Research Article

Gating of hippocampal activity, plasticity, and memory by entorhinal cortex long-range inhibition

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Science  08 Jan 2016:
Vol. 351, Issue 6269, aaa5694
DOI: 10.1126/science.aaa5694

Fine-tuned information flow in the brain

In addition to providing well-characterized excitatory inputs, the entorhinal cortex also sends long-range inhibitory projections to the hippocampus. Basu et al. described this input in detail and characterized its role for learning and memory. Multimodal sensory stimuli activate long-range inhibitory input in vivo. This input enables precisely timed information transfer within the cortico-hippocampal circuit. In this way, long-range inhibitory projections play an important role in providing specificity of fear conditioning, and thus help prevent overgeneralization.

Science, this issue p. 10.1126/science.aaa5694

Structured Abstract


The precise association of contextual cues with a behavioral experience enables an animal to discriminate between salient (harmful or rewarding) versus neutral environments. What signaling mechanisms during learning help select specific contextual signals to be stored as long-term memories? Hippocampal CA1 pyramidal neurons integrate direct multisensory excitatory input from entorhinal cortex (EC) with indirect, mnemonic excitatory input from the upstream hippocampal CA3 area, and both pathways have been implicated in memory storage. Paired activation of the direct and indirect inputs at a precise timing interval that matches the dynamics of the cortico-hippocampal circuit induces a long-term enhancement of the activation of CA1 neurons by their CA3 inputs (input timing–dependent plasticity or ITDP). However, EC additionally sends long-range inhibitory projections (LRIPs) to CA1, the function of which is largely unknown. Here, we explore the role of the LRIPs in regulating hippocampal synaptic activity and memory.


GABAergic neurons (which release the inhibitory transmitter γ-aminobutyric acid or GABA) in medial entorhinal cortex (MEC) were recently found to send to hippocampus LRIPs that form relatively weak and sparse synapses on CA1 GABAergic interneurons. As lateral entorhinal cortex (LEC) conveys important contextual and object-related information to hippocampus, we examined whether this region also sends LRIPs to CA1. We expressed channelrhodopsin-2 (ChR2) selectively in LEC inhibitory neurons and examined the synaptic effects of LRIP photostimulation. The behavioral impact of the LRIPs was determined by selectively silencing these inputs locally in CA1 during contextual fear conditioning (CFC) and novel object recognition (NOR) tasks. We also used in vivo Ca2+ imaging to assess how different sensory and behavioral stimuli that typically make up a contextual experience activate the LEC LRIPs. Finally, we examined how the LRIPs influence information flow through the cortico-hippocampal circuit and contribute to ITDP.


LRIPs from LEC produced strong inhibitory postsynaptic potentials in a large fraction of CA1 interneurons located in the region of the EC inputs. Although pharmacogenetic silencing of LRIPs in hippocampus did not prevent CFC or NOR memory, it caused mice to show an inappropriate fear response to a neutral context and a diminished ability to distinguish a novel object from a familiar object. Calcium imaging revealed that the LRIP axons and presynaptic terminals responded to various sensory stimuli. Moreover, pairing such signals with appetitive or aversive stimuli increased LRIP activity, consistent with a role of the LRIPs in memory specificity.

Intracellular recordings demonstrated that the LRIPs powerfully suppressed the activity of a subclass of cholecystokinin-expressing interneurons (CCK+ INs). These interneurons were normally strongly excited by the CA3 inputs, which results in pronounced feedforward inhibition (FFI) of CA1 pyramidal neuron dendrites. By transiently and maximally suppressing the INs in a 15- to 20-ms temporal window, the LRIPs enhanced CA3 inputs onto CA1 pyramidal neurons that arrived within that timing interval. This disinhibition enabled temporally precise, paired activation of EC–Schaffer collateral (EC-SC) inputs (15 to 20 ms apart) to trigger dendritic spikes in the distal dendrites of CA1 PNs and to induce ITDP.


LRIPs from EC act as a powerful, temporally precise disinhibitory gate of intrahippocampal information flow and enable the induction of plasticity when cortical and hippocampal inputs arrive onto CA1 PNs at a precise 20-ms interval. We propose that the LRIPs increase the specificity of hippocampal-based long-term memory by assessing the salience of mnemonic information relayed by CA3 to the immediate sensory context conveyed by direct excitatory EC inputs.

Long-range inhibitory projections gate cortico-hippocampal information flow in the short and long term.

(Top) The cortico-hippocampal circuit. Inputs from EC arrive at CA1 directly through excitatory perforant path (PP) and LRIPs and indirectly through SCs of the trisynaptic path [dentate gyrus (DG)→CA3→CA1]. (Bottom) Recordings from different EC LRIP→CA1 circuit elements. (Top left) A CA1 IN that normally inhibits the pyramidal neuron (PN) dendrite is inhibited maximally by LRIP (blue, LRIP intact) 20 ms after EC stimulation (dotted guide lines). (Bottom left) This disinhibits the PN dendritic depolarization evoked by a SC input arriving 20 ms after EC input. Multiple EC-SC pairings result in more disinhibition (middle), which triggers dendritic Ca2+ spikes (10× pairings for 10 s) and (right) induces somatic long-term plasticity (90× pairings for 90 s) in the CA1 PN, where SC responses are potentiated for >1 hour. LRIP silencing (red) decreases dendritic depolarization and spike probability and blocks somatic plasticity. [Background from a plate by C. Golgi et al.1886, text translated and republished with plates in Brain Res. Bull. 54, 461–483 (2001)]


The cortico-hippocampal circuit is critical for storage of associational memories. Most studies have focused on the role in memory storage of the excitatory projections from entorhinal cortex to hippocampus. However, entorhinal cortex also sends inhibitory projections, whose role in memory storage and cortico-hippocampal activity remains largely unexplored. We found that these long-range inhibitory projections enhance the specificity of contextual and object memory encoding. At the circuit level, these γ-aminobutyric acid (GABA)–releasing projections target hippocampal inhibitory neurons and thus act as a disinhibitory gate that transiently promotes the excitation of hippocampal CA1 pyramidal neurons by suppressing feedforward inhibition. This enhances the ability of CA1 pyramidal neurons to fire synaptically evoked dendritic spikes and to generate a temporally precise form of heterosynaptic plasticity. Long-range inhibition from entorhinal cortex may thus increase the precision of hippocampal-based long-term memory associations by assessing the salience of mnemonic information to the immediate sensory input.

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