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

The hippocampus and entorhinal cortex (EC) are physically interconnected brain areas. The CA1 cells in the hippocampus integrate direct excitatory input from the EC with indirect excitatory input from the upstream hippocampal CA3 area, and both pathways are implicated in memory storage. Interestingly it was recently found that medial EC additionally sends long-range inhibitory projections (LRIPs) that form synapses on CA1 inhibitory neurons.

Here the authors investigate whether lateral EC also sends inhibitory connection to the CA1 area of the hippocampus and if so how this influences paired EC and hippocampal CA3 inputs thus long-term memory storage. Neurons in the lateral EC in contrast to neurons in medial EC exhibit little spatial selectivity but lateral EC conveys important contextual and object-related information to the hippocampus.

The authors used a customized Bruker two-photon microscope (Ultima) that allowed for calcium-imaging in head fixed mice, photoactivation and integration with electrophysiological instrumentation.

They confirmed the presence of the LRIPs from LEC to the CA1 area. Although the silencing of LRIPs in hippocampus did not prevent memory formation in behavioral tests, it caused mice to show inappropriate fear response to a neutral context and a diminished ability to distinguish a novel object from a familiar object. The long-range projecting interneurons form synapses on interneurons in the CA1. Intracellular recording demonstrated that LRIP suppressed the activity of a subclass of cholecystokinin-expressing interneurons (CCK IN). These interneurons were normally strongly excited by the CA3 input. The LRPI transiently inhibited the activity of CCK IN allowing for enhancing CA3c input to the CA1 that arrives precisely 20 ms after LRPI activation. This disinhibition enabled generation of dendritic spikes in the distal dendrites of the CA1 pyramidal neurons and to induce synaptic plasticity.

The facilitating effect of LRIPs on the CA3 excitation and synaptic plasticity found in this paper is in line with emerging recognition that interneurons can control memory through either direct inhibition of pyramidal cells or disinhibitory circuits (Freund and Gulyas 1997, Lovett-Barron et al. 2014, Wolff et al. 2014). It seems that disinhibition is a conserved circuit mechanism contributing to learning and memory expression and can be linked to most behavioral functions including auditory fear learning (Letzkus et al. 2011) and spatial navigation (Chambers et al. 2003).