NMDA Receptor-Dependent Afterdepolarizations Are Curtailed by Carbonic Anhydrase 14: Regulation of a Short-Term Postsynaptic Potentiation

Abstract

In the hippocampus, extracellular carbonic anhydrase (Car) speeds the buffering of an activity-generated rise in extracellular pH that impacts H+-sensitive N-methyl-D-aspartate receptors (NMDARs). We studied the role of Car14 in this brain structure, where it is expressed solely on neurons. Current-clamp responses were recorded from CA1 pyramidal neurons in wild type (WT) vs. Car14 knock out (KO) mice 2 s. before (control) and after (test) a 10 pulse, 100 Hz afferent train. In both WT and KO, the half width (HW) of the test response, and its number of spikes, were augmented relative to the control. An increase in presynaptic release was not involved, as AMPAR-mediated EPSCs were depressed after a train. The increases in HW and spike number were both greater in the Car14 KO. In 0 Mg2+ saline with picrotoxin (using a 20 Hz train), the HW measures were still greater in the KO. The Car inhibitor benzolamide (BZ) enhanced the test response HW in the WT, but had no effect on the already-prolonged HW in the KO. With intracellular MK-801, the curtailed WT and KO responses were indistinguishable, and BZ caused no change. By contrast, the extracellular alkaline changes evoked by the train were not different between WT and KO, and BZ amplified these alkalinizations similarly. These data suggest that Car14 regulates pH transients in the perisynaptic microenvironment, and govern their impact on NMDARs, but plays little role in buffering pH shifts in the broader, macroscopic, extracellular space.

Transcriptional Profiling of Somatostatin Interneurons in the Spinal Dorsal Horn

“…A recent large scale single-cell RNA-seq study in the visual cortex identified Car12 as a unique marker of Layer 6 cortical neuron subtype (Tasic et al, 2016), but apart from this, virtually nothing is known about the function of Car12 in the nervous system. However, other extracellular carbonic anhydrases (ECAs) such as Car4 and Car14 have been well-studied in the brain, where they have been shown to modulate neuronal activity by regulating extracellular pH (Makani and Chesler, 2007;Svichar et al, 2009;Makani et al, 2012). In the hippocampus, several studies have shown that ECAs regulate excitatory synaptic transmission via pH-mediated modulation of NMDA receptor activation (Chen and Chesler, 2015).…”

Acetazolamide potentiates the afferent drive to prefrontal cortex in vivo

“…Mechanistic explorations should also study selective intracellular versus extracellular carbonic anhydrase inhibitors (e.g., Perez Velazquez ; Makani et al. ; Collier et al. ) in their effects on presynaptic plasticity.…”

Acute neuroinflammation provokes intracellular acidification in mouse hippocampus

“…Thus, changes in pH could modify the efficiency of enzymes [22], receptors [5, 23–26], ionic pumps [4, 27, 28], and ionic channels [29–31]. Many pH-sensitive molecules are membrane-bound and involved in the regulation of cellular excitability.…”