Neurotransmitters

Glutamate is the major excitatory neurotransmitter in the brain.

GABA and glycine are the major inhibitory transmitters in the brain.

For the moment, just consider the amino acids in the image below. Glutamate and aspartate are very similar, glycine too. If aspartate or glutamate levels are too high, then some neurons will be excited to death in a process known as "excitotoxicity".

Glutamate is an agonist for NMDA receptors.

Health note: aspartame is the chemical name for the brand names of artificial sweetners such as NutraSweet, Equal, Spoonful, and Equal-Measure. Aspartame is 40% aspartic acid and 50% phenylalanine. It accounts for over 75 percent of the adverse reactions to food additives reported to the FDA in the US. Are you excited?

Image: Purves et al, 2001.

Ionotropic versus Metabotropic Receptors

Main points: in general, ionotropic receptors allow ions to flow across the cell's outer membrane (plasma membrane) into the cell's cytoplasm; metabotropic receptors trigger a cascade of metabolic events that lead to Ca2+ release from internal stores such as the endoplasmic reticulum (ER).

The two basic types of neurotransmitter receptors are ionotropic and metabotropic; they use different mechanisms to transduce extracellular signals (the binding of neurotransmitters to receptors) to intracellular responses.

A brain builder would use ionotropic receptors for rapid information transfer. For slower and longer lasting functions, the builder would use metabotropic receptors.

Ionotropic receptors are also known as ligand-gated ion channels. They combine receptor and channel functions into a single protein complex. When a ligand binds to this type of receptor, the channel changes conformation such that it is more or less permeable to one or more ions. Thus, the receptor acts directly, i.e. no intermediate metabolic steps are required. Note: "tropos" means to move in response to a stimulus.

The activation of an ionotropic receptor allows ions to pass through its channel. These channels are relatively fast, the channel opens and closes rapidly, and their time constants are about 0.5 ms. AMPARs are much fasters than NMDARs.

Metabotropic receptors usually activate G-proteins, which modulate ion channels directly or indirectly through enzymes and second messengers. They do not combine receptor and channel functions into a single protein complex. Note: these receptors are called "metabotropic" because the (delayed) movement of ions through the channel requires metabolic steps.

Metabotropic glutamate (mGlu) receptors are G-protein coupled receptors (GPCRs) that have been subdivided into three groups. The groups are based on sequence similarity, pharmacology and intracellular signalling mechanisms. Group I mGlu receptors (mGlu1 and mGlu5) are coupled to PLC and intracellular calcium signalling. Group II (mGlu2 and mGlu3) and group III receptors (mGlu4, mGlu6, mGlu7 and mGlu8) are negatively coupled to adenylyl cyclase.

mGluRs plus the GABA B receptor, Ca2+ sensing receptors, pheremone receptors, and taste receptors are distinct from the adrenergic-type GPCRs.

The activation of metabotropic receptors indirectly opens nearby ion channels, e.g. a channel on the cell's outer membrane (plasma membrane) as shown in the image below.

mGluRs can also open many calcium channels on the endoplasmic reticulum (in effect, the original input signal gets amplified). After the first messenger (a neurotransmitter outside the cell) binds to the receptor on the the cell's outer membrane (PM), the second messenger is produced and delivered to the target receptors, e.g. IP3 receptors that open Ca2+ channels in the ER membrane. Channels associated with these receptors take longer to open than ionotropic receptors -- from 30 ms up to 1 second. In this case the mGluRs works slowly because the second messenger (IP3) must diffuse in the cytosol before it can bind to IP3 receptors on the ER. In cases where the second messenger is Ca2+, the process is also slow because Ca2+ is delivered by diffusion -- but Ca2+ diffuses in the cytosol less easily than IP3 due to calcium buffers (Ca2+ is inactivated when it binds to a buffer).

Metabotropic receptors not only amplify an input signal, they offer precise control over cell behaviour over a wide range of times.

Ionotropic receptors have a fast and direct effect on their micro-domains. Their channels remain open for a few milliseconds. They provide a way to deliver a sharp ion spike to a very specific location. For example: voltage dependent calcium channels can deliver a sudden [Ca2+] increase proximate to a presynaptic vesicle(s). In contrast, metabotropic receptors are much slower. They may operate on a time scale of seconds to minutes and over larger domains, e.g. elevate [Ca2+] in one or more cells.

The release of one type of neurotransmitter may activate both metabotropic receptors and ligand-gated ion channels to produce both fast and slow post synaptic potentials at the same synapse.

Image: Purves et al, 2001.

Signal Transmission

How are signals transmitted in the nervous system?

Neurons send and/or receive signals. This process is very similar regardless of whether signals are sent to a neuron, muscle, or gland cell. However, neuron-to-neuron transmissions (communications) are by far the most numerous.

Electrical transmission occurs where cells are in direct contact. An action potential causes depolarisation of the presynaptic cell membrane followed immediately by a depolarisation of the postsynaptic cell membrane. This transmission of information is very fast and always excitatory (depolarising).

In contrast, chemical transmission occurs where neurotransmitter molecules diffuse across a narrow region of extracellular space from the presynaptic terminal to the postsynaptic terminal. The binding of transmitters may excite (depolarise) or inhibit (hyperpolarise) the postsynaptic cell. The strength of this connection may be finely tuned. In other words, it provides the system with more control.

