The electrical activity of neurons is associated with rapid changes in the pH of brain extracellular fluid. Within milliseconds, a rise in extracellular H can be detected that is caused by activation of the plasma membrane calcium ATPase (PMCA), as it pumps calcium out of neurons in exchange for extracellular hydrogen ions. A significant increase in external pH can occur due to the inability of the fluid to buffer hydrogen ions in a fat time frame. This is because extracellular forms of the enzyme carbonic anhydrase, which catalyze the buffering reaction, are limited in activity. The significance of the rapid elevation o extracellular pH lies in the sensitivity of several membrane channels to hydrogen ions. In this application we propose that the activity of the PMCA in a single neuron results in a boost of the current through its own post-synaptic N-methyl-D-aspartate receptors (NMDARs). Pilot data suggest that both the amplitude and time course of current through NMDARs are modulated by the rise in surface pH generated by the same cell. Additional data suggest that hippocampal interneurons are subject to similar modulation, due to the pH sensitivity of their post-synaptic kainate receptors. Pyramidal neurons and interneurons will be studied these contexts, using ex vivo hippocampal slice preparations. The consequences of these pH shifts for network activity are addressed in the final aim of this application, which investigates a short-term enhancement of post-synaptic responses of CA1 pyramidal neurons in the slice model. This potentiation is especially pronounced in preparations with a knock out of the carbonic anhydrase 14 isoform, and is postulated to occur through a transient rise in extracellular pH, mediated via the PMCA. These concepts are extended to the pathological setting of seizure generation by use of brain slice preparations, as well as an in vivo mouse model. We hypothesize that the transition to seizure is fostered by an extracellular alkalosis, and mitigated by the expression of carbonic anhydrase 14. To accomplish these aims work will make use of animals with a deletion of specific carbonic anhydrases, and will employ transgenic mice with green fluorescence protein expressed in specific interneurons. The physiological significance of these studies lies in the increased understanding of short-term plasticity in the brain and local circuit function. Its translational impact is directly relevant to the epilepsies, as well as other disorders in which increased excitability and spreading depression have been implicated, such as migraine and the exacerbation of tissue damage after stroke and traumatic brain injury.

Public Health Relevance

This project will focus on the mechanisms by which rapid acid-base changes modulate excitatory synaptic transmission in the brain. These physiological processes are relevant to brain pathologies associated with aberrant, excessive excitability, such as epilepsy, other forms of seizure, and cortical spreading depression. As all of these events of hyper-excitability are implicated in the exacerbation of brain damage after stroke and traumatic injury, the basic studies of this project are relevant to the pathophysiology of these disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS032123-18A1
Application #
8666349
Study Section
Special Emphasis Panel (ZRG1-MDCN-C (04))
Program Officer
Silberberg, Shai D
Project Start
1993-09-01
Project End
2018-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
18
Fiscal Year
2014
Total Cost
$546,446
Indirect Cost
$224,059
Name
New York University
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Svichar, Nataliya; Esquenazi, Susana; Chen, Huei-Ying et al. (2011) Preemptive regulation of intracellular pH in hippocampal neurons by a dual mechanism of depolarization-induced alkalinization. J Neurosci 31:6997-7004
Makani, Sachin; Chesler, Mitchell (2010) Barium plateau potentials of CA1 pyramidal neurons elicit all-or-none extracellular alkaline shifts via the plasma membrane calcium ATPase. J Neurophysiol 104:1438-44
Makani, Sachin; Chesler, Mitchell (2010) Rapid rise of extracellular pH evoked by neural activity is generated by the plasma membrane calcium ATPase. J Neurophysiol 103:667-76
Svichar, Nataliya; Waheed, Abdul; Sly, William S et al. (2009) Carbonic anhydrases CA4 and CA14 both enhance AE3-mediated Cl--HCO3- exchange in hippocampal neurons. J Neurosci 29:3252-8
Makani, Sachin; Chesler, Mitchell (2007) Endogenous alkaline transients boost postsynaptic NMDA receptor responses in hippocampal CA1 pyramidal neurons. J Neurosci 27:7438-46
Fedirko, Nataliya; Avshalumov, Marat; Rice, Margaret E et al. (2007) Regulation of postsynaptic Ca2+ influx in hippocampal CA1 pyramidal neurons via extracellular carbonic anhydrase. J Neurosci 27:1167-75
Fedirko, Nataliya; Svichar, Nataliya; Chesler, Mitchell (2006) Fabrication and use of high-speed, concentric h+- and Ca2+-selective microelectrodes suitable for in vitro extracellular recording. J Neurophysiol 96:919-24
Tong, Chi-Kun; Chen, Kevin; Chesler, Mitchell (2006) Kinetics of activity-evoked pH transients and extracellular pH buffering in rat hippocampal slices. J Neurophysiol 95:3686-97
Svichar, Nataliya; Esquenazi, Susana; Waheed, Abdul et al. (2006) Functional demonstration of surface carbonic anhydrase IV activity on rat astrocytes. Glia 53:241-7
Shah, Gul N; Ulmasov, Barbara; Waheed, Abdul et al. (2005) Carbonic anhydrase IV and XIV knockout mice: roles of the respective carbonic anhydrases in buffering the extracellular space in brain. Proc Natl Acad Sci U S A 102:16771-6

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