Metabolism represents a series of biochemical pathways that provide cells with solutions to utilize and produce energy, to maintain cellular health. These biochemical pathways comprise the synthesis (anabolism) and degradation (catabolism) of complex molecules (DeBerardinis & Thompson, 2012). Anabolism and catabolism represent two complementary processes. While catabolism consists in the degradation of macromolecules to synthetize the energetic “currency” of the cells (e.g., ATP, GTP and NADPH), anabolism, in contrast, consists in the consumption of this currency to drive energy-requiring biosynthetic reactions (Krebs, 1972). For instance, ATP and NADPH are used to synthesize proteins, nucleic acids, and lipids, as well as to carry out other energy-requiring cellular processes (Agteresch et al., 1999, Xiao et al., 2018). Importantly, the metabolic capacities of various tissues within the body are not uniform and can differ in their capacity to utilize different metabolic substrates, such as glucose, lactate or fatty acids (Judge & Dodd, 2020). Among these metabolic substrates, glucose occupies a central position in cellular energy resources. The metabolism of glucose comprises anabolic (gluconeogenesis) and catabolic (glycolysis) pathways. Gluconeogenesis consists in glucose production from non-carbohydrate precursors such as lactate, oxaloacetate, and glycerol (Pilkis et al., 1988, Pilkis and Granner, 1992). This mechanism predominantly takes place in peripheral tissues such as the renal cortex or liver (Chung et al., 2015). However, it has been reported that brain astrocytes are also capable of storing glycogen (Rial et al., 2015). In contrast, glycolysis is a ubiquitous mechanism, which converts glucose to pyruvate, an ATP precursor (Barros et al., 2021).

While ATP plays a role as universal energy currency, its mode of production differs under various biochemical conditions. The cellular energetic machinery can operate via aerobic or anaerobic metabolism. Aerobic metabolism relies on oxygen and involves mitochondria. It serves as the primary mechanism for generating ATP, by effectively extracting the potential energy stored in various macromolecules such as carbohydrates, fats, and proteins. Briefly, through a series of complex enzymatic reactions occurring in the inner mitochondrial membrane, oxidative phosphorylation (OXPHOS) utilizes the electron transport chain (ETC) and chemiosmosis to couple the oxidation of reducing agents (NADH and FADH2) derived from fuel sources with the phosphorylation of adenosine diphosphate (ADP) to ATP. As a result, the OXPHOS mechanism produces approximately 34 molecules of ATP from one molecule of glucose. The activation kinetics of OXPHOS are relatively slow in nature, which is attributable to two key factors: mitochondrial translocation and the involvement of numerous enzymes in this intricate process. The spatial separation of mitochondria necessitates the transport of substrates across their double membrane structure, which contributes to a delay in the initiation of OXPHOS. Furthermore, the regulation of this metabolic pathway involves a significant number of enzymes, introducing complexity and additional steps, further slowing down the overall process. This process enables cells to efficiently harvest and utilize the energy derived from the breakdown of organic compounds, thereby providing the energy for cellular functions and maintenance (Saraste, 1999).

Anaerobic glucose metabolism, often named glycolysis, refers to metabolic pathways that occur in the absence of oxygen, typically taking place in the cytoplasm of cells. The absence of oxygen leads to a shift in metabolic processes towards fermentation. This process allows for the partial breakdown of glucose and other substrates, resulting in the production of only 2 molecules of ATP per one molecule of glucose. However, unlike OXPHOS, which involves the complete oxidation of substrates, anaerobic metabolism does not fully oxidize substrates. In fact, pyruvate is partially metabolized to lactate by lactate dehydrogenase. Therefore, by-products such as lactate are accumulated and exported to the extracellular environment by monocarboxylate transporters (MCT). Glycolysis serves as an alternative means for cells to produce energy when oxygen is limited or unavailable. While it is a less efficient pathway compared to OXPHOS, it enables cells to maintain a basal level of ATP production. Remarkably, although the OXPHOS mechanism predominantly serves as the primary means for ATP synthesis, various tissues and cellular phenotypes display diverse metabolic profiles that allow for the utilization of either OXPHOS or anaerobic glycolytic mechanisms, thereby demonstrating a considerable heterogeneity. The brain stands as a prototypical organ exemplifying this metabolic diversity (Granchi et al., 2010, Rabinowitz and Enerback, 2020).

