Mild metabolic stress is sufficient to disturb the formation of pyramidal cell ensembles during gamma oscillations

Abstract

Disturbances of cognitive functions occur rapidly during acute metabolic stress. However, the underlying mechanisms are not fully understood. Cortical gamma oscillations (30–100 Hz) emerging from precise synaptic transmission between excitatory principal neurons and inhibitory interneurons, such as fast-spiking GABAergic basket cells, are associated with higher brain functions, like sensory perception, selective attention and memory formation. We investigated the alterations of cholinergic gamma oscillations at the level of neuronal ensembles in the CA3 region of rat hippocampal slice cultures. We combined electrophysiology, calcium imaging (CamKII.GCaMP6f) and mild metabolic stress that was induced by rotenone, a lipophilic and highly selective inhibitor of complex I in the respiratory chain of mitochondria. The detected pyramidal cell ensembles showing repetitive patterns of activity were highly sensitive to mild metabolic stress. Whereas such synchronised multicellular activity diminished, the overall activity of individual pyramidal cells was unaffected. Additionally, mild metabolic stress had no effect on the rate of action potential generation in fast-spiking neural units. However, the partial disinhibition of slow-spiking neural units suggests that disturbances of ensemble formation likely result from alterations in synaptic inhibition. Our study bridges disturbances on the (multi-)cellular and network level to putative cognitive impairment on the system level.

Transient Oxygen-Glucose Deprivation Causes Region- and Cell Type-Dependent Functional Deficits in the Mouse HippocampusIn Vitro

“…The vulnerability of PV+ FSI is a particularly important issue, and it is presently unclear to which extent their altered function contributes to impaired post-hypoxic network activity (Johansen et al, 1983;Nitsch et al, 1989;Moga et al, 2002;Wang, 2003;Elzoheiry et al, 2019;Povysheva et al, 2019). Earlier studies found unchanged numbers of PV-IN in contrast to reduced CA1 pyramidal cell numbers several days after HI in vivo (Johansen et al, 1983;Nitsch et al, 1989).…”

“…Calciumbinding properties of parvalbumin are discussed to reduce neurotoxic effects of calcium overload during HI (Tortosa and Ferrer, 1993). However, more recent studies indicate impaired function of inhibitory neurons compared to excitatory neurons after transient metabolic insults (Moga et al, 2002;Wang, 2003;Elzoheiry et al, 2019;Povysheva et al, 2019). It is important to note the methodical differences in those studies in terms of insult severity and outcome measures (histological cell death versus electrophysiological function).…”

“…Of particular importance for such fast synchronization processes are fast-spiking parvalbumin+ interneurons (PV-IN) (Ylinen et al, 1995). Importantly, these cells might be especially vulnerable to HI-induced functional loss and cell damage (Kann et al, 2014;Kann, 2016;Elzoheiry et al, 2019;Povysheva et al, 2019). At the network level, this may lead to decreased inhibition-excitation ratio, disturbed activity patterns and altered coupling between cellular spikes and local field potential (LFP) oscillations.…”

Neuronal gamma oscillations and activity‐dependent potassium transients remain regular after depletion of microglia in postnatal cortex tissue

“…Thus, [K + ] o rarely exceeds 0.5 mM from a baseline of 3.0 mM during gamma oscillations reflecting the maintenance of K + homeostasis (Kann et al., 2011, 2016; Somjen, 2002), which differs from the larger [K + ] o transients induced by artificial repetitive electrical stimulation in situ and in vivo (Heinemann & Lux, 1977; Kann et al., 2003; Liotta et al., 2012). Conversely, gamma oscillations are exquisitely sensitive to metabolic and oxidative stress (Elzoheiry et al., 2019; Huchzermeyer et al., 2008; Papageorgiou et al., 2016).…”

GM-CSF induces noninflammatory proliferation of microglia and disturbs electrical neuronal network rhythms in situ

“…We investigated the effects of GM-CSF on microglianeuron interactions in organotypic hippocampal slice cultures of the rat, which feature well-preserved cytoarchitecture and functional neuronal networks (Figs. 2 and 3) [30,32,37,44]. Slice cultures inherently lack leukocyte infiltration during experimental exposures and thus permit to explore the reactivity of microglia in the absence of invading granulocytes, monocytes, and lymphocytes [22][23][24].…”