title: 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.
authors.affiliation: Department of Physiology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, PR China.
authors.forename: Chao
authors.initials: C
authors.lastname: He
authors.affiliation: Department of Physiology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, PR China.
authors.forename: Fenlan
authors.initials: F
authors.lastname: Luo
authors.affiliation: Department of Histology and Embryology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, PR China.
authors.forename: Xingshu
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Physiology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, PR China.
authors.forename: Fang
authors.initials: F
authors.lastname: Chen
authors.affiliation: Department of Physiology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, PR China.
authors.forename: Chao
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Physiology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, PR China.
authors.forename: Shuancheng
authors.initials: S
authors.lastname: Ren
authors.affiliation: Department of Physiology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, PR China.
authors.forename: Qicheng
authors.initials: Q
authors.lastname: Qiao
authors.affiliation: Department of Physiology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, PR China.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Stanford University, Palo Alto, CA 94304, USA.
authors.forename: Luis
authors.initials: L
authors.lastname: de Lecea
authors.affiliation: Department of Sleep and Psychology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, PR China.
authors.forename: Dong
authors.initials: D
authors.lastname: Gao
authors.affiliation: Department of Physiology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, PR China.
authors.forename: Zhian
authors.initials: Z
authors.lastname: Hu
mesh_terms: D000818:Animals; D015220:Calcium Channels / Q000502:physiology; D018728:Entorhinal Cortex / Q000187:drug effects / Q000502:physiology*; D018698:Glutamic Acid / Q000502:physiology; D006632:Histamine / Q000008:administration & dosage / Q000502:physiology*; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D024661:Potassium Channels, Inwardly Rectifying / Q000037:antagonists & inhibitors / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011969:Receptors, Histamine H1 / Q000502:physiology; D065853:Spatial Learning / Q000187:drug effects / Q000502:physiology*; D055366:Synaptic Potentials / Q000187:drug effects; D005680:gamma-Aminobutyric Acid / Q000502:physiology
chemical_list: D015220:Calcium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011969:Receptors, Histamine H1; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D006632:Histamine
keywords: histaminergic system; kir channels; medial entorhinal cortex; spatial learning