The brain, which represents only ∼2% of body weight, consumes up to a quarter of the body energy under normal resting conditions (Sonnay et al., 2017). With elevated metabolic demands but a low capacity for energy storage, the brain is heavily reliant on a continuous influx of energy substrates and on proper utilization of these substrates (Camandola & Mattson, 2017). As such, the brain is particularly vulnerable to defects in energy intake/production/utilization. As proper brain development requires tightly regulated metabolic homeostasis (Camandola & Mattson, 2017), disrupted energy supply and/or utilization during critical developmental periods may irreversibly impact brain maturation. The dependence of neurons on the vasculature for energy supply highlights the importance of a proper interplay between vascular and neuronal systems for neural growth and function (Carmeliet & Jain, 2011). The brain can consume several substrates including glucose, lactate, acetate, fatty acids and ketone bodies. However, to maintain normal function, brain energy metabolism primarily relies on glucose, provided from the blood to fuel both resting and activated states (Sonnay et al., 2017). Moreover, brain metabolism must be tightly regulated both temporally and spatially from a systems level down to single synapses (Watts et al., 2018). While neurons are responsible for massive energy consumption to maintain their excitability, the brain is made up of many cell types, each with a specific role in regulating brain function and metabolism (Watts et al., 2018). A synergistic function of vascular endothelial cells, pericytes, astrocytes and neurons is required to uphold brain metabolism (Bélanger et al., 2011). These cell types function in a complex ensemble known as the neurovascular unit (NVU) (Fig. 1), which regulates energy import and utilization (Benarroch, 2014). The metabolic fate of glucose in the brain depends on the cell type and on the energy demands. Despite having similar energetic potential in theory, different brain cells demonstrate varied metabolic profiles (Camandola & Mattson, 2017). Glucose transport is predominantly mediated by facilitated diffusion through glucose transporters (GLUT) such as the glucose transporter-1 (GLUT-1) and GLUT-3 (Sonnay et al., 2017). GLUT-1 is highly expressed by endothelial cells, and to a lesser extent in astrocytes, while GLUT-3 mediates uptake of glucose by neurons (Camandola & Mattson, 2017). These transporters mediate energy-independent transport of glucose bi-directionally (Sonnay et al., 2017). GLUT-1 is in fact the main carrier involved in the import of glucose into the brain from the blood circulation. Uptake of alternative fuels such as lactate, pyruvate or ketone bodies is mediated by monocarboxylate transporters (MCTs) that are mostly expressed by neurons and astrocytes (Camandola and Mattson, 2017, Sonnay et al., 2017).

Activity of brain cells and neural circuits results in bioenergetic challenges that must be rapidly met to maintain cellular and organ function (Bélanger et al., 2011; Camandola & Mattson, 2017; Rothman, 1994; Watts et al., 2018). From birth and throughout adulthood, managing the function of these cells is key in maintaining a healthy brain (Barros et al., 2021, Camandola and Mattson, 2017, Vannucci and Vannucci, 2000). Anomalies in brain metabolism have been identified in disorders including neurodegenerative diseases, including Alzheimer’s disease (AD) (Grizzanti et al., 2023) and NDDs, such as detailed in this review. Yet, the underlying mechanisms tying metabolic anomalies to NDDs remain to be fully comprehended. The cells (neuronal, vascular, mural and glial) forming the NVU rely on each other metabolically, altogether orchestrating proper brain maturation and function (Andreone et al., 2015; Lacoste et al., 2014; Lacoste & Gu, 2015; Ouellette & Lacoste, 2021; Ouellette et al., 2020). Therefore, genetic mutations associated with NDDs may potentially lead to perturbed neurovascular cellular machinery, resulting in a brain metabolic imbalance. Studies have started to identify metabolic contributions to NDDs (Oyarzabal et al., 2021), but the underlying mechanisms need to be clarified. The purpose of this review is to provide an overview of metabolic regulation within the constituents of the NVU and their involvement in Autism Spectrum Disorders, Fragile X syndrome, Rett’s syndrome and Down syndrome.