Elsevier

Neurobiology of Disease

Volume 90, June 2016, Pages 75-85
Neurobiology of Disease

The interneuron energy hypothesis: Implications for brain disease

https://doi.org/10.1016/j.nbd.2015.08.005Get rights and content

Abstract

Fast-spiking, inhibitory interneurons – prototype is the parvalbumin-positive (PV+) basket cell – generate action potentials at high frequency and synchronize the activity of numerous excitatory principal neurons, such as pyramidal cells, during fast network oscillations by rhythmic inhibition. For this purpose, fast-spiking, PV+ interneurons have unique electrophysiological characteristics regarding action potential kinetics and ion conductances, which are associated with high energy expenditure. This is reflected in the neural ultrastructure by enrichment with mitochondria and cytochrome c oxidase, indicating the dependence on oxidative phosphorylation for adenosine-5′-triphosphate (ATP) generation. The high energy expenditure is most likely required for membrane ion transport in dendrites and the extensive axon arbor as well as for presynaptic release of neurotransmitter, gamma-aminobutyric acid (GABA). Fast-spiking, PV+ interneurons are central for the emergence of gamma oscillations (30–100 Hz) that provide a fundamental mechanism of complex information processing during sensory perception, motor behavior and memory formation in networks of the hippocampus and the neocortex. Conversely, shortage in glucose and oxygen supply (metabolic stress) and/or excessive formation of reactive oxygen and nitrogen species (oxidative stress) may render these interneurons to be a vulnerable target. Dysfunction in fast-spiking, PV+ interneurons might set a low threshold for impairment of fast network oscillations and thus higher brain functions. This pathophysiological mechanism might be highly relevant for cerebral aging as well as various acute and chronic brain diseases, such as stroke, vascular cognitive impairment, epilepsy, Alzheimer's disease and schizophrenia.

Introduction

Research on cortical information processing and brain energy metabolism has focussed on neurons, such as granule and pyramidal cells, that release excitatory neurotransmitter, glutamate (Attwell and Laughlin, 2001, Burke and Barnes, 2006, Erecińska and Silver, 2001, Ho et al., 2011, Kann and Kovács, 2007, Mattson, 2012, Nicholls and Budd, 2000). Such excitatory principal cells are projection neurons that are generally thought to process, transfer, store and retrieve information. These features underlie the emergence of higher brain functions such as sensory perception, motor behavior and memory formation (Hájos and Paulsen, 2009, Lisman and Buzsáki, 2008, Traub and Whittington, 2010).

Complex neuronal information processing, however, critically depends on the precise spatial and temporal coordination of the activities of principal cells in local cortical networks (Buzsáki, 2006, Fries et al., 2007, Traub and Whittington, 2010). Such coordination is provided by different classes of network oscillations that enable synchronous activity of principal cells during normal brain function (Buzsáki and Draguhn, 2004, Traub and Whittington, 2010, Uhlhaas and Singer, 2010). Network oscillations cover a wide range of frequencies (~ 0.05 to 600 Hz), and they define different cognitive and behavioral states (Buzsáki and Draguhn, 2004). In cortical networks, the most prominent oscillation patterns comprise the theta- (4–12 Hz), beta- (13–30 Hz) and gamma- (~ 30–100 Hz) bands. These oscillations synchronize the generation of action potentials (neuronal ‘spiking’) in principal cells with great precision (Buzsáki, 2006, Uhlhaas and Singer, 2010).

Inhibitory interneurons have a key role in the emergence of cortical network oscillations (Bartos et al., 2007, Mann and Paulsen, 2007). In the cortex, synaptic inhibition is mainly mediated by neurotransmitter, gamma-aminobutyric acid (GABA) (Mann and Paulsen, 2007, Möhler, 2007). Among the population of GABAergic interneurons a great heterogeneity has been discovered at the molecular, morphological and functional level (Klausberger and Somogyi, 2008). However, if certain subtypes of interneurons were crucial for synchronization of principal cell activities it would be fundamental to define the electrophysiological and bioenergetical characteristics of GABAergic interneurons, including the impact on cortical information processing in physiological and pathophysiological conditions.

