Histamine Enhances Theta-Coupled Spiking and Gamma Oscillations in the Medial Entorhinal Cortex Consistent With Successful Spatial Recognition

Encoding of spatial information in the superficial layers of the medial entorhinal cortex (sMEC) involves theta-modulated spiking and gamma oscillations, as well as spatially tuned grid cells and border cells. Little is known about the role of the arousal-promoting histaminergic system in the modification of information encoded in the sMEC in vivo, and how such histamine-regulated information correlates with behavioral functions. Here, we show that histamine upregulates the neural excitability of a significant proportion of neurons (16.32%, 39.18%, and 52.94% at 30 μM, 300 μM, and 3 mM, respectively) and increases local theta (4-12 Hz) and gamma power (low: 25-48 Hz; high: 60-120 Hz) in the sMEC, through activation of histamine receptor types 1 and 3. During spatial exploration, the strength of theta-modulated firing of putative principal neurons and high gamma oscillations is enhanced about 2-fold by histamine. The histamine-mediated increase of theta phase-locking of spikes and high gamma power is consistent with successful spatial recognition. These results, for the first time, reveal possible mechanisms involving the arousal-promoting histaminergic system in the modulation of spatial cognition.