Developmental maturation of activity‐induced K⁺ and pH transients and the associated extracellular space dynamics in the rat hippocampus

Abstract

Key points Neuronal activity induces fluctuation in extracellular space volume, [K+]o and pHo, the management of which influences neuronal function The neighbour astrocytes buffer the K+ and pH and swell during the process, causing shrinkage of the extracellular space In the present study, we report the developmental rise of the homeostatic control of the extracellular space dynamics, for which regulation becomes tighter with maturation and thus is proposed to ensure efficient synaptic transmission in the mature animals The extracellular space dynamics of volume, [K+]o and pHo evolve independently with developmental maturation and, although all of them are inextricably tied to neuronal activity, they do not couple directly. Abstract Neuronal activity in the mammalian central nervous system associates with transient extracellular space (ECS) dynamics involving elevated K+ and pH and shrinkage of the ECS. These ECS properties affect membrane potentials, neurotransmitter concentrations and protein function and are thus anticipated to be under tight regulatory control. It remains unresolved to what extent these ECS dynamics are developmentally regulated as synaptic precision arises and whether they are directly or indirectly coupled. To resolve the development of homeostatic control of [K+]o, pH, and ECS and their interaction, we utilized ion‐sensitive microelectrodes in electrically stimulated rat hippocampal slices from rats of different developmental stages (postnatal days 3–28). With the employed stimulation paradigm, the stimulus‐evoked peak [K+]o and pHo transients were stable across age groups, until normalized to neuronal activity (field potential amplitude), in which case the K+ and pH shifted significantly more in the younger animals. By contrast, ECS dynamics increased with age until normalized to the field potential, and thus correlated with neuronal activity. With age, the animals not only managed the peak [K+]o better, but also displayed swifter post‐stimulus removal of [K+]o, in correlation with the increased expression of the α1‐3 isoforms of the Na+/K+‐ATPase, and a swifter return of ECS volume. The different ECS dynamics approached a near‐identical temporal pattern in the more mature animals. In conclusion, although these phenomena are inextricably tied to neuronal activity, our data suggest that they do not couple directly.

Molecular mechanisms of K+ clearance and extracellular space shrinkage—Glia cells as the stars

“…The recordings were normalized to the [K + ] o at the end of the stimulus to illustrate the shift in the shape of the K + dynamics with maturation. Adapted from (a) Larsen et al () with permission; (b) Larsen, Stoica, et al (); and (c) Larsen, Stoica, and MacAulay () with permission…”

“…Most studies report predominant expression of the α3 isoform in neurons, probably alongside α1, both paired with β1, while the astrocytic Na + /K + ‐ATPase activity is dominated by α2 paired with β2 or, to a lesser extent, β1 (Cameron et al, ; Cholet, Pellerin, Magistretti, & Hamel, ; McGrail et al, ; McGrail & Sweadner, ; Richards, Bommert, Szabo, & Miles, ; Stoica et al, ; Tokhtaeva, Clifford, Kaplan, Sachs, & Vagin, ; Watts, Sanchez‐Watts, Emanuel, & Levenson, ; Zhang et al, ), Figure b. The expression profile for all these isoforms demonstrates steep elevation in the first few weeks of postnatal development, which aligns with a growing ability to clear [K + ] o efficiently from the extracellular space during neuronal activity, and thus predicted synaptic efficiency (Larsen et al, ), Figure c. In primary culture of rat astrocytes, the favored Na + /K + ‐ATPase isoform shifts from the α2 detected in acutely isolated astrocytes to α1 (Stoica et al, ).…”

“…In primary culture of rat astrocytes, the favored Na + /K + ‐ATPase isoform shifts from the α2 detected in acutely isolated astrocytes to α1 (Stoica et al, ). It is possible that cell culturing may alter the Na + /K + ‐ATPase abundance as well, since the Na + /K + ‐ATPase V max is generally larger in astrocytic than neuronal cultures (Hajek, Subbarao, & Hertz, ; Walz & Hertz, ), in spite of the α3 subunit being six fold more abundant in hippocampus in situ than its α2 counterpart (and 20‐fold more than α1, promoting α3 as the dominant Na + /K + ‐ATPase in the mammalian brain (Clapcote et al, ; Larsen et al, ). The cell‐specific organization of the different Na + /K + ‐ATPase isoforms suggests that these serve diverse physiological roles in the mammalian brain.…”

Synaptic cleft microenvironment influences potassium permeation and synaptic transmission in hair cells surrounded by calyx afferents in the turtle

“…These changes are not reflected in the bulk extracellular solution, and measuring them poses technical challenges (Larsen et al . ) given the minute volumes and the speed with which ions diffuse and concentrations vary. There are locations within the central auditory and peripheral vestibular systems, however, where calyces (Retzius, ; Held, ) form large appositions between presynaptic and postsynaptic cells, and where the dynamics of synaptic transmission and ion accumulation can be measured using electrophysiological (Forsythe, ; Lim et al .…”

“…Ongoing neural activity is associated with rapid and dynamic changes in ion concentration at many synaptic sites in the brain, especially at those enveloped by astrocytic processes (Špaček, 1985;Ventura & Harris, 1999). These changes are not reflected in the bulk extracellular solution, and measuring them poses technical challenges (Larsen et al 2019) given the minute volumes and the speed with which ions diffuse and concentrations vary. There are locations within the central auditory and peripheral vestibular systems, however, where calyces (Retzius, 1884;Held, 1893) form large appositions between presynaptic and postsynaptic cells, and where the dynamics of synaptic transmission and ion accumulation can be measured using electrophysiological (Forsythe, 1994;Lim et al 2011;Contini et al 2012Contini et al , 2017 or optical (Highstein et al 2014) techniques.…”