1. Neurotransmitters
   Synthesis, storage, release, receptors, degradation, and clinical correlations of acetylcholine, catecholamines, serotonin, GABA, glutamate, glycine, histamine, and neuropeptides.
2. Cerebral energy metabolism
   Glucose dependence of the brain, blood-brain barrier transport, ketone-body use during prolonged fasting, and effects of hypoglycemia and hypoxia.
3. Myelin and lipids
   Composition and synthesis of myelin, sphingolipids, cerebrosides, gangliosides, and demyelinating or lysosomal-storage disorders.
4. Blood-brain barrier and cerebrospinal fluid
   BBB structure and transport, CSF formation and composition, and related clinical conditions.
5. Molecular basis of neurologic disease
   Protein misfolding, oxidative stress, excitotoxicity, mitochondrial dysfunction, and selected inborn errors of metabolism.
6. High-yield disease correlations
   Parkinson disease, Alzheimer disease, Huntington disease, depression, epilepsy, hepatic encephalopathy, and leukodystrophies.

CNS neurotransmitters: synthesis pathways

1. Acetylcholine (ACh)

Choline + Acetyl-CoA
        │
        └─ Choline acetyltransferase (ChAT)
                         ↓
                 Acetylcholine

• Choline enters the nerve terminal through a high-affinity Na⁺-dependent transporter.
• Acetyl-CoA is supplied by mitochondrial metabolism.
• ChAT is the synthetic enzyme.
• ACh is loaded into vesicles by the vesicular ACh transporter, VAChT.
• It is broken down in the synaptic cleft by acetylcholinesterase into choline + acetate. Choline is recycled.

• ChAT deficiency can cause congenital myasthenic syndromes.
• Loss of central cholinergic neurons is associated with Alzheimer disease.
• Organophosphates inhibit acetylcholinesterase.

2. Catecholamines: dopamine, norepinephrine, epinephrine

Phenylalanine
   │ phenylalanine hydroxylase, BH4
   ↓
Tyrosine
   │ tyrosine hydroxylase, BH4, O2
   ↓
L-DOPA
   │ aromatic L-amino acid decarboxylase, PLP (vitamin B6)
   ↓
Dopamine
   │ dopamine β-hydroxylase, ascorbate, Cu2+
   ↓
Norepinephrine
   │ phenylethanolamine N-methyltransferase, SAM
   ↓
Epinephrine

Rate-limiting step

• Requires tetrahydrobiopterin (BH4) and oxygen.
• This is the major regulatory step of catecholamine synthesis.

Cellular location

• Formation of dopamine occurs in the cytosol.
• Dopamine enters the storage vesicle via VMAT.
• Dopamine β-hydroxylase lies inside vesicles and converts dopamine to norepinephrine.
• In adrenal medulla and a few CNS neurons, norepinephrine returns to cytosol and is methylated to epinephrine by PNMT.
• PNMT uses S-adenosylmethionine (SAM); cortisol induces PNMT in the adrenal medulla.

• Parkinson disease: reduced dopamine in the nigrostriatal pathway.
• L-DOPA bypasses tyrosine hydroxylase and enters the brain.
• Carbidopa inhibits peripheral aromatic L-amino acid decarboxylase.
• Reserpine blocks VMAT and depletes vesicular monoamines.
• Monoamine oxidase inhibitors reduce catecholamine breakdown.

3. Serotonin: 5-hydroxytryptamine, 5-HT

Tryptophan
   │ tryptophan hydroxylase, BH4, O2
   ↓
5-Hydroxytryptophan (5-HTP)
   │ aromatic L-amino acid decarboxylase, PLP
   ↓
Serotonin (5-HT)

• Tryptophan hydroxylase is rate-limiting.
• Requires BH4.
• Aromatic L-amino acid decarboxylase requires pyridoxal phosphate, PLP, the active form of vitamin B6.
• Serotonin is stored by VMAT and mainly metabolized by monoamine oxidase-A to 5-hydroxyindoleacetic acid, 5-HIAA.

• SSRIs inhibit serotonin reuptake through SERT.
• Low CSF 5-HIAA may be associated with reduced serotonergic turnover.
• Carcinoid tumors can divert tryptophan toward serotonin production, contributing to niacin deficiency.

