Neurotransmitters 2000 words

There are over one hundred known neurotransmitters in the human brain which permit neurons to communicate with each other via a process of chemical transmission. These known neurotransmitters have been classified into two broad categories, the first characterised as small-molecule neurotransmitters, which mediate small synaptic actions, when a rapid neurological response is necessary and the second known as Neuropeptides, “tend to modulate slower, ongoing synaptic functions or peripheral target tissue” (Purves 2001).

The two most common neurotransmitters in the human brain are both small molecular transmitters, known as Glutamate (the major excitatory neurotransmitter) and GABA (Gamma-Aminobutyric Acid) and Glycine (the major inhibitory neurotransmitters) (Bowery and Smart p. S109). For neurotransmission to take place, generally four factors must align. The chemical substance must be:

present within the pre-synaptic neuron, released in response to pre-synaptic depolarisation, the release must be Ca²⁺-dependent and specific receptors for the substance must be present on the postsynaptic cell (Purves 2001; also Bowery and Smart, p. S114).

The knowledge of the impact of these major excitatory and inhibitory transmitters has developed in the past 50 years, a time period in which major brain neurotransmission identification occurred (Bowery and Smart, p. S 109). In particular, chemical transporters cross the synaptic cleft, with their protein receptors “embedded in the plasma membrane of postsynaptic cells” (Purves 2001). The binding of neurotransmitters in the synaptic cleft by receptor molecules, involves a process of converting chemical signals into electrical signals. This process either directly or indirectly causes ionic current channels in the postsynaptic membrane to open or close. This changes the permeability of the post synaptic membrane altering its potential and thereby mediates the transfer of information across the synapse. The currents created change the conductance of the post-synaptic cell, either increasing or decreasing its excitability.

The postsynaptic action of a particular neurotransmitter as either excitatory or inhibitory is contingent upon “the class of ion channel affected by the transmitter and by the concentration of permeant ions inside and outside the cell” (Purves 2001). As such, the impact of the two main brain neurotransmitters upon the post-synaptic membrane depends upon which class of post-synaptic receptor is involved in the transmission process. In some instances, the receptor molecule is also an ion channel, known as Ionotropic Receptors (or Ligand-Gated Ion channels) which instigate rapid post-synaptic responses often lasting a matter of milliseconds (Purves 2001). In other cases, the receptor and ion channel involve separate molecules, known as Metabotropic Receptors, which produce slower postsynaptic effects which endure (Purves 2001).

Post synaptic neurons are:

usually innervated by many different inputs, the integrated effect of the conductance changes underlying all EPSPs and IPSPs produced in a postsynaptic cell at any moment determines whether or not the cell fires an action potential (Purves 2001).

At the actual synapse involved in the transmission process, “a tremendous diversity of transmitter-mediated effects is possible”(Purves 2001), since “the combination of receptor subtypes, G-protein subtypes, and ion channels are expressed in the postsynaptic cell” (Purves, 2001). As Best notes:

postsynaptic membranes with the membrane potential directly influenced by neurotransmitters in this way act like small computers — summing-up the excitatory and inhibitory inputs from many axons, with a resultant firing (ie, generating an action potential in the postsynaptic neuron) or not firing (Best 1991).

According to Levi and Gallo (1986, p 1627), the “two neurotransmitter amino acids, one excitatory (glutamic acid) and the other inhibitory (aminobutyric acid, GABA) seem to mediate neurotransmission between all the inter-neurons of the cerebellar cortex.”

Neuronal synapses which rely upon glutamate as the transmitter have receptors which open ion channels which are “non-selectively open to cations.”  Upon activation, both Na⁺ and K⁺ flow across the postsynaptic membrane. Due to the ratio of the reversal potential of current and the resting potential of neurons, the EPSP will depolarize the postsynaptic potential, increasing the odds that the postsynaptic neuron will produce an action potential and thereby define the given synapse as excitatory (Purves 2001).

Unlike the neurotransmission process occurring at the vertebrate neuromuscular junction, where acetylcholine (ACH) is the chemical messenger (Matthews, p. 93), and the outcome is the contraction of the post-synaptic muscle cell, combined with increased permeability for the sodium and potassium, neuron to neuron transfer within the brain shows some significant differences, in terms of the impact of the transmitter upon the postsynaptic membrane.

According to Renner et al, the viscosity of the postsynaptic membrane (PSM) ^“determines its capacity to regulate the net flux of synaptic membrane proteins such as neurotransmitter receptors” (2009, p. 2926). The research team found a higher membrane viscosity at inhibitory than excitatory contacts. They also found that “lipid composition and actin-dependent protein compaction regulate viscosity of the PSM” (Renner et al 2009, p 2926).

A major excitatory neurotransmitter, GABA or Gamma-Aminobutyric acid causes depolarisation at the postsynaptic membrane, firing it for an action potential. According to Olsen,

a greater number of agents of diverse classes appear to affect GABA action at the postsynaptic membrane, as determined from both electrophysiological and biochemical studies. The recently developed in vitro radioactive receptor binding assays have led to a wealth of new information about GABA action and its alteration by drugs (p. 261)

Furthermore, “the action of GABA involves a rapid and reversible binding to a chemically specific recognition site in the postsynaptic cell membrane surface, including receptor protein” (Olsen, p. 261). The opening and closing of the receptor is controlled by the presence of GABA at the receptor. As the:

equilibrium Nernst potential is near the cell resting potential, activation of channels by GABA stabilises the postsynaptic cell membrane potential near the resting level and inhibits the cell by preventing any significant depolarization during any simultaneous excitatory input (Olsen, p. 261).

