within single neurons tended to be genes related to neuronal communication. The converse was also found, as classes of transcripts such as glial-associated markers were under represented in CA1 pyramidal neuron expression profiles relative to regional hippocampal dissections. These observations highlight a dilution effect that is likely to occur in conventional regional microarray and qPCR studies. Thus, single population studies of specific neurons and intrinsic circuits will likely yield informative gene expression profile data that may be subthreshold and/or underrepresented in regional studies with an admixture of cell types.

Dataset Information

Strong CA2 pyramidal neuron synapses define a powerful disynaptic cortico-hippocampal loop.

Publications

Strong CA2 pyramidal neuron synapses define a powerful disynaptic cortico-hippocampal loop.

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