Brain metabolism & Neurotransmitters Reference: Devlin Ch 23 Selective reading! MOHAMAD NUSIER, M.D., Ph.D.

Discuss the biochemical and molecular aspects of: Brain metabolism Neurotransmitters Related disorders

Objectives Know the major source for brain energy and what limits its supply Know the main aspects of metabolic pathways for neurotransmitters: acetylcholine, dopamine, norepinephrine, epinephrine, serotonin, glutamate, and GABA. Know how neurotransmitters are degraded and inactivated Know major neuropeptides and how they act

Aspects of Brain Metabolism Carbohydrate Metabolism Amino Acids Metabolism Lipid Metabolism

Key points Brain is command center: always functioning and requires a large amount of energy to keep it operational Glucose is the main source for energy (80 g/day). 25% of total body glucose consumption TCA cycle functions at near maximum capacity Glycolysis functions at 20% capacity Ketone bodies in starvation but CAN NOT REPLACE GLUCOSE

Key points Why brain needs energy? Maintain ionic gradients across the plasma membranes Various storage and transport processes Synthesis of neurotransmitters Synthesis of other cellular components

Key points Lipids are used in brain to maintain membrane integrity rather than in metabolic roles

Key points Brain proteins are rapidly turned over (degraded) than other body proteins (Why…….?)

Carbohydrate Metabolism Normally, the brain energy source is aerobic oxidation of glucose Brain glycogen stores are small (about 1/10th of muscle)

Carbohydrate Metabolism Glucose crosses Blood Brain Barrier (BBB) by facilitated diffusion (insulin-independent) Therefore, brain is very susceptible to hypoglycemia

Carbohydrate Metabolism During prolonged starvation (> 48 h) and in neonate, ketone bodies can be used as brain energy source When ketone bodies levels in blood are high, specific transporters are upregulated

Under ordinary conditions The basic substrate for brain energy metabolism is glucose Brain glucose levels depend on: Blood glucose levels Uptake across BBB

Glycogen levels vary and depends on plasma glucose levels; thus, Brain is very susceptible to hypoglycemia Glucose crosses BBB and taken up by brain cells by a specific transporters (Glut 1 & Glut 3) Glut 1: expressed by glial cells Transport glucose into the endothelial cells of the barrier Glut 3: located on neurons facilitate glucose transport from ECF into neurons

Amino Acid Metabolism LNAA: Large Neutral Amino Acids (phenylalanine, leucine, tyrosine (catecholamine precursor!), isoleucine, valine, tryptophan (serotonin precursor!), methionine, histidine, L-DOPA) are transported across BBB Via a single AA-transporter L-system transporter L stands for (leucine preferring)

Amino Acid Metabolism They compete for entry with one another Thus, elevated levels of, say, phenylalanine as in phenylketonuria (PKU) affect brain supplies of other essential amino acids

Amino Acid Metabolism Small neutral AAs (GABA, glycine, alanine, proline): Have restricted entry: otherwise they change neurotransmitters content Synthesized in brain Some are transported out via A-system carrier A stands for (Alanine preferring)

Vitamins have specific transporters through the BBB as in most tissues

Amino Acid Metabolism Basic and acidic AAs Glutamate & aspartate are both transmitters & metabolic intermediates They are synthesized in the brain, but are also transported across BBB (slow)

In the brain, there is a relatively high content of glutamate, aspartate, glutamine, and GABA In addition, tyrosine and tryptophan are precursors for several neurotransmitters and thus are of extreme importance

Dietary sources of brain amino acids are very important and may regulate the levels of neurotransmitters in the brain

Since tyrosine and tryptophan are each precursors for neurotransmitters (catecholamines and serotonin, respectively), their uptake into the brain is important

Both amino acids (tyrosine and tryptophan) share the same brain uptake system which is for large neutral amino acids (LNAA) such as tryptophan, tyrosine, phenylalanine, isoleucine, and valine

Diets which contain proteins result in lower brain levels of tryptophan because most dietary proteins contain less tryptophan than other LNAA which can then compete for the uptake carrier

Carbohydrate diets stimulate insulin secretion which lowers the plasma level of all the LNAA except for tryptophan Thus, tryptophan uptake is facilitated resulting in higher brain levels and increased synthesis of serotonin Sweets (chocolate …….good mood?)

Lipid Metabolism Lipids store energy as triglycerides, but NOT in the BRAIN (almost no triglycerides there) Lipids function as messengers (steroid hormones, eicosanoids)

Lipids are structural membrane components, especially important in myelin Major ones include cerebroside (a sphingolipid) and cholesterol A number of diseases result from genetic defects in sphingolipid degradation. Many have neurologic consequences, including Niemann-Pick, Gaucher's, Tay-Sachs.

The brain is one of the richest portions of the body in total lipid content; approximately half the dry weight of white matter and 1/3 of the gray matter of the human brain is lipid The brain lipids are comprised of three major categories: Cholesterol Sphingolipids Glycerophospholipids

Triglycerides and free fatty acids constitute only a very small percent The lipids are incorporated into membrane structures and are especially rich in myelin Cholesterol is the only sterol in the brain in significant amounts

Lipid synthesis Most lipids are synthesized in the brain Exceptions: essential ones (linoleic & linolenic acid) are taken up by specific transporters Very long-chain fatty acids are synthesized in brain important for myelin formation