Acidosis leads to neurological disorders through overexciting cortical pyramidal neurons

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Abstract

The patients suffering from acidosis usually sign psychological deficits. The cerebral dysfunction is reportedly caused by an acid-induced functional impairment of GABAergic neurons; however, the role of pyramidal neurons in this process remains unclear. By using electrophysiological method and changing extracellular pH, we investigated the influence of acidic environment on pyramidal neurons in the cortical slices, such as their ability of firing spikes and response to synaptic inputs. A low pH of artificial cerebral spinal fluid elevates the responses of pyramidal neurons to excitatory synaptic inputs and their ability of encoding digital spikes, as well as reduces the signal transmission at GABAergic synapses. The elevated ability of neuronal spiking is associated with the decreases of refractory periods and threshold potentials. Therefore, acidosis deteriorates brain functions through making the activities between cortical pyramidal neurons and GABAergic neurons imbalanced toward the overexcitation of neural networks, a process similar to neural excitotoxicity.

Highlights

► Extracellular low pH impairs cortical pyramidal neurons in response to excitatory synaptic inputs. ► Extracellular low pH impairs the abilities of encoding spikes at these pyramidal neurons. ► Neuronal impairment is associated with the decreases of spike refractory periods and thresholds. ► Extracellular low pH impairs GABAergic synaptic transmission at these pyramidal neurons.

Introduction

The neurons integrate synaptic signals and produce action potentials as brain codes for controlling well-organized behaviors and cognitions [1], [2], [3], [4]. Pathogens, such as ischemia and acidosis, impair brain functions including seizure [5], anxiety [6], [7] and mental illness [8], [9], [10], [11]. Ischemic cerebral dysfunctions are owing to the impairment of the encoding processes at the neurons and synapses [12], [13], [14], [15], [16], [17]. How acidosis impairs neuronal and synaptic dysfunctions for psychological deficits needs to be systemically documented.

Acidosis in severe disorders of metabolism, kidney and respiration impairs brain function [6], [7], which make the nervous system to be unable to regulate these organs well. Protecting brain functions is one of key strategies to block this negative loop. To fulfill this goal, the mechanisms underlying acidosis-induced cerebral deficits need to be studied. In terms of cellular pathology for acidic neural overexcitation, a current report shows that acidosis impairs the function of GABAergic cells [18]. The coordination between GABAergic cells and principal neurons maintains the balanced neural network [19], [20], [21], [22], [23], [24]. How does acidosis influence the function of principal neurons? We investigated the effects of acidosis on the functions of pyramidal cells including their intrinsic properties and synaptic transmission by whole-cell patch-clamp in the cortical slices.

Section snippets

Brain slices and neurons

The entire procedures were approved by IACUC in Harbin Heilongjiang, China. Cortical slices (400 μm) were made from FVB-Tg(Gad GFP)4570Swn/J mice (Jackson Lab, Bar Harbor, ME 04609, USA) during postnatal day 17–22. Mice were anesthetized by inhaling isoflurane and decapitated by guillotine. Slices were cut with a Vibratome in oxygenated (95% O2 and 5% CO2) artificial cerebrospinal fluid (ACSF) in the concentrations (mM) of 124 NaCl, 3 KCl, 1.2 NaH2PO4, 26 NaHCO3, 0.5 CaCl2, 4 MgSO4, 10 dextrose,

Results

The patients with acidosis show the disorder of brain functions [6], [7]. In terms of cellular mechanisms underlying psychological deficits, it is found that acidosis leads to malfunction of GABAergic cells [18]. As a balance between GABAergic neurons and principal neurons is essential to fulfill the brain functions [22], [23], [24], here, we examined the influences of acidosis on the functions of cortical pyramidal neurons including their responses to synaptic inputs and ability to encoding

Discussion

Our studies indicate that extracellular low pH elevates the functions of cortical pyramidal neurons including excitatory synaptic transmission (Fig. 1) and spike encoding (Fig. 2), as well as reduces GABA synaptic transmission (Fig. 4). This imbalance between cellular excitation and inhibition toward neural overexcitation may be mechanistically responsible for psychological deficits in acidosis patients. The mechanisms underlying acidosis-induced enhancement of neuronal spike encoding include

Acknowledgments

We thank Dr. J.H. Wang for adviser in project design and execution. This study is granted by Science Funds Research Project of Heilongjiang Province to Z.H.

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