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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. 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 (like glutamate, GABA (gamma-aminobutyric acid) and glycine), biogenic amines (small signalling molecules like noradrenaline, dopamine, serotonin and acetylcholine) and peptides (short chains of amino acids, like substance P, somatostatin and cholecystokinin). Amino acids carry most fast excitatory and inhibitory signals, whereas amines and peptides often act more slowly, to modulate groups of neurones.
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. They are the CNS equivalent of Schwann cells, which are responsible for myelination in the peripheral nervous system.
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.
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, because the CNS also has a meningeal lymphatic system (lymphatic vessels in the membranes around the brain) and resident T cells (a type of immune cell).
The blood brain barrier (BBB) is a highly selective barrier formed by endothelial cells (the cells that line the blood vessels) joined by tight junctions (seals that stop substances slipping between neighbouring cells), and 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. 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. This means that they either form ion channels, which let ions (like Na+, K+, or Ca2+) pass through, or they 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), but 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, so this can lead to long-term potentiation (a lasting strengthening of the synapse) or long-term depression (a lasting weakening of the synapse, which is unrelated to the mood disorder).
This ability of synapses to change in strength is called synaptic plasticity.
GABA is the main inhibitory neurotransmitter in the brain, and glycine is the main inhibitory neurotransmitter in the brainstem and spinal cord.
GABA-A and glycine receptors are ionotropic anion channels (channels that let negatively charged ions through). Their activation increases the flow of these ions and commonly inhibits firing, either by hyperpolarisation (the inside of the cell becomes more negative) or by shunting (ion flow that holds the membrane near its resting level, so other inputs have less effect). Whether the cell hyperpolarises depends on the ion gradient and the membrane potential, so the effect is sometimes not hyperpolarising. 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 make use of the GABA receptors in the brain as both of these classes of medication increase the effects of GABA receptors in the brain. This gives them an anti-anxiety and sedative effect and they carry a risk of tolerance, dependence and misuse.
Examples: noradrenaline, dopamine, serotonin, histamine and acetylcholine. Acetylcholine is a choline ester rather than a true amine, and some texts treat it as a class of its own, but it is grouped with the amines here.
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 mainly as an excitatory neurotransmitter at both nicotinic and muscarinic receptors. 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.
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 (the preganglionic and postganglionic neurones), and it is 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 prolactin levels down (blocking it raises prolactin). The dysfunction of these pathways causes different pathologies.
Dysfunction of the motor control pathway results in Parkinson’s disease, a condition caused by the loss of dopaminergic neurones in certain pathways in the brain. 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), whereas too little 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 conditions such as narcolepsy and refractory ADHD (attention deficit hyperactivity disorder), and 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 (involved in sensation, including pain), somatostatin, cholecystokinin.
There is a third class of neurotransmitters in the CNS and in the wider body. Their CNS functions are beyond the scope of this article, but their other relevant functions (such as the effects of somatostatin and cholecystokinin in the gastrointestinal tract) should be learnt.
Edited by: Dr. Marcus Judge
Reviewed by: Adrian Judge
Quiz
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