Surfaces known to accommodate GABA have been empirically immobilised by Saiffuddin (2003) with the observation of electrophysiology to survey surface interaction between GABA and postsynaptic membrane receptor channels (Saiffiddin, p. 191).

According to Purves et al (2001), the:

mechanism of GABA removal is similar to that for glutamate: Both neurons and glia contain high-affinity transporters for GABA. Most GABA is eventually converted to succinate, which is metabolized further in the tricarboxylic acid cycle that mediates cellular ATP synthesis… Inhibition of GABA breakdown causes a rise in tissue GABA content and an increase in the activity of inhibitory neurons.

The second major brain excitatory neurotransmitter, Glutamate is ionotropic (Alexander, p. S87), supported by ample evidence to be a major excitatory neurotransmitter in the mammalian Central Nervous System (CNS) (Wu et al., p. 832), and arguably features the “most complicated of all neurotransmitter receptors, namely the NMDA glutamate receptor (Best 1990). NMDA, short for N-Methyl-D-Aspartate is a:

synthetic chemical not naturally found in biological systems, but it binds specifically to the NMDA glutamate receptor” (Best 1990). Most thickly populated in the cerebral cortex (hippocampus, especially — particularly the CA1 region), amygdala, & basal ganglia…they are particularly vulnerable to glutamic acid excitotoxicity, (which is the) damaging effects due to excessive excitatory neurotransmitter release. Both aspartic acid and glutamic acid (the two amino acids having 2 carboxyl groups — the “acidic amino acids”) have the capacity for destroying neurons when released in excessive amounts (although calcium seems to be more of a cause than acidity) (Best 1990).

In contrast to these excitants, Glycine is known to be the major inhibitory neurotransmitters in the brain, which has a noticeable impact upon the postsynaptic membrane: At inhibitory synapses, the “neurotransmitter prevents the postsynaptic cell from firing an actual potential, keeping the membrane potential of the postsynaptic cell more negative than the threshold potential” (Matthews, p. 115). Glycine is the simplest structured amino acid chain that acts as a chemical neurotransmitter (Bowery and Smart, S 113) as well as the smallest (Loapez-Corcuera (2001, p. 13). The inhibitory capacity of Glycine has been noted by Bowery and Smart (S113), citing studies where glycine has been applied to spinal neurons. In two separate instances, it was reported that the action of potential firing in such cells was reduced by glycine (see Bowery and Smart S113).

There are several transmission functions served by Glycine in the central nervous system (CNS). As an inhibitory neurotransmitter, it participates in the:

processing of motor and sensory information that permits movement, vision, and audition. This action of Glycine is mediated by the strychnine-sensitive Glycine receptor, whose activation produces inhibitory post-synaptic potentials (Bowery and Smart, p. 114).

Within the Central Nervous System, Glycine appears to be released simultaneously with GABA, significant “inhibitory amino acid neurotransmitters” (Bowery and Smart, p. 114). Contemporary thought holds “that the termination of the different synaptic actions of Glycine is produced by rapid reuptake through two sodium-and-chloride-coupled transporters, GLYT1 and GLYT2, located in the plasma membrane of glial cells or pre-synaptic terminals, respectively” (Bowery and Smart p. 114). Further research has indicated that:

the synaptic action of glycine ends by reducing extracellular transmitter concentrations, a task that is achieved by specific high-affinity transporters located in neuronal and glial plasma membranes. The reuptake of glycine is an active process energized by the electrochemical gradient of sodium through the plasma membrane that is maintained by the Na+-K+ ATPas e. The process is also chloride dependent. Glycine transports into pre-synaptic terminals or surrounding glial process which permits glycine accumulation against its concentration gradient and controls the availability of neurotransmitter in the synaptic cleft (Bowery and Smart, p. 114). Nonetheless, Loapez-Corcuera (2001, p. 18), warn of limited advancement in Glycine transporter pharmacological knowledge. They also advocate a:

need for regulation to provide promising directions for future research regarding the organization of the transporters in the pre synaptic membrane, its possible interaction with modulatory or structural elements, and its contribution to the mechanism of Glycine release (Loapez-Corcuera (2001, p. 18).

Gundersen (p. 1114), reminds us that Glycine is a:

“simple, easily available, and inexpensive amino acid with low toxicity and widespread biological effects. This is well documented in a series of experimental (and some clinical) studies. So far, its use in clinical medicine has been modest.

In a cautionary note, Savtchenko (2005) observes that the impact upon the postsynaptic membrane of neural transmission is not exclusively due to the excitatory or inhibitory qualities of the transmitter, but also influenced by the geometry of an axo-dendritic synapse and its position on a dendrite. Nevertheless, Wollf (p.553), has warned of the “detection of free postsynaptic thickenings in adult superior cervical ganglion always found in the cells of the ganglionic sheath and on the walls of the blood vessels.” In other words, the prolonged application of GABBA can result in subtle structural changes to the ganglions, a process which may reflect a parallel phenomenon with reference to neurotransmission in the human brain.

The impact of the excitatory and inhibitory neurotransmitters upon some features of the human brain is well established. The more subtle impacts upon minute components of the brain such as the postsynaptic membranes need more substantial and thorough research, to build a more comprehensive profile of the operations of the brain, including the conductive processes and cyclical nature of message systems which rely upon electro-chemical exchange. The known processes which terminate postsynaptic activity, such as the “degradation of the transmitter in the synaptic cleft, the transport of the transmitter back into cells and the diffusion out of the synaptic cleft” (Purves 2001), require further understanding, to aid a more lucid grasp of the brain’s communication and operational mechanisms. Such knowledge, in tandem with a repertoire of brain malfunction research and drug remediation studies, will allow human societies to better safeguard this rare possession – the human brain.

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