Chapter 6: Neurotransmitter Metabolism and Energy—The Metabolic Layer of Mental Disorders

Positioning in the Four-Layer Interaction Framework: This chapter corresponds to the metabolic layer. While the developmental layer (Chapter 5) constructs the structural blueprint of the brain, the metabolic layer determines the immediate state of this structure at "runtime." Neurotransmitter concentrations, energy supply, inflammation levels, and hormonal rhythms—these biochemical parameters are the direct causes of clinical symptoms, but not the root causes; they are downstream manifestations of upstream genetic abnormalities and developmental deviations. Pharmacotherapy for mental disorders is, in essence, an intervention at the metabolic layer.

6.1 Synapses and Neurotransmitters

Chapter 5 established the developmental blueprint of the brain from embryo to adulthood. Now, we focus our attention on the most fundamental information-transmission unit in neural networks—the synapse—and the chemical messengers that play a key role within it: neurotransmitters.

6.2 The Synapse: The Bridge of Information Transmission Between Neurons, and the Gatekeeper of Pathology

Neurons are the basic information-processing units that make up the brain and nervous system. They communicate through synapses—which serve as the core gatekeepers of information transmission, where dysfunction directly leads to neural circuit abnormalities.

• Definition and Structure: A synapse is a key structure for transmitting information between neurons or between neurons and effector cells (muscle cells, gland cells). A typical chemical synapse consists of three parts: the presynaptic membrane (the axon terminal of the information-sending neuron), the synaptic cleft (the tiny gap between the presynaptic and postsynaptic membranes), and the postsynaptic membrane (the dendrite or cell body of the information-receiving neuron, containing specific receptors).

• Information Transmission Process: When an action potential reaches the presynaptic membrane, it triggers the release of neurotransmitters from presynaptic vesicles into the synaptic cleft. The neurotransmitters diffuse across the cleft and bind to specific receptors on the postsynaptic membrane, causing changes in the postsynaptic membrane potential and generating excitatory or inhibitory signals.

• Synaptic Plasticity: The strength and efficiency of synapses are adjusted based on experience and neural activity. Synaptic plasticity is the foundation of learning and memory, and a key capability for the brain to adapt to the environment. However, the range of synaptic plasticity is limited—structural damage (such as excessive synaptic pruning in schizophrenia) exceeds the repair capacity of plasticity.

6.3 Neurotransmitters: The Brain's Chemical Messengers

Neurotransmitters are chemical substances that transmit information between neurons, influencing mood, cognition, behavior, and physiological functions.

• Monoamine Neurotransmitters:

  • Serotonin (5-HT): Associated with mood, sleep, appetite, memory, and learning. Imbalances in the serotonin system are linked to depression and anxiety disorders.
  • Dopamine (DA): Associated with reward, motivation, motor control, and cognition. Abnormalities in the dopamine system are linked to schizophrenia (hyperactivity), Parkinson's disease (deficiency), and addictive behaviors.
  • Norepinephrine (NE): Associated with alertness, attention, and stress response. Imbalances are linked to depression, anxiety disorders, and ADHD.

• Amino Acid Neurotransmitters:

  • Glutamate: The most primary excitatory neurotransmitter in the central nervous system, involved in learning, memory, and synaptic plasticity. Hyperactivity is linked to epilepsy and neurodegenerative diseases.
  • GABA: The most primary inhibitory neurotransmitter in the central nervous system, exerting sedative and anxiolytic effects. Dysfunction is linked to anxiety disorders, epilepsy, and insomnia.

• Others: Acetylcholine (learning, memory, muscle movement), endorphins (pain regulation, mood), histamine, etc.

Neurotransmitter imbalance is the core mechanism of many mental disorders. Pharmacotherapy for mental disorders largely works by regulating the synthesis, release, reuptake, or receptor activity of neurotransmitters to restore chemical balance.

