Restraint Stress Intensifies Interstitial K+ Accumulation during Severe Hypoxia

Christian Schnell,Belinda Kempkes,Michael Müller,Swen Hülsmann,Oliwia A Janc,Carolina Araya Callis,Gabriele Flügge

doi:10.3389/fphar.2012.00053

Abstract

Chronic stress affects neuronal networks by inducing dendritic retraction, modifying neuronal excitability and plasticity, and modulating glial cells. To elucidate the functional consequences of chronic stress for the hippocampal network, we submitted adult rats to daily restraint stress for 3 weeks (6 h/day). In acute hippocampal tissue slices of stressed rats, basal synaptic function and short-term plasticity at Schaffer collateral/CA1 neuron synapses were unchanged while long-term potentiation was markedly impaired. The spatiotemporal propagation pattern of hypoxia-induced spreading depression episodes was indistinguishable among control and stress slices. However, the duration of the extracellular direct current potential shift was shortened after stress. Moreover, K+ fluxes early during hypoxia were more intense, and the postsynaptic recoveries of interstitial K+ levels and synaptic function were slower. Morphometric analysis of immunohistochemically stained sections suggested hippocampal shrinkage in stressed rats, and the number of cells that are immunoreactive for glial fibrillary acidic protein was increased in the CA1 subfield indicating activation of astrocytes. Western blots showed a marked downregulation of the inwardly rectifying K+ channel Kir4.1 in stressed rats. Yet, resting membrane potentials, input resistance, and K+-induced inward currents in CA1 astrocytes were indistinguishable from controls. These data indicate an intensified interstitial K+ accumulation during hypoxia in the hippocampus of chronically stressed rats which seems to arise from a reduced interstitial volume fraction rather than impaired glial K+ buffering. One may speculate that chronic stress aggravates hypoxia-induced pathophysiological processes in the hippocampal network and that this has implications for the ischemic brain.

Highlights

Repeated stressful experiences have a profound impact on neuronal plasticity in the hippocampal formation
SYNAPTIC FUNCTION AND PLASTICITY Synaptic function and plasticity were assessed by recording evoked field potentials in st. radiatum of the CA1 subfield of acute hippocampal tissue slices
Induction of long-term potentiation (LTP) by a single high-frequency stimulus (100 Hz, 1 s train, stimulation intensity adjusted to elicit half-maximum responses) caused a clear post-tetanic potentiation (PTP) of Field excitatory postsynaptic potentials (fEPSPs) amplitudes that was indistinguishable among control (n = 5) and stress slices (n = 7; Figure 1E)

Summary

Introduction

Repeated stressful experiences have a profound impact on neuronal plasticity in the hippocampal formation (for review see Fuchs et al, 2006; Popoli et al, 2012). Among the underlying cellular changes, dendritic remodeling of hippocampal pyramidal neurons has been documented after chronic stress exposure (Magariños et al, 1996, 1997; Kole et al, 2004), and the regression of the geometrical length of apical dendrites of CA3 pyramidal neurons is probably the most thoroughly investigated anatomical change (Watanabe et al, 1992). Such alterations in dendritic morphology directly affect neuronal functioning as a shortening of even a few dendrites has been shown to enhance backpropagation of action potentials (Golding et al, 2001; Schaefer et al, 2003). Extensive dendritic sprouting, and enhanced spine density were observed when the number of axonal afferents was increased (Kossel et al, 1997), whereas the loss of afferents induced dendritic atrophy (Valverde, 1968; Benes et al, 1977; Deitch and Rubel, 1984)

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