Defects in Bioenergetic Coupling in Schizophrenia

Abstract

Synaptic neurotransmission relies on maintenance of the synapse and meeting the energy demands of neurons. Defects in excitatory and inhibitory synapses have been implicated in schizophrenia, likely contributing to positive and negative symptoms as well as impaired cognition. Recently, accumulating evidence has suggested that bioenergetic systems, important in both synaptic function and cognition, are abnormal in psychiatric illnesses such as schizophrenia. Animal models of synaptic dysfunction demonstrated endophenotypes of schizophrenia as well as bioenergetic abnormalities. We report findings on the bioenergetic interplay of astrocytes and neurons and discuss how dysregulation of these pathways may contribute to the pathogenesis of schizophrenia, highlighting metabolic systems as important therapeutic targets.

Keywords: Bioenergetic coupling; Glucose utilization; Lactate shuttle; Metabolism; Mitochondria; Schizophrenia.

Figure 1

Bioenergetic coupling in normal brain. Glycolysis and oxidative metabolism via tricarboxylic acid (TCA) cycle are key pathways in maintaining synaptic function. Both neurons and astrocytes undergo glycolysis even during aerobic conditions. Glucose, which feeds the glycolytic pathway, can enter cells through glucose transporters (GLUTs) or be derived from the breakdown of glycogen in astrocytes. Meeting the energy demand of neurons is highly reliant on the metabolic coupling of neurons to glycolysis and lactate production in astrocytes. There are several key enzymes in glycolysis, including hexokinase (HXK) and lactate dehydrogenase (LDH). This metabolic coupling also requires monocarboxylate transporters (MCTs), which rapidly transport lactate generated by astrocytes into the extracellular space and into neurons. Here lactate is converted back to pyruvate by LDH, which may enter the TCA cycle and oxidative phosphorylation to generate 30–36 molecules of adenosine triphosphate (ATP). This net flow of energetic substrates from astrocytes to neurons to support neuronal activity is termed the “astrocyte-neuron lactate shuttle.”

Figure 2

Genetic and environmental risk factors for schizophrenia include genomic variants and stressful events that impact the NMDA receptor signaling complex. There is a close interrelationship between the development of glutamatergic synapses and the meeting of bioenergetic demands, which if disrupted could in return affect synaptic function, generating a pathological cycle and possibly an intermediate metabolic phenotype. This phenotype could include a metabolic uncoupling of astrocytes and neurons, affecting pathways such as the astrocyte neuron lactate shuttle, and result in an inability to support increases in neuronal activity. There is evidence that the astrocyte neuron lactate shuttle is necessary for cognitive functions such as long-term memory, suggesting bioenergetic uncoupling could contribute to cognitive deficits in adulthood in this illness. Abbreviations. Dorsolateral prefrontal cortex (DLPFC); hippocampus (HC).