An electrical synapse is made by a gap junction. A gap junction is a set of pores on both membranes that may be open. They are aligned opposite each other such that when an action potential (depolarisation) arrives at a gap junction on one cell, the action potential continues directly across the membranes into the next cell, e.g. a post-synaptic neuron. They are well suited for the regulation of rhythmic or synchronised electrical activity such as breathing.

A chemical synapse is made by neurotransmitters and receptors. The presynaptic terminal (where neurotransmitters are released) is not directly connected to the postsynaptic terminal (e.g., where one of many mushroom shaped spines are attached to the postsynaptic neuron). The terminals are separated by an extremely narrow slice of extracellular space known as a synaptic cleft.

Chemical synapses are far more common than electrical synapses in mammals.

Image: Purves et al, 2001.

The synaptic cleft (for chemical transmission) is approximately 20 nm wide (20 x 10^-9 m). The presynaptic terminal manages pools of synaptic vesicles which contain neurotransmitters. All neurotransmitters have a similar life cycle (1) synthesis, (2) storage, (3) release, (4) binding, and (5) inactivation. Here are some common neurotransmitters.

•  Small molecules: acetylcholine.  
•  Monoamines:  dopamine,  norepinephrine (aka, noradrenaline), epinephrine,  serotonin (5-HT),  and histamine.   
•  Amino acids:  glutamate and g-aminobutyric acid (GABA).  
•  Large molecules: neuropeptides -- over 50 kinds have been isolated in nerve cells.   For example,  Substance P and enkephalins, which are active during inflammation and pain transmission in the PNS, and endorphins, which are endogenous opiates that produce euphoria, suppress pain, or regulate response to stress.

Other transmitters include kainate and adenosine triphosphate (ATP).

Signal transmission may be divided into three regions.
1.  Presynaptic terminal

The local depolarisation causes Ca2+ channels to open. Ca2+ rushes into the presynaptic cell via voltage gated calcium channels because the Ca2+ concentration is much greater outside the cell than inside. Ca2+ ions bind to calmodulin and this causes vesicles filled with neurotransmitter to migrate towards the presynaptic membrane. When the vesicle merges with the presynaptic membrane it forms a continuous membrane such that the neurotransmitter is released into the synaptic cleft (exocytosis).

2.  Synaptic Cleft

Neurotransmitter molecules diffuse across the synaptic cleft and bind to receptors. The time period from neurotransmitter release to postsynaptic receptor channel binding is less than a millisecond.

3. Postsynaptic terminal

After the neurotransmitters bind to the postsynaptic receptors, positive ions (sodium and calcium) rush in an depolarise this patch of membrane.  The summation of positive currents flowing in via this and other synapses located on its dendritic tree and soma may cause the membrane potential to increase to the point where the postsynaptic neuron fires an action potential.

Image: Purves et al, 2001.

To simplify matters, the terminals can be viewed as resource managers.   The presynaptic terminal manages pools of vesicles, presynaptic ligand gated receptors (such as preNMDARs) and voltage gated calcium channels, and many other things.   Meanwhile the post-synaptic terminal manages, for example,  the number and location AMPA, NMDA, P2X, and other receptors on its membrane.

There are many types of receptors at various synaptic and extra-synaptic locations, i.e. on both neurons, and on the astrocyte that enwraps the synaptic cleft. Furthermore, the quality and quantity of receptors varies greatly, even within the same brain region and same type of neuron.

Synaptic plasticity may be implemented in the pre- and/or post-synaptic terminal ( and in other locations? ).    First, the probability of vesicle release from the presynaptic terminal may be increased/decreased (possibly due to higher/lower calcium levels).   Second, the postsynaptic terminal could change the number and/or quality of receptors on its membrane.   The resulting changes may be short term or long term.   The details of how synapses implement plasticity are complicated ... they will be the subject of future posts.

This animation shows a network of neurons and a signal (aka action potential).   In general, when a neuron receives enough input,  it fires an action potential that travels  down its axon.  A single axon may form many branches and include thousands of  terminals (output points).   These terminals (aka boutons) maintain pools of vesicles that contain neurotransmitters such as glutamate.    Near the end of the animation, the action potential arrives at a terminal.   Although not shown explicitly,   the action potential causes voltage gated channels to open such that calcium  rushes into the terminal and binds to calcium sensors.   This causes some presynaptic vesicles to fuse with the membrane and release their contents into the synaptic cleft (a ~20 nm gap between the output  and input terminals).   The released neurotransmitters bind to receptors (ligand gated) on the postsynaptic neuron.   These receptor channels open and allow ions to enter.   So now the signal has been transmitted from one neuron to the next via a "chemical synapse".   Of course this animation omits many details about the strength of the synapse and so on, for example, the probability of vesicle release, the number and locations of the voltage gated channels,  the number, locations, and types of ligand gated receptors, and how the synapse changes over time.

Introduction

This blog will be about neuroscience in general, synaptic plasticity and computational models of the synapse in particular.

The synapse is a chemical connection between two neurons, and the strength of such connections changes over time -- they are "plastic".

Although the synapse has been studied for many years; exactly how synaptic strength changes is still the subject of research.

Some blog entries will be revised periodically in an effort to add interesting details.