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Next Lesson - Arterial Supply to the Brain
Contents
Abstract
- The CNS is made up of neurones and their supporting cells, called glia. Astrocytes are one of the most numerous types of glial cell, provide support and nutrition for neurones, and help to maintain the blood brain barrier (the tightly controlled border between the blood and the brain). Oligodendrocytes create the myelin sheath of neurones in the CNS. Microglia are the immune cells of the CNS.
- There are three main categories of neurotransmitter in the brain: amino acids, biogenic amines and peptides. Amino acids (like glutamate, glycine and GABA, short for gamma-aminobutyric acid) carry most fast signals. These signals are either excitatory (they make the next neurone more likely to fire) or inhibitory (they make it less likely to fire). Biogenic amines (small signalling molecules like noradrenaline, dopamine, serotonin and histamine) often act more slowly, to modulate groups of neurones. Acetylcholine is not one of them: it forms a transmitter system of its own, the cholinergic system. Peptides (short chains of amino acids, like substance P, somatostatin and cholecystokinin, a gut hormone that helps digestion) often act in the same way.
Core
The central nervous system is made up of neurones and their supporting cells, called glia.
Neurones receive information and transmit this to other neurones. Glial cells support, nourish and insulate neurones, and remove ‘waste’ from the neurones.
Astrocytes are one of the most numerous types of glial cell. They have a number of functions:
- Structural support of neurones
- Help support neuronal energy metabolism. Brain glycogen is stored predominantly in astrocytes, but neurones also have active glycogen metabolism.
- Control concentrations of neurotransmitters such as glutamate by taking them back up from the synapse (reuptake), which prevents toxicity.
- Maintain the ionic environment by taking up potassium and buffering it (soaking up the excess so that its level stays steady).
- Help to maintain the blood brain barrier by supporting the cells that line the brain’s blood vessels.
Oligodendrocytes are responsible for myelination of axons in the central nervous system. As a general rule, one oligodendrocyte myelinates several neighbouring axons. They are the CNS equivalent of Schwann cells, which are responsible for myelination in the peripheral nervous system, but a Schwann cell myelinates only one axon.
Microglia are the immune cells of the central nervous system and are the brain’s main defence system. They are activated by foreign material in the brain and undergo phagocytosis to remove this. They also act as antigen presenting cells (cells that display fragments of foreign material to T cells, white blood cells that help to start an immune response).
The brain is described as relatively immune privileged: the entry of immune cells from the blood is tightly regulated, which reduces the risk of harmful inflammation. This privilege is not absolute. The CNS also has a meningeal lymphatic system (lymphatic vessels in the membranes around the brain) and resident T cells.
The blood brain barrier (BBB) is a highly selective barrier. It is formed by endothelial cells (the cells that line the blood vessels) joined by tight junctions (seals that stop substances slipping between neighbouring cells). The barrier is also supported by astrocyte end-feet (the flattened tips of astrocyte processes that touch the vessel wall) and pericytes (cells wrapped around the small blood vessels). It controls the environment of neurones by selectively regulating solute transport into the CNS. Small lipid-soluble (fat-soluble) molecules can cross the BBB by diffusing through the cell membranes, whereas the tight junctions restrict water-soluble substances from passing between the cells. Other substances, such as glucose, amino acids and potassium, are transported across the BBB so their concentrations can be tightly controlled.
There are many neurotransmitters in the CNS, and the exact number depends on how they are defined and counted. They can be split broadly into three chemical classes:
Examples: glutamate, GABA, glycine.
There are two main types of amino acid neurotransmitters: excitatory (they make the next neurone more likely to fire) and inhibitory (they make it less likely to fire).
The main excitatory amino acid is glutamate, which is responsible for the majority of excitatory synapses in the CNS.
The inhibitory amino acids are GABA and glycine.
Glutamate receptors can be classified into ionotropic or metabotropic receptors. Ionotropic receptors form ion channels, which let ions (like Na+, K+, or Ca2+) pass through. Metabotropic receptors work through chemical messengers inside the cell (such as cyclic AMP, a small messenger molecule).
