High Pressure and Ca2+ Produce an Inverse Modulation of Synaptic Input Strength and Network Excitability in the Rat Dentate Gyrus

摘要

Hyperbaric environments induce the high pressure neurological syndrome (HPNS) characterized by hyperexcitability of the central nervous system (CNS) and memory impairment. Human divers and other animals experience the HPNS at pressures beyond 1.1 MPa. High pressure depresses synaptic transmission and alters its dynamics in various animal models. Medial perforant path (MPP) synapses connecting the medial entorhinal cortex with the hippocampal formation are suppressed by 50% at 10.1MPa. Reduction of synaptic inputs is paradoxically associated with enhanced ability of dentate gyrus (DG)’ granule cells (GCs) to generate spikes at high pressure. This mechanism allows MPP inputs to elicit standard GC outputs at 0.1–25 Hz frequencies under hyperbaric conditions. An increased postsynaptic gain of MPP inputs probably allows diving animals to perform in hyperbaric environments, but makes them vulnerable to high intensity/frequency stimuli producing hyperexcitability. Increasing extracellular Ca²⁺ ([Ca²⁺]o) partially reverted pressure-mediated depression of MPP inputs and increased MPP’s low-pass filter properties. We postulated that raising [Ca²⁺]o in addition to increase synaptic inputs may reduce network excitability in the DG potentially improving its function and reducing sensitivity to high intensity and pathologic stimuli. For this matter, we activated the MPP with single and 50 Hz frequency stimuli that simulated physiologic and deleterious conditions, while assessing the GC’s output under various conditions of pressure and [Ca²⁺]o. Our results reveal that the pressure and [Ca²⁺]o produce an inverse modulation on synaptic input strength and network excitability. These coincident phenomena suggest a potential general mechanism of networks that adjusts gain as an inverse function of synaptic inputs’ strength. Such mechanism may serve for adaptation to variable pressure and other physiological and pathological conditions and may explain the increased sensitivity to strong sensory stimulation suffered by human deep-divers and cetaceans under hyperbaric conditions.