Hello YNCA readers, and welcome to our third Basics of Neuroscience lesson. Today, we will explain how neurons communicate with each other. Last month, we explained how each neuron acts as an independent relay stations. In this issue, we hope to discuss the molecular events underlying communication between neurons. These first three lessons will set the foundation for future lessons as we delve deeper into the fascinating world of neuroscience. Understanding how neurons are structured and how they communicate is, we believe, essential to a thorough understanding of the workings of the brain.
You may already know that a dendrite from one cell and an axon from the other cell are joined in special areas called synapses. But what exactly goes on at the synapse? To communicate with a nearby dendrite at a synapse, axons release neurotransmitters, specialized signaling molecules used in the nervous system.
Neurotransmitters are stored in special axonal structures known as synaptic vesicles. When an action potential (see previous issue) reaches the edge of the axon (axon terminal), a series of molecular events cause the synaptic vesicles to release neurotransmitter into the gap between the axon and dendrite, known as the synaptic cleft.
The neurotransmitter then binds to specialized proteins on the receiving dendrite known as receptors. One broad class of receptor is the ionotropic receptor. When a neurotransmitter binds to an ionotropic receptor, the receptor acts as an ion channel. There are two main types of ion channels; one excitatory, the other inhibitory. The Na+, or sodium ion channel, when opened, causes sodium ions to flow into the receiving neuron, increasing the membrane voltage, exciting the neuron. Th K+, or Potassium ion channel allows potassium ions to leave the neuron, lowering the membrane voltage. The reaction of the neurotransmitter with the ionotropic neuroreceptor causes gates in the ion channels to open, thus allowing movement of ions along their concentration gradient. Depending on the neuroreceptor, this can create an EPSP or IPSP. The second broad class of neuroreceptor is the metabotropic receptor. This class of receptors acts indirectly; as opposed to acting as an ion channel, they activate a signaling cascade that can result in protein modification or altered transcription, among other things. Found in all types of cells, G-Protein Coupled Receptors are a major type of metabotropic receptor-- Upon contact with a neurotransmitter molecule, their alpha subunit dissociates from the protein, moving away from the receptor. This subunit then activates a signaling cascade of chemical reactions, which lead to the release of intracellular molecules known as second messengers. It is these second messengers that perform a function in the cell. This function can range from cellular contraction to protein synthesis to a mitotic split. This second messenger system allows cells to perform complicated functions by working together. In this manner, the nervous system performs a similar function to the intracellular genome; allowing the organization of responses to a stimulus.
Neurotransmitters and Neuroreceptors: An Overview
Probably at the very core of interneuronal communication are the chemicals most involved in the communication process: neurotransmitters. Neurotransmitters occur in two basic types: small-molecule neurotransmitters and neuropeptides. Small-molecule neurotransmitters are synthesized inside of the axon terminal, while neuropeptides are synthesized out of amino acids outside of the axon terminal, and then transported there. Both types are then held in synaptic vesicles until needed. When an action potential occurs, voltage-dependant Ca2+ ion channels on the presynaptic axon terminal membrane open. This allows Ca2+ ions to flood into the cell. These calcium ions then react with the proteins linked to the synaptic vesicles, causing the synaptic vesicle to release its contents into the synaptic cleft and react with the postsynaptic neuron.
As stated above, neurotransmitters can be either ionotropic or metabotropic. Ionotropic neurotransmitters are involved with passing on an electric signal while metabotropic neurotransmitters trigger a change in the receiving neuron. Here at the YNCA, we’ve compiled a list of many of the most common neurotransmitters and their functions.
One of the most prevalent amino acid neurotransmitters is glutamate. Glutamate is an excitatory neurotransmitter, and it acts on several different receptors. Perhaps the two most important of these are the AMPA and NMDA receptors, named for other molecules that activate them. These two neurotransmitters are involved with the process of Long-Term Potentiation, the cellular mechanism by which memories are formed.
Two important inhibitory neurotransmitters in the Central Nervous System are GABA (Gamma-Aminobutyric Acid) and Glycine. GABA acts primarily within the brain, and is linked to various fear, anxiety, and anguish conditions. Some anti-anxiety drugs act as GABA agonists, helping to increase inhibitory signals in the brain. Much like anti-anxiety drugs, alcohol acts on GABA at first, which can explain how it reduces people’s inhibition. At higher concentrations, though, alcohol interferes with NMDA receptor functioning, harming the formation of short term memories. Furthermore, abnormalities in GABA and Glycine signaling contribute to seizures. Glycine acts in the spinal cord, so it lacks the importance to consciousness that GABA has. Nonetheless, Glycine also works as a very important inhibitory neurotransmitter alongside GABA.