AMPA and NMDA receptors are ionotropic glutamate receptors (named after the molecules that selectively activate them: alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and N-methyl-D-aspartate) and both contribute to excitatory synaptic responses. AMPA receptors mediate the initial fast depolarisation (the inside of the cell becomes less negative). One excitatory response may not be enough to reach the threshold for an action potential.
NMDA receptors need two things before they open. First, glutamate must bind, together with a co-agonist (a second molecule, such as glycine, that must also bind). Second, the cell must be depolarised enough to push out the magnesium ion that plugs the channel at rest (the magnesium block). Calcium can then enter the cell and start signalling that changes the strength of the synapse. Whether the synapse strengthens or weakens depends on the pattern of activity. The calcium signal can therefore lead to long-term potentiation (a lasting strengthening of the synapse) or long-term depression (a lasting weakening of the synapse). This is unrelated to the mood disorder called depression.
This ability of synapses to change in strength is called synaptic plasticity.
GABA is the main inhibitory neurotransmitter in the brain, and glycine is a major inhibitory neurotransmitter in the brainstem and spinal cord, where GABA also has an important inhibitory role.
GABA-A and glycine receptors are ionotropic anion channels (channels that let negatively charged ions through, mainly chloride). Their activation increases the flow of these ions. This commonly inhibits firing in one of two ways. One is hyperpolarisation (the inside of the cell becomes more negative). The other is shunting (ion flow that holds the membrane near its resting level, so other inputs have less effect). Whether the cell hyperpolarises depends on the chloride gradient and the membrane potential. In some cells, for example during early development, GABA depolarises the cell instead, but it can still be inhibitory because of shunting. GABA-B receptors are metabotropic G-protein-coupled receptors (receptors that work through messenger proteins inside the cell) and mediate slower inhibition.
Medications such as barbiturates and benzodiazepines (two classes of sedative medicine, for example phenobarbital and diazepam) act on the GABA receptors in the brain. Both classes increase the effects of GABA receptors. This gives them an anti-anxiety and sedative effect and they carry a risk of tolerance, dependence and misuse.
Examples: noradrenaline, dopamine, serotonin and histamine. Histamine is made by neurones in the tuberomammillary nucleus (a group of neurones in the posterior hypothalamus). These neurones are active during waking and help to maintain wakefulness and attention. Acetylcholine is not a biogenic amine. It is a choline ester (choline joined to acetic acid) and forms a transmitter system of its own, the cholinergic system, which has its own section below.
Biogenic amines often act as neuromodulators in the CNS. Rather than giving a fast, point-to-point signal, a neuromodulator is released more diffusely and adjusts how strongly groups of neurones respond.
Acetylcholine (ACh) has two main roles: one within the CNS and one in the peripheral nervous system (the nerves outside the brain and spinal cord).
The first is widespread within the brain itself, where it acts as a neuromodulator at both nicotinic and muscarinic receptors, and its effects can be excitatory or inhibitory. Nicotinic receptors are ion channels that open when acetylcholine binds. Muscarinic receptors are G-protein-coupled receptors, which work through messenger molecules inside the cell rather than by opening a channel directly. There are five muscarinic subtypes, which couple to different types of G protein (named Gq and Gi/o), so the effect on a cell depends on the subtype.
The second is in the peripheral nervous system. At the neuromuscular junction (the synapse between a motor neurone and a muscle fibre), acetylcholine is the neurotransmitter of the somatic motor system. It is also used between the two neurones of each autonomic pathway. These are the preganglionic neurone and the postganglionic neurone, which lie before and after a ganglion (a cluster of nerve cell bodies outside the CNS). Acetylcholine is also the transmitter released by parasympathetic postganglionic neurones onto their target organs.
Acetylcholine is therefore involved in many functions: arousal, motor control, learning and memory, as well as the functions of the parasympathetic nervous system. One example of its role in memory is the use of cholinesterase inhibitors in Alzheimer’s disease. These drugs block the breakdown of acetylcholine, which raises its concentration in the synapses. In the UK, donepezil, galantamine and rivastigmine are recommended by NICE as options for mild to moderate Alzheimer’s disease.