Recent studies have started to define the cellular mechanisms and the bioenergetics of cortical gamma oscillations (30–100 Hz) that have a strong relationship to higher brain functions (Bartos et al., 2007, Fries et al., 2007, Lisman and Buzsáki, 2008, Uhlhaas and Singer, 2010). The available experimental evidence from many in vitro and some in vivo studies in animals and humans indicates that complex information processing in the hippocampus and the neocortex critically depends on the activity of a specific type of GABAergic interneurons, i.e., fast-spiking, parvalbumin-positive (PV+) interneurons (Bartos et al., 2007, Fries, 2009, Hu et al., 2014). Since fast-spiking interneurons also feature high energy expenditure these cells are crucial for the maintenance or the decline of cognitive functions when metabolic stress occurs. This has been recently summarized as the ‘interneuron energy hypothesis’ (Kann et al., 2014). The present review highlights key aspects of this hypothesis and defines some general implications for brain aging and disease, such as vascular cognitive impairment, stroke, epilepsy, Alzheimer's disease and schizophrenia.

Section snippets

Gamma oscillations and fast-spiking, PV+ interneurons in cortical networks

The ‘interneuron energy hypothesis’ primarily originates from a critical review of morphological, biochemical, electrophysiological and behavioral studies from the rodent and the human hippocampus, with the emphasis on fast neuronal network oscillations in the gamma-frequency band (30–100 Hz) (Kann et al., 2014). This does not preclude the importance of slower network oscillations for higher brain functions (Buzsáki, 2006, Schroeder and Lakatos, 2009). Gamma oscillations have been found in most

Bioenergetics of gamma oscillations (30–100 Hz)

Recent studies have started to directly address the energy metabolism of different activity states in local neuronal networks using slice preparations from mouse and rat. Recordings of local field potential and interstitial partial oxygen pressure (pO2) with high spatiotemporal resolution revealed a positive correlation between the power of gamma oscillations and oxygen consumption (Kann et al., 2011). This was supported by another study demonstrating the about twofold increase in oxygen

Interneuron energy hypothesis

While this key role of fast-spiking, PV+ basket cells for fast rhythmic network activity has been consistently recognized, the underlying bioenergetics have gained much less attention. Indeed, several findings indicate that fast-spiking interneurons utilize much more energy than other cortical neurons. This might render them highly vulnerable to conditions of metabolic stress. Cellular energy expenditure is counterbalanced by generation of ATP through glycolysis in the cytosol and oxidative

Stroke and vascular cognitive impairment

Gamma oscillations and fast-spiking, PV+ interneurons have been also studied in view of the marked vulnerability of higher brain functions (Kann, 2012). Importantly, the rapid abolishment in the power of gamma oscillations has been described in various experimental conditions in slice preparations: (1) when the pO2 of the ambient atmosphere was lowered to the normoxic range under semi-interface recording condition (Huchzermeyer et al., 2008), (2) when the flow rate of oxygenated recording

Aging, Alzheimer's disease, epilepsy and schizophrenia

In addition to metabolic stress, fast-spiking, PV+ interneurons might also experience higher levels of oxidative stress in both physiological and pathophysiological conditions (Fig. 2). The small amount of electron leakage (0.1% to 4%) at the mitochondrial respiratory-chain induces one-electron reduction of oxygen, which results in the relatively stable superoxide anion (Brown, 2010, Morán et al., 2012). Superoxide anion is a free radical with biological toxicity. Superoxide anion is generated

Conclusions

Highly energized fast-spiking, PV+ interneurons are a central element of complex cortical information processing. These cells might be critical for cognitive decline when energy supply becomes limited and/or oxidative stress occurs. Future research may focus not only on excitatory principal cells in the cortex but also on the characteristics and functions of GABAergic interneurons. Specialized inhibitory interneuron subtypes, such as fast-spiking, PV+ interneurons, may set low thresholds for

Conflict of interest

The author declares that he has no conflict of interest.

Acknowledgments

The author thanks Andrea Lewen for text editing assistance. This work was funded by the German Research Foundation (DFG) within the Collaborative Research Center (SFB) 1134 (project B02).

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