Highly energized inhibitory interneurons are a central element for information processing in cortical networks

Abstract

Gamma oscillations (∼30 to 100 Hz) provide a fundamental mechanism of information processing during sensory perception, motor behavior, and memory formation by coordination of neuronal activity in networks of the hippocampus and neocortex. We review the cellular mechanisms of gamma oscillations about the underlying neuroenergetics, i.e., high oxygen consumption rate and exquisite sensitivity to metabolic stress during hypoxia or poisoning of mitochondrial oxidative phosphorylation. Gamma oscillations emerge from the precise synaptic interactions of excitatory pyramidal cells and inhibitory GABAergic interneurons. In particular, specialized interneurons such as parvalbumin-positive basket cells generate action potentials at high frequency ('fast-spiking') and synchronize the activity of numerous pyramidal cells by rhythmic inhibition ('clockwork'). As prerequisites, fast-spiking interneurons have unique electrophysiological properties and particularly high energy utilization, which is reflected in the ultrastructure by enrichment with mitochondria and cytochrome c oxidase, most likely needed for extensive membrane ion transport and γ-aminobutyric acid metabolism. This supports the hypothesis that highly energized fast-spiking interneurons are a central element for cortical information processing and may be critical for cognitive decline when energy supply becomes limited ('interneuron energy hypothesis'). As a clinical perspective, we discuss the functional consequences of metabolic and oxidative stress in fast-spiking interneurons in aging, ischemia, Alzheimer's disease, and schizophrenia.

Figure 1

Gamma oscillations are exemplified from the CA3 network of the hippocampus. (A) The hippocampal formation consists of the dentate gyrus (DG) with excitatory granule cells (white ovals) and subfields, CA3 and CA1 with excitatory pyramidal cells (orange triangles). Parvalbumin-positive (PV+) interneurons are also illustrated (intermittent blue spheres). Red arrows indicate main routes of information processing in the hippocampal formation. (B) Example trace of persistent gamma oscillations that occur in local field potential (LFP) recordings in the presence of cholinergic or glutamatergic receptor agonists. The power spectrum (PS) was calculated from the same trace. (C) and (D) Immunohistochemical stainings of PV+ interneurons, visualized with 3,3'-diaminobenzidine (DAB) (C) or fluorescent secondary antibody (D). The images show parts of the CA3 subfield. Note both location of somata (C, black dots) and numerous synaptic contacts of PV+ interneurons to the perisomatic region of pyramidal cells (D, turquoise meshwork). Nuclei of neurons and glial cells are counterstained with 4',6-diamidino-2-phenylindole (DAPI) (D, grey dots). (E) A single PV+ interneuron contacts numerous pyramidal cells (PC) via GABAergic synapses. Excitatory synapses from pyramidal cells onto the interneuron are not shown. (F) Rhythmic action potentials (blue vertical bars) of PV+, fast-spiking interneurons (first line) evoke synchronous inhibitory postsynaptic potentials in pyramidal cells that are reflected by oscillations in the local field potential (LFP) (second line). This rhythmic perisomatic inhibition provides a temporal matrix for individual pyramidal cells (orange triangles) to generate action potentials (red vertical bars) during brief time windows, resulting in a well-defined aggregate sequence of action potentials (black vertical bars) from a given pyramidal cell group and thus precise information processing in neuronal networks (bottom line). Scale bar, 100 μm (C and D).

Figure 2

Highly energized inhibitory interneurons are a central element for information processing in cortical networks (interneuron energy hypothesis). (A) Synchronized rhythmic activity of pyramidal cells (PC, orange cell population on the left) highly depends on mutual interactions with inhibitory GABAergic interneurons (IN, heterogeneous cell population on the right) via excitatory (EPSPs, arrow-headed connections) and inhibitory postsynaptic potentials (IPSPs, line-headed connections). GABAergic interneurons exert different types of inhibition in pyramidal cells (three solid spheres with diverse blue colors), including fast phasic inhibition (intermittent blue spheres). In particular, fast-spiking interneurons such as parvalbumin-positive basket cells are central for fast rhythmic synchronization of pyramidal cell activity (‘clockwork'). Fast-spiking interneurons are characterized by unique electrophysiological and neuroenergetical properties such as high numbers of mitochondria. Note that gamma oscillations in local field potential recordings (LFP) primarily reflect synchronized IPSPs. (B) As a perspective, the functional consequences of metabolic stress in fast-spiking interneurons are illustrated. Even moderate metabolic stress, which occurs either acutely (e.g., hypoxia/ischemia and mitochondrial poisoning) or chronically (e.g., arteriosclerosis or mitochondrial disorders), might cause dramatic decreases in ATP levels and GABA release in fast-spiking interneurons (switch from intermittent to solid blue spheres). This is associated with a decrease of action potentials in fast-spiking interneurons, the loss of gamma oscillations in the local field potential (LFP) (‘blurred clockwork') and the precise temporal sequence of information processing in the neuronal network, and, consequently, higher brain functions (compare three lines at the bottom in A and B). This pathophysiological mechanism might be worsened by acute or chronic oxidative stress in fast-spiking interneurons. By contrast, other types of inhibition (three solid spheres with diverse blue colors) as well as pyramidal cell excitation might be less affected because of higher cellular thresholds to metabolic stress. The scheme is modified from Bartos et al.

Figure 3

The simplified scheme illustrates the perspective on metabolic and oxidative stress in fast-spiking, parvalbumin-positive interneurons. The small circle reflects acute effects of hypoxia/ischemia or mitochondrial poisoning that rapidly result in neuronal network dysfunction. The large circle reflects chronic effects of mitochondrial dysfunction and/or cerebral hypoperfusion that finally result in neurodegeneration. Note that the pathophysiological mechanisms illustrated in both circles may partially interact, depending on the course of the disease and pathogenic factors such as alterations in expression of ion channels, parvalbumin or PGC-1α that may result in imbalances of oxidative and anti-oxidative processes. [Ca²⁺]_m, mitochondrial Ca²⁺-concentration; GABA, γ-aminobutyric acid; NO, nitric oxide; NOS, nitric oxide synthase; O₂^•−, superoxide anion; ΔΨ, mitochondrial membrane potential; RNS, reactive nitrogen species; ROS, reactive oxygen species; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator 1-alpha; PV, parvalbumin.