The Spinal Cord Has an Intrinsic System for the Control of pH

Abstract

For survival of the organism, acid-base homeostasis is vital [1, 2]. The respiratory and renal systems are central to this control. Here we describe a novel mechanism, intrinsic to the spinal cord, with sensors that detect pH changes and act to restore pH to physiological levels by reducing motor activity. This pH sensor consists of somatostatin-expressing cerebrospinal fluid-contacting (CSF-c) neurons, which target the locomotor network. They have a low level of activity at pH 7.4. However, at both alkaline and acidic pH, the activity of the individual CSF-c neuron is markedly enhanced through the action of two separate channel subtypes. The alkaline response depends on PKD2L1 channels that have a large conductance and an equilibrium potential around 0 mV, both characteristics of mouse PKD2L1 channels [3-5]. The acidic response is due to an activation of ASIC3 [6]. The discharge pattern of the CSF-c neurons is U-shaped with a minimum frequency around pH 7.4 and a marked increase already at slightly lower and higher pH. During ongoing locomotor activity in the isolated spinal cord, both an increase and as a decrease of pH will reduce the locomotor burst rate. A somatostatin antagonist blocks these effects, suggesting that CSF-c neurons are responsible for the suppression of locomotor activity. CSF-c neurons thus represent a novel innate homeostatic mechanism, designed to sense any deviation from physiological pH and to respond by causing a depression of the motor activity. Because CSF-c neurons are found in all vertebrates, their pH-sensing function is most likely conserved.

Commentary: The Spinal Cord Has an Intrinsic System for the Control of pH

“…Rather than demonstrating minimum CSF-c neuron activity at resting in vivo pH values, the true resting values are, in fact, on the right-hand side of ascending part of the “U” (see Figure 4F of Jalalvand et al, 2016). CSF-c neurons, therefore, offer no protective or homeostatic influence by minimizing locomotion when pH deviates in either direction from its resting value because a realistic acidosis of fluid in contact with these neurons would decrease inhibitory tone of the locomotor network, and hence increase locomotion.…”

“…Recently in Current Biology, Jalalvand et al (2016) described a novel pH sensing system in the spinal cord of lampreys with an ability to inhibit locomotor activity. This system involves inhibitory spinal neurons in intimate contact with the cerebrospinal fluid, termed CSF-c neurons that increase firing frequencies whenever pH deviates in either direction from 7.4.…”

“…This presents a unique and unusual mechanism whereby extracellular pH exerts direct regulation of locomotor activity. The authors conclude that this sensory system represents a “novel innate homeostatic mechanism, designed to sense any deviation from physiological pH and to respond by causing a depression of the motor activity” (Jalalvand et al, 2016). In the following, we argue that the pH sensory system uncovered by Jalalvand et al does not support this conclusion because the pH of 7.4—interpreted as the control condition—is incorrect for ectothermic animals, such as lampreys when studied at low body temperature (Wang and Jackson, 2016).…”

“…While mammals regulate arterial blood pH (pH a ) at 7.4 at their normal body temperature of 37°C, Jalalvand et al (2016) ignore that both pH a and CSF pH (pH CSF ) increase by ~0.015 unit per °C when body temperature decreases in ectothermic vertebrates (Burton, 2002). This so-called alphastat regulation serves to maintain protein ionization (Reeves, 1977), and explains why the normal and regulated pH a of the closely related sea lamprey, Petromyzon marinus , is ~8.1 at 8–10°C (Tufts et al, 1992).…”

“…The much higher in vivo pH than that used in the in vitro experiments completely alters the interpretation of the “U-shaped curve” with minimum firing frequencies of CSF-c neurons at 7.4 (Jalalvand et al, 2016). Rather than demonstrating minimum CSF-c neuron activity at resting in vivo pH values, the true resting values are, in fact, on the right-hand side of ascending part of the “U” (see Figure 4F of Jalalvand et al, 2016).…”