4. Histamine

Histidine
   │ histidine decarboxylase, PLP
   ↓
Histamine

• Histidine decarboxylase requires PLP/vitamin B6.
• Histamine promotes wakefulness, attention, appetite regulation, and vestibular signaling.
• First-generation H1 antihistamines can cross the BBB and cause sedation.

5. Glutamate

Glucose → pyruvate → TCA cycle → α-ketoglutarate
                                  │ transamination
                                  ↓
                              Glutamate

Astrocyte: Glutamate + NH3 + ATP
               │ glutamine synthetase
               ↓
           Glutamine
               │ transported to neuron
               ↓
Neuron: Glutamine
               │ glutaminase
               ↓
           Glutamate

• Glutamate is stored in vesicles by VGLUT.
• Major receptors:
  • Ionotropic: NMDA, AMPA, kainate
  • Metabotropic: mGlu receptors
• Excess glutamate can cause excitotoxicity, with excessive Ca²⁺ influx, neuronal injury, and cell death.

• NMDA receptor overactivation contributes to ischemic brain injury and seizures.
• Memantine is an NMDA receptor antagonist used in Alzheimer disease.
• Ketamine produces antidepressant effects partly through NMDA receptor antagonism.

6. GABA: gamma-aminobutyric acid

Glutamate
   │ glutamate decarboxylase, GAD
   │ PLP (vitamin B6)
   ↓
GABA

• Glutamate decarboxylase (GAD) requires PLP.
• GABA is packaged by the vesicular GABA transporter, VGAT.
• It is degraded by GABA transaminase:

GABA + α-ketoglutarate
   │ GABA transaminase
   ↓
Succinic semialdehyde
   │ succinic semialdehyde dehydrogenase
   ↓
Succinate → TCA cycle

• Vitamin B6 deficiency decreases GABA synthesis and can cause seizures, particularly in infants.
• Vigabatrin inhibits GABA transaminase, increasing GABA.
• Benzodiazepines and barbiturates enhance GABA-A receptor signaling.
• Baclofen is a GABA-B receptor agonist.

7. Glycine

Serine
   │ serine hydroxymethyltransferase, PLP
   ↓
Glycine

• Glycine also acts as an obligatory co-agonist at the NMDA receptor.
• Inhibitory glycine receptors are ligand-gated chloride channels.

• Strychnine blocks glycine receptors, causing severe muscle spasms and convulsions.
• Tetanus toxin prevents release of inhibitory glycine and GABA from interneurons, producing spastic paralysis.

8. Aspartate

Oxaloacetate
   │ transamination
   ↓
Aspartate

• Produced from the TCA-cycle intermediate oxaloacetate.
• Can activate NMDA-type glutamate receptors.

9. Neuropeptides

Gene transcription
   ↓
Prepropeptide synthesized in rough ER
   ↓
Propeptide processing in Golgi apparatus
   ↓
Packaging into dense-core vesicles
   ↓
Axonal transport to nerve terminal
   ↓
Proteolytic cleavage to active peptide

• Peptide precursors are cleaved by prohormone convertases.
• Neurotransmitter peptides are usually inactivated by extracellular peptidases rather than being reuptaken.
• They commonly act through G-protein-coupled receptors and have slower, longer-lasting effects.

10. Purines: ATP and adenosine

ATP → released from neuron or glia
       ↓ extracellular ectonucleotidases
ADP → AMP → Adenosine

• ATP can act as a cotransmitter.
• Adenosine generally has inhibitory, sleep-promoting effects, especially through A1 receptors.
• Caffeine antagonizes adenosine receptors.

11. Nitric oxide: NO

Arginine
   │ nitric oxide synthase, NOS
   │ NADPH, O2, BH4, Ca2+-calmodulin
   ↓
Nitric oxide + Citrulline

• NO diffuses freely across cell membranes and may act as a retrograde messenger.
• It activates soluble guanylyl cyclase in target cells, increasing cGMP.

High-yield cofactor summary

One-line revision chart

Choline + Acetyl-CoA → Acetylcholine

Tyrosine → DOPA → Dopamine → Norepinephrine → Epinephrine

Tryptophan → 5-HTP → Serotonin

Histidine → Histamine

Glutamine → Glutamate → GABA

Serine → Glycine

Arginine → Nitric oxide