Week 29 Learning Objectives
Biochemistry of Brain Function
1. Describe in overview the energetic needs of the brain, metabolic compartmentation within the
brain, and the consequences to the brain of interrupted oxygen and glucose supplies.
The human brain has very high metabolic demands which must be met in order to maintain proper
function. It comprises only 2% of the total bodyweight of an individual yet it accounts for 20% of all
bodily oxygen consumption and 25-50% of total body utilization of glucose which it uses as its primary
source of energy. This glucose is almost entirely oxidized into CO2 and H2O during the process of
metabolism. There are three primary ways that the brain uses glucose for energy:
Glycolysis
The Trycarboxylic Acid Cycle
Oxidative Phosphorylation
All of these processes involved the processing of glucose in various ways to form units of ATP and
NADPH which serves as the primary energy source for the brain. All of this energy is required because
the brain depends a lot on ATP-reliant pumps (90%) to maintain effective concentration gradients and
also on ATP-dependant enzymes (10%) for metabolism. To provide all of these requirements, the brain
receives 15% of all blood flow in the body.
Metabolic compartmentation is a term used for the isolation of a metabolic process. In essence, if all of
the body’s enzymes were simply put together in a “soup” there would be biochemical chaos.
Compartmentation is the segregation of these enzymes into particular areas to ensure that chemicals do
not mix unintentionally. This is done to make sure that all normal biological reactions can happen
normally. In addition, this compartmentation allows the body to control segmented compartments
easily as it permits control over smaller groups of chemical reactions as opposed to a huge “soup” of
biochemicals. Compartments are often determined by physical barriers such as selectively permeable
membranes which dictate what biochemicals have access to which compartment.
In the brain metabolic compartmentation is of particular concern to glutamate and gamma-
aminobutyric acid (GABA). Glutamate is an important molecule for cellular metabolism while GABA is an
essential neurotransmitter, both of which are required for proper function. Creation of these two
products comes from the processing of glucose. However, this processing can happen through two
distinct pathways; one through neurons and one through astrocytes. These two pathways are
compartmentalized as they occur in two different cell types. Glutamate and GABA are produced by
neurons and excreted. Astrocytes take up glutamate and GABA in order to re-convert them back to
glutamine. The astrocytes will then return this glutamine to the neurons where they can be converted
back into glutamate and GABA. In this system; glutamate, glutamine and GABA are regulated – an
overproduction of any of these products would be harmful to the body.
Because the brain has a critical dependence on aerobic glucose metabolism and an interruption to the
supply of either oxygen or glucose (or both) will cause adverse effects resulting in an encephalopathy. In
other words, the brain is highly susceptible to hypoglycemia, hypoxia or any enzymatic disorders relating
to glucose.
If the supply of glucose for the brain is halted, all three of the primary energy producing systems
(Glycolysis, TCA Cycle and Oxydative Phosphorylation) would fail as they all depend on glucose as their
starting point. The clinical manifestations of this hypoglycemia would be sweating, palpitations,
dizziness, anxiety and hunger. Since the brain itself has an almost non-existent capacity to store
glycogen, the body will want to take in food in order to increase the blood glucose level. Should the
blood glucose level drop below 2.5mM, confusion and delirium may set in. If that level drops below
1.0mM then the production of ATP will be adversely affected. Additionally, once below the 2.5mM
point, the body will begin to use keytone bodies as an alternative fuel.
Side note: The neuro-glia lactate shuttle prevents damage to neurological function in this situation since
blood borne lactate cannot cross the BBB. Also, insulin shock can take place where the body will
increase peripheral glucose uptake. This will starve the brain of more glucose and can result in a coma.
Severe hypoglycemia will result in cessation of action potentials in the brain, irreversible brain damage
and even death. The hippocampal and cortical structures are most susceptible to hypoglycemia. In terms
of backups, the brain can result to intermediates of the TCA cycle such as citrate and succinate. Amino
acids such as glutamate and glutamine can also be used but can only meet energy demands for about 15
minutes.
