Superficial Layer-Specific Histaminergic Modulation of Medial Entorhinal Cortex Required for Spatial Learning

Abstract

The medial entorhinal cortex (MEC) plays a crucial role in spatial learning and memory. Whereas the MEC receives a dense histaminergic innervation from the tuberomamillary nucleus of the hypothalamus, the functions of histamine in this brain region remain unclear. Here, we show that histamine acts via H1Rs to directly depolarize the principal neurons in the superficial, but not deep, layers of the MEC when recording at somata. Moreover, histamine decreases the spontaneous GABA, but not glutamate, release onto principal neurons in the superficial layers by acting at presynaptic H3Rs without effect on synaptic release in the deep layers. Histamine-induced depolarization is mediated via inhibition of Kir channels and requires the activation of protein kinase C, whereas the inhibition of spontaneous GABA release by histamine depends on voltage-gated Ca(2+) channels and extracellular Ca(2+). Furthermore, microinjection of the H1R or H3R, but not H2R, antagonist respectively into the superficial, but not deep, layers of MEC impairs rat spatial learning as assessed by water maze tasks but does not affect the motor function and exploratory activity in an open field. Together, our study indicates that histamine plays an essential role in spatial learning by selectively regulating neuronal excitability and synaptic transmission in the superficial layers of the MEC.

Short-term sleep deprivation disrupts the molecular composition of ionotropic glutamate receptors in entorhinal cortex and impairs the rat spatial reference memory

“…The present study for the first time, to the best of our knowledge, symmetrically investigated the influence of short-term SD on the AMPAR and NMDAR subunit expression in the EC, which is the 'hub' between neocortex and hippocampus and serves a vital role in spatial cognition [16,18,22,35,36]. We found 4h SD differently affected the AMPAR subunit surface expression primarily via influencing their membrane trafficking.…”

Histamine facilitates GABAergic transmission in the rat entorhinal cortex: Roles of H1 and H2 receptors, Na+‐permeable cation channels, and inward rectifier K+ channels

“…Our results that HA‐induced net currents displayed an inward rectification and are Cs + ‐sensitive suggest that Kirs are involved. Similar to the leak K + channels, Kirs are also involved in the controlling of RMPs (Hibino et al, ) and are targets for HA‐induced increases in neuronal excitability (Gorelova and Reiner, ; He et al, ).…”

“…Neuromodulatory actions of HA typically involve enhancement of neuronal excitability via H 1 and/or H 2 and both receptors influence a variety of different ionic conductances. The H 1 is implicated in the inhibition of background K + channels (McCormick and Williamson, ; Reiner and Kamondi, ; Whyment et al, ) and inward rectifier K + channels (Kirs) (Gorelova and Reiner, ; He et al, ), activation of a TTX‐insensitive Na + channels (Gorelova and Reiner, ; Bell et al, ), nonselective cation channels (Hardwick et al, ), and Na + ‐Ca 2+ exchanger (Zhang et al, ). Activation of H 2 results in inhibition of K + conductances (Munakata and Akaike, ; Starodub and Wood, ) including the voltage‐gated (Atzori et al, ) and Ca 2+ ‐activated (Haas, ) K + channels, and activation of hyperpolarization‐activated cation channels (Ih) (McCormick and Williamson, ; Zhang et al, ).…”

“…GABAergic transmission is critical for maintenance of network activity and its dysfunction is implicated in MEC‐related disorders. Although HA has been reported to reduce the frequency of miniature inhibitory postsynaptic currents (mIPSCs) recorded in the presence of TTX via an H 3 ‐dependent manner (He et al, ), it remains unknown whether HA modulates other forms of GABAergic transmission. We tested this possibility and observed that HA increased the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) via activation of H 1 or H 2 receptors.…”

The Brain, Explained: A Comprehensive Theory of Brain Function

“…Histamine neurons are excited by their adjacent OX neurons, and are classically thought to be tonically active and to promote circadian wakefulness, exhibiting high frequency firing in wakefulness and silence in sleep. Histamine excites motoneurons [Coslovich et al, 2017], depolarizes the superficial, but not the deep, MEC layers [He et al, 2016], excites NE and ACh, and affects SER. H3Rs promote/oppose D1Rs/D2Rs [Rapanelli, 2017].…”