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Rediscovering area CA2: unique properties and functions

Key Points

  • Hippocampal area CA2, contrary to popular perception, has a distinct molecular profile and connectivity compared with its neighbouring areas CA1 and CA3.

  • The 'molecular' definition of area CA2 differs substantially from the 'classic' definition in rodents.

  • Plasticity at some synapses in CA2 is severely limited by robust calcium handling processes and some gene expression in CA2 pyramidal neurons. Nevertheless, CA2 synapses can be modulated by caffeine and by the neuropeptides oxytocin and vasopressin, which mediate social behaviours.

  • Knockout of a vasopressin receptor, which is highly expressed in area CA2, causes impairments in several forms of social recognition memory in mice. Silencing or destroying CA2 neurons leads to similar deficits.

  • CA2 neurons have place fields, but carry less spatial information than those in area CA1 or CA3. CA2 place fields are highly unstable over time and remap upon exposure to social and novel contexts, suggesting a potential mechanism for encoding time and modified contexts.

  • CA2 neurons are resistant to cell death in response to many forms of insults in humans and animal models. Moreover, CA2 neurons may contribute to epileptic activity found in temporal lobe epilepsy.

Abstract

Hippocampal area CA2 has several features that distinguish it from CA1 and CA3, including a unique gene expression profile, failure to display long-term potentiation and relative resistance to cell death. A recent increase in interest in the CA2 region, combined with the development of new methods to define and manipulate its neurons, has led to some exciting new discoveries on the properties of CA2 neurons and their role in behaviour. Here, we review these findings and call attention to the idea that the definition of area CA2 ought to be revised in light of gene expression data.

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Figure 1: Hippocampal area CA2 in the mouse brain.
Figure 2: Connectivity of CA2 neurons within the rodent hippocampal circuit.
Figure 3: Comparison of neuron spatial firing in CA regions.
Figure 4: A role for CA2 in social memory.

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Acknowledgements

The authors thank D. Lustberg and other members of the Dudek laboratory for comments on the manuscript. This research was supported by the Intramural Research Program of the National Institute of Environmental Health Sciences, US National Institutes of Health (Z01 ES100221).

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Glossary

Cornu Ammonis

(CA). Latin for Ammon's horn, CA is now known as the hippocampus proper and was used by Rafael Lorente de Nó when subdividing the regio superior and regio inferior into CA1, CA2, CA3 and CA4.

Mossy fibres

The axons of the dentate gyrus granule neurons most noted for forming very large synapses on the thorny excrescences on proximal dendrites of CA3 neurons, and now known to also form synapses on many CA2 neurons in rats and mice.

Long-term potentiation

(LTP). A lasting increase in the effectiveness of synaptic potentials induced by high-frequency afferent stimulation.

Cell ensembles

A collection of cells that show coordinated firing activity and are thought to encode a particular memory trace or engram.

Place fields

Locations (or places) within a two-dimensional arena at which a particular neuron will fire while the animal traverses it.

Global remapping

Changes in the primary place field location of a neuron in response to a change in the environment — for example, the context or the passage of time.

Excitotoxicity

The property of excitatory amino acids such as glutamate to cause neuron death, beginning with massive depolarization of the cell membrane and influx of calcium.

Status epilepticus

A state of prolonged seizure activity lasting for more than 5 minutes, or multiple seizure events without returning to normal consciousness.

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Dudek, S., Alexander, G. & Farris, S. Rediscovering area CA2: unique properties and functions. Nat Rev Neurosci 17, 89–102 (2016). https://doi.org/10.1038/nrn.2015.22

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