6.4 Brain Energy Metabolism: Fuel Supply for a High-Energy-Consuming Organ

The brain is one of the most energy-consuming organs in the human body—accounting for only about 2% of body weight, yet consuming approximately 20% of oxygen and 25% of glucose. This immense energy demand is used to support neuronal electrical activity, neurotransmitter synthesis and release, ion pump operation, and cellular maintenance.

• Glucose is the primary fuel for the brain, delivered through the blood circulation, and generates ATP (the cell's immediate energy currency) via glycolysis and oxidative phosphorylation.
• Oxygen is critical for the oxidative breakdown of glucose. The brain is extremely sensitive to hypoxia; even a brief interruption in oxygen supply can lead to neuronal damage.
• Ketone bodies can serve as alternative fuel during starvation or low-carbohydrate diets. Fatty acids generally cannot cross the blood-brain barrier directly.

6.5 Metabolism: The Dynamic Balance and Imbalance of the Brain

Metabolism is the general term for all chemical reactions through which living organisms maintain life activities, including anabolism and catabolism. Brain metabolism is highly active and finely regulated; an imbalance in any link can impair its function.

• Energy Metabolism and Mitochondria: Mitochondria convert glucose and oxygen into ATP through oxidative phosphorylation. Mitochondrial dysfunction is associated with the onset and progression of bipolar disorder and depression.
• Neurotransmitter Metabolism: The synthesis, release, reuptake, and degradation of neurotransmitters involve complex metabolic processes. Mental disorders are frequently linked to these metabolic abnormalities, and pharmacotherapy restores balance by regulating these metabolic pathways.
• Neuroinflammation: Pro-inflammatory cytokines (such as IL-6, TNF-α) released during systemic or cerebral inflammation affect neurotransmitter metabolism and damage neuronal function. The abnormal activation of the tryptophan metabolic pathway (kynurenine pathway) can lead to the accumulation of neurotoxic metabolites. Neuroinflammation is considered an important pathological mechanism in depression and schizophrenia.
• HPA Axis and Endocrine System: The hypothalamic-pituitary-adrenal (HPA) axis is the core of the stress response. Overactivity of the HPA axis and chronically elevated cortisol levels can affect brain structure and function, increasing the risk of mental disorders.
• Oxidative Stress: High-intensity metabolic activity in the brain generates reactive oxygen species, such as free radicals. When this exceeds antioxidant defense capabilities, it leads to oxidative stress, damaging cell structures and functions. Oxidative stress is a common pathological mechanism in neurodegenerative diseases and mental disorders.

The normal function of the brain depends on a stable energy supply and finely regulated metabolism. The metabolic layer is a direct bridge connecting developmental structures with clinical symptoms—genetic and developmental abnormalities ultimately manifest as emotional, cognitive, and behavioral disturbances through metabolic imbalance.

6.6 Disorder-Specific Mechanisms of Neurotransmitter and Metabolic Imbalance

The previous sections discussed the general principles of neurotransmitter systems and metabolic mechanisms. Now, let us examine the specific manifestations of metabolic imbalance in different mental disorders—these imbalances are the direct molecular expressions of developmental abnormalities, constituting the core content of the metabolic layer within the "four-layer interaction" framework.

6.6.1 Bipolar Disorder: A State-Dependent Chemical Seesaw

The metabolic imbalance in bipolar disorder exhibits a unique "state-dependency"—the same neurotransmitter system displays opposite abnormalities during manic and depressive phases.

• State Flipping of Monoamine Neurotransmitters: During manic phases, DA and NE activity is excessively high (flight of ideas, impulsive behavior); during depressive phases, DA and NE activity is deficient (anhedonia, lack of energy); 5-HT dysfunction persists across both poles (emotional instability).
• Glutamate/GABA Imbalance: Glutamate hyperactivity and insufficient GABA function lead to a disturbance in the excitation-inhibition balance.
• HPA Axis Dysfunction: Overactivity of the HPA axis, accompanied by abnormal cortisol levels.
• Multi-Target Mechanism of Lithium: As the "gold standard" for bipolar treatment, lithium intervenes in multiple metabolic pathways simultaneously by inhibiting GSK-3β and IMPase, regulating ionic homeostasis, and increasing BDNF expression.