Much more complex are the neurotransmitters that react with metabotropic receptors. These neurotransmitters can serve various functions, and, in some cases (like acetylcholine), act as ionotropic receptors as well. The first neurotransmitter to be discovered, and perhaps one of the most famous, is acetylcholine, abbreviated as ACh. This neurotransmitter acts on two receptor subtypes: nicotinic (ionotropic) and muscarinic (metabotropic). Outside of the CNS, ACh acts on nicotinic cholinergic receptors at the neuromuscular junction to trigger movement. Within the central nervous system, it is responsible for many higher processes, and has been implicated in many neurological disorders including Alzheimer’s disease (see our previous issue for more information on this).
Serotonin, another neurotransmitter, is highly implicated in mood. So much, in fact, that many commercial antidepressants target serotonin to have their effects. Fluoxetine, more commonly known by its trade name Prozac, acts as an SSRI (Selective Serotonin Reuptake Inhibitor). All SSRIs block reuptake channels in the synapse, allowing Serotonin to remain in the synapse longer than is biologically necessary and hence allowing it to create a stronger signal in the post-synaptic neuron. This helps to improve mood significantly.
Another neurotransmitter highly implicated in controlling mood is dopamine. Dopamine abnormalities have been implicated in many psychiatric disorders, including Schizophrenia, illustrating its significant effects on higher functions. Furthermore, dopamine is also linked to drug addiction, and through a pathway involving the ventral tegmental area, nucleus accumbens, and prefrontal cortex. In another pathway, dopamine is also involved in motor control. The substantia nigra is one of the most important regions producing dopamine in the brain, so it is no coincidence that Parkinson’s disease is caused by the loss of dopaminergic neurons in this region (more specifically the substantia nigra pars compacta).
Endorphins, the abbreviated name for endogeneous opioids, are responsible for the so-called “runner’s high” some people feel when exercising. They are powerful painkillers, which explains why drugs having the ability to mimic their action (i.e. morphine) have such a powerful analgesic effect. Interestingly enough, endorphins were discovered by researchers who hoped to discover how opiate drugs alter brain activity.
As some of you may have guessed by now, neurotransmitters are involved in many processes. Stress is one of these processes. The two main stress neurotransmitters, epinephrine (adrenaline), and norepinephrine (noradrenaline) are monoamine catecholamines. Both are synthesized in the adrenal glands, located on top of the kidneys. Epinephrine is released under conditions of stress, and works to energize the body by increasing blood flow to muscles, quickly using blood sugar, dilating the pupils. Epinephrine does have some involvement in the brain, but no clear role has been identified. Norepinephrine, on the other hand, functions primarily as a neurotransmitter and secondarily as a hormone. Norepinephrine is released in the brain and in the sympathetic nervous system of the peripheral nervous system. In the sympathetic nervous system, norepinephrine functions alongside epinephrine to help respond to stress. In the Central Nervous System, however, norepinephrine has wider implications involving arousal, mood, alertness, and memory.
Perhaps the most relevant neurotransmitter to this month’s theme is orexin. Also known as hypocretin, orexin is an excitatory neurotransmitter, necessary for wakefulness. A neuropeptide, orexin regulates functions such as appetite and arousal. Low levels in orexin are linked to narcolepsy (as discussed in significant detail in the disease section). Also linked to sleep is the neurotransmitter adenosine (ATP without phosphate groups). Adenosine signaling indicates that the brain is using up its energy supply; thus, adenosine acts to induce sleep so the brain’s supply of ATP is restored.
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Jacob Umans is an aspiring physician-scientist in the Stanford University Class of 2020. As a cofounder of the IYNA, he is passionate about science education and hopes to share his excitement about all subfields of neuroscience -- especially glial biology and neuroimmunity -- with students around the world. He hopes to go on to earn an MD/Ph.D. after graduating from Stanford and to use his clinical experience develop a research focused on developing a better understanding of and improved therapies for neurodegenerative diseases. Outside of neuroscience, Jacob is an avid fan of puns, table tennis, and reading.