As mentioned before the brain takes up 20% of total oxygen usage in the body. A normal brain will
consume 3.3ml of oxygen per 100g of brain tissue every minute. Should this rate fall the brain will
experience hypoxia. There are a number of different types of hypoxia:
Cerebral hypoxia is typically grouped into four categories depending on the severity and location of the
brain’s oxygen deprivation:
Diffuse cerebral hypoxia. A mild to moderate impairment of brain function due to low oxygen
levels in the blood.
Focal cerebral ischemia. A small localized reduction in the flow of oxygen from the blood to the
brain. Damage to neurons is usually irreversible. Mild strokes.
Cerebral infarction. A complete stoppage of the flow of oxygen from the blood to a region of the
brain. Significant irreversible brain damage occurs in the region around the blockage. Major
strokes are an example of cerebral infarction.
Global cerebral ischemia. A complete stoppage of blood flow to the brain.
Cerebral hypoxia can also be classified by the cause of the reduced brain oxygen:
Hypoxic hypoxia. Limited oxygen in the environment causes reduced brain function. Divers,
aviators, mountain climbers and fire fighters are all at risk for this kind of cerebral hypoxia. The
term also includes oxygen deprivation due to obstructions in the lungs. Choking, strangulation,
the crushing of the windpipe all cause this sort of hypoxia. Severe asthmatics may also
experience symptoms of hypoxic hypoxia.
Hypemic hypoxia. Reduced brain function is caused by inadequate oxygen in the blood despite
adequate environmental oxygen. Anemia and carbon monoxide poisoning are common causes
of hypemic hypoxia.
Ischemic hypoxia (a.k.a. stagnant hypoxia). Reduced brain oxygen is caused by inadequate blood
flow to the brain. Stroke, shock, and heart attacks are common causes of stagnant hypoxia.
Ischemic hypoxia can also be created by pressure on the brain. Cerebral edema, brain
hemorrhages and hydrocephalus exert pressure on brain tissue and impede their absorption of
oxygen.
Histotoxic hypoxia. Oxygen is present in brain tissue but cannot be metabolized. Cyanide
poisoning is a well known example.
Any time there is hypoxia to any degree, the brain’s ability to process glucose through 2 of its
mechanisms (the TCA Cycle and Oxydative Phosphorilation) will be hindered based on the degree of
oxygen starvation. In order to counter this, the body will either bring more blood to the brain or
increase glycolysis which is an anerobic function. Neither of these mechanisms can completely sustain
the brain for extended periods of time alone however.
Like many systems in the body, the brain has ways of adapting in order to sustain itself and it does this
by activating other pathways to generate energy. These alternate pathways however are not very
efficient and cannot be sustained for extended periods of time. Eventually, these alternative systems
will break down leaving no backup system – this can result in death.
2. Describe the principles of chemical synaptic transmission and the role of receptors and ion channels
in neuronal signal transduction.
Chemical synaptic transmission is the primary means of communication in the human nervous system.
There are 3 distinct elements of this system; a pre-synaptic element, a synapse and a post-synaptic
element. A membrane separates the pre and post synaptic elements from the synapse or synaptic cleft.
The pre-synaptic element consists of the messenger cell and this cell has the inbound signal. Once the
signal comes through the cell, it will release neurotransmitters into the synaptic cleft with its secretory
vessels. The synaptic cleft is essentially a small medium for which these neurotransmitters can travel.
Once a neurotransmitter crosses the synaptic cleft, it will bind with a neurotransmitter-receptor on the
post-synaptic membrane.
Neurotransmitter receptors are embedded on the surface membrane of the post-synaptic cell. A
neurotransmitter binding to these receptors will alter the structure of the receptor thus leading to an
alteration of its function. This alteration will include either a direct opening of ion channels (known as
ionotropic receptors) or the initiation of secondary messenger pathways.
Ion channels are small pores also on the surface membrane of the post-synaptic cell. A binding of a
neurotransmitter to a receptor will cause a conformational change in the pores which will permit ions to
pass through them. Sodium channels will lead to depolarization (Exitatory Post Synaptic Potential) and
chloride channels will lead to hyperpolarization (Inhibitory Post Synaptic Potential).