6.6.2 Major Depressive Disorder (MDD): Chronic Deficiency of the Monoamine System and Inflammatory Metabolism

• Monoamine Hypothesis: Deficient activity of 5-HT, NE, and DA is the most classic metabolic explanation.
• Glutamate System Hyperactivity: The rapid antidepressant effect of ketamine (an NMDA receptor antagonist) validates this pathway.
• HPA Axis Overactivity: Chronic stress → elevated cortisol → increased pro-inflammatory cytokines → further activation of the HPA axis, forming a positive feedback loop.
• Neuroinflammation: Microglial activation and elevated levels of pro-inflammatory cytokines (IL-6, TNF-α, CRP).
• Mitochondrial Dysfunction: Reduced ATP production, which is associated with fatigue and cognitive decline.

6.6.3 Schizophrenia: The Dual Imbalance of Dopamine and Glutamate

• Dopamine Hypothesis: Increased DA activity in the mesolimbic pathway → positive symptoms (delusions, hallucinations); deficient DA activity in the mesocortical pathway → negative symptoms and cognitive deficits.
• Glutamate Hypothesis: Insufficiency of NMDA receptor function, associated with cognitive and negative symptoms.
• GABAergic Interneuron Deficits: Leading to a cortical excitation-inhibition imbalance, associated with abnormal gamma oscillations.

6.6.4 Eating Disorders (Anorexia Nervosa): Dual Abnormalities in Reward and Metabolism

• 5-HT System Abnormalities: Associated with appetite regulation, and mood and impulse control disorders.
• Alterations in the DA Reward System: Weakened reward response to food, combined with an enhanced reward response to self-restrictive behaviors.
• Metabolic-Endocrine Disturbances: Severe dysregulation of leptin, ghrelin, and insulin; the metabolic cascade of starvation: severe malnutrition → decreased basal metabolic rate → electrolyte disturbance → risk of sudden death.

6.6.5 Substance Use Disorders: The Chemical Hijacking of the Reward System

• Hijacking of the DA Reward Pathway: Repeated substance use causes excessive release of DA, altering the brain's response to natural rewards.
• Neuroadaptation and Tolerance: Long-term use leads to GABA ↓ and glutamate ↑, driving tolerance and withdrawal.
• Specific Mechanisms of Alcohol: Enhances GABA-A receptor function (sedation), inhibits NMDA receptors (cognitive impairment), and releases endogenous opioid peptides and DA (reward effect).

6.6.6 The Metabolic Logic of Pharmacological Intervention

The core logic of pharmacotherapy for mental disorders is to intervene at the metabolic layer—by regulating neurotransmitter concentrations, receptor activity, or metabolic pathways to restore the brain's chemical balance. Understanding the metabolic layer is the key to understanding "why medications work" and "why different medications have varying effects on different individuals."

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This chapter established the complete picture of the metabolic layer: from synaptic transmission to energy metabolism, every link of the metabolic layer can become a direct cause of mental disorders. However, metabolic abnormalities are not the root causes—they are downstream manifestations of upstream genetic variations and developmental deviations. The next chapter will ascend to the systemic level, exploring how brain networks and connectomics integrate metabolic abnormalities into the symptom landscape of mental disorders.

References:

• Research on Human Nervous System Development and Metabolism—Google Gemini 2.5 DeepSearch
• Stahl, S.M. (2013). Stahl's Essential Psychopharmacology. Cambridge University Press.
• Duman, R.S., & Aghajanian, G.K. (2012). Synaptic dysfunction in depression. Science, 338(6103), 68-72.
• Howes, O.D., & Kapur, S. (2009). The dopamine hypothesis of schizophrenia. Schizophrenia Bulletin, 35(3), 549-562.
• Miller, A.H., & Raison, C.L. (2016). The role of inflammation in depression. Nature Reviews Immunology, 16(1), 22-34.

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