Dopaminergic pathways (pathways of neurones that release dopamine) in the brain are involved in several ways. The nigrostriatal pathway contributes to motor control, and the mesolimbic and mesocortical pathways contribute to mood, arousal and reward. A fourth, the tuberoinfundibular pathway, helps to keep levels of prolactin (a hormone that stimulates milk production) down, so blocking dopamine in this pathway raises prolactin. Dysfunction of these pathways causes different conditions, and two of them are described below.
Dysfunction of the motor control pathway results in Parkinson’s disease. This condition is caused by the loss of dopaminergic neurones in the substantia nigra (part of the midbrain), where the nigrostriatal pathway begins. Its motor symptoms can be treated by giving levodopa (L-DOPA), a dopamine precursor that crosses the blood brain barrier and is converted to dopamine within the brain. Levodopa is given with a dopa-decarboxylase inhibitor (carbidopa or benserazide) that stops it being converted to dopamine outside the brain, which reduces side-effects. NICE recommends levodopa first for people in the early stages of Parkinson’s disease whose motor symptoms affect their quality of life. It eases symptoms, but no treatment has yet been proven to slow the disease.
Dysfunction of the pathways involved in mood, arousal and reward (the mesolimbic and mesocortical pathways) has been implicated in the condition schizophrenia. It is thought that too much dopamine activity in the mesolimbic pathway contributes to the positive symptoms (such as hallucinations and delusions). Too little dopamine activity in the mesocortical pathway is linked to the negative symptoms (such as reduced motivation) and to cognitive impairment. The dopamine hypothesis has been revised as evidence has grown, and dopamine is not thought to explain everything. Antipsychotic medicines act on dopamine receptors. Most are dopamine receptor antagonists, which reduce the effects of excess dopamine, but some, such as aripiprazole, are partial agonists (they only partly activate the receptor).
Noradrenaline acts as a neurotransmitter within the central nervous system and the autonomic nervous system. Most noradrenaline in the brain is produced in a group of neurones called the locus coeruleus.
Noradrenaline has a role in wakefulness and mood. This is shown through the actions of some medicines. Amphetamines increase the levels of noradrenaline and dopamine, which increases alertness and can raise mood. In the UK, dexamfetamine is used for narcolepsy (a rare condition that causes sleepiness that a person cannot control, and in some people sudden muscle weakness called cataplexy). It is also licensed for ADHD (attention deficit hyperactivity disorder) in children and young people aged 6 to 17 years when the usual first-choice medicine, methylphenidate, has not worked well enough (refractory ADHD). Treatment is started under specialist supervision. In adults, NICE advises considering dexamfetamine for people whose ADHD symptoms respond to lisdexamfetamine (a longer-acting stimulant medicine for ADHD) but who cannot tolerate that longer-lasting effect. This is an off-label use (the medicine is not licensed for it). Amphetamines are controlled drugs with a risk of misuse. Some antidepressants, such as the serotonin and noradrenaline reuptake inhibitors venlafaxine and duloxetine, raise noradrenaline as well as serotonin.
Serotonin has similar functions to noradrenaline in the brain in that it contributes to sleep/wakefulness and mood. Medications such as SSRIs (selective serotonin reuptake inhibitors) act to increase the amount of serotonin in the synapses by blocking its reuptake (its return into the neurone that released it). They are used to treat depression and some anxiety disorders. The benefit is not immediate: antidepressants usually take 1 to 2 weeks to start having an effect and can take up to 8 weeks to work fully.
Peptides are short chains of amino acids. Examples: enkephalins (the body’s own opioid painkillers), substance P (carries pain signals from sensory neurones to the next neurones in the spinal cord and brainstem), somatostatin, cholecystokinin.
Peptides are the third class of neurotransmitter, found in the CNS and in the wider body. Their CNS functions are beyond the scope of this article, but the effects of two of them in the gastrointestinal tract should be learnt. Cholecystokinin increases the output of pancreatic enzymes and causes the gallbladder to contract. Somatostatin has mainly inhibitory effects: it reduces gastrointestinal, endocrine, exocrine pancreatic and pituitary secretions.
Edited by: Dr. Marcus Judge
Reviewed by: Adrian Judge
Quiz
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