Distinct mechanisms of Up state maintenance in the medial entorhinal cortex and neocortex

Abstract

The medial entorhinal cortex (mEC) is a key structure which controls the communication between the hippocampus and the neocortex. During slow-wave sleep, it stands out from other cortical regions by exhibiting persistent activity that outlasts neocortical Up states, decoupling the entorhinal cortex-hippocampal interaction from the neocortex. Here, we compared the mechanisms involved in the maintenance of the Up state in the barrel cortex (BC) and mEC using whole cell recordings in acute mouse brain slices. Bath application of an NMDA receptor antagonist abolished Up states in the BC, and reduced the incidence but not the duration of Up states in the mEC. Conversely, blockade of kainate receptors decreased Up state duration in the mEC, but not in the BC. Voltage clamp recordings demonstrated the presence of a non-NMDA glutamate receptor-mediated slow excitatory postsynaptic current, sensitive to the selective kainate receptor antagonist UBP-302, in layer III neurons of the mEC, which was not observed in the BC. Moreover, we found that kainate receptor-mediated currents assist in recovery back to the Up state membrane potential following a current-induced hyperpolarisation of individual cells in the mEC. Finally, we were able to generate Up state activity in a network model of exponential integrate-and-fire neurons only supported by AMPA and kainate receptor-mediated currents. We propose that synaptic kainate receptors are responsible for the unique properties of mEC Up states.

Cortical Up states induce the selective weakening of subthreshold synaptic inputs

“…5b ). Under our conditions, this also blocked evoked Up states, which is consistent with a role for NMDAR in Up state initiation in acute slices of mEC 41 . However, this data does suggest that NMDAR drive synaptically evoked spine Ca 2+ transients, although other Ca 2+ sources are likely to contribute to these spine transients, and their additional boost during Up states.…”

Up and Down States and Memory Consolidation Across Somatosensory, Entorhinal, and Hippocampal Cortices

“…The longer Up states in MEC potentially arise from intrinsic membrane and synaptic properties of pyramidal neurons in MEC. Pyramidal cells in MEC have persistent firing and a Kainate receptor dependent slow glutamatergic current (Digby et al, 2017). This current is not found in pyramidal cells in primary somatosensory cortex (S1).…”

Structure, Function, and Pharmacology of Glutamate Receptor Ion Channels

“…Kainate receptor function has been examined at cortical synapses [e.g., Wu et al (2005)], but the relevance of their signaling to higher-order cognitive processing is unexplored. In the entorhinal cortex, kainate receptors contribute to up-states (Digby et al, 2017), possibly through layer 3 pyramidal neurons (Cunningham et al, 2006;West et al, 2007). The pharmacological properties of these entorhinal currents and the expression patterns suggest that GluK2-and GluK5-containing receptors underlie this function (West et al, 2007;Beed et al, 2009).…”