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A frequency-dependent switch from inhibition to excitation in a hippocampal unitary circuit


The hippocampus, a brain structure essential for memory and cognition, is classically represented as a trisynaptic excitatory circuit. Recent findings challenge this view, particularly with regard to the mossy fibre input to CA3, the second synapse in the trisynaptic pathway1. Thus, the powerful mossy fibre input to CA3 pyramidal cells might mediate both synaptic excitation and inhibition2,3. Here we show, by recording from connected cell pairs in rat entorhinal–hippocampal slice cultures, that single action potentials in a dentate granule cell evoke a net inhibitory signal in a pyramidal cell. The hyperpolarization is due to disynaptic feedforward inhibition, which overwhelms monosynaptic excitation. Interestingly, this net inhibitory synaptic response changes to an excitatory signal when the frequency of presynaptic action potentials increases. The process responsible for this switch involves the facilitation of monosynaptic excitatory transmission coupled with rapid depression of inhibitory circuits. This ability to immediately switch the polarity of synaptic responses constitutes a novel synaptic mechanism, which might be crucial to the state-dependent processing of information in associative hippocampal networks.

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Figure 1: Unitary responses induced by single GC action potentials.
Figure 2: Frequency-dependent properties of monosynaptic mossy fibre transmission to PCs.
Figure 3: Switch in unitary postsynaptic potentials from inhibitory-dominant to excitatory-dominant with increasing frequency.
Figure 4: Depression of both GC–interneuron (GC–IN) and interneuron–PC (IN–PC) synapses at high frequency contributes to the switch from inhibitory to excitatory CA3 responses.


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We thank H. Blum, S. Giger, H. Kasper, L. Rietschin, and R. Schöb for technical assistance, and P. Streit for help in image processing. This work was funded by the Swiss National Science Foundation, the NCCR on Neural Plasticity and Repair, and the Hartmann Müller Foundation.

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Correspondence to Masahiro Mori.

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Supplementary information

Supplementary Figure 1

Morphology of a typical GC (a) and examples of synaptic contacts in GC-IN pairs (b-i). (JPG 111 kb)

Supplementary Figure 2

Morphology of a representative GC-PC pair. (JPG 64 kb)

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Mori, M., Abegg, M., Gähwiler, B. et al. A frequency-dependent switch from inhibition to excitation in a hippocampal unitary circuit. Nature 431, 453–456 (2004).

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