2 Glutamatergic system

From: <a href="http://fblt.cz/en/skripta/regulacni-mechanismy-2-nervova-regulace/5-neurotransmisni-systemy/">4. Neurotransmitter Systems • Functions of Cells and Human Body</a>

Glutamatergic system

Glutamate is the main excitatory neurotransmitter in the CNS. It is distributed so widely that it is impossible to talk about individual centres or projections.

It plays an indispensable role in synaptic plasticity, i.e. the removal of old, unused synapses, potentiation of others and the formation of new synapses. These changes, to a large extent mediated by the glutamatergic system (not exclusively), may in principle alter interneuronal connections virtually on a minute by minute scale.

It is thought that synaptic plasticity is the neurobiological process behind memory retention and learning.

Synthesis and inactivation of glutamate – cycle neuron-astrocyte

The blood-brain barrier is set up in such a way that glutamate essentially never traverses from blood into the brain. Under normal conditions glutamate is only transported from the CNS into blood.

Most glutamate is produced in neurons from glutamine (via glutaminase), which is mainly formed in astrocytes and transported into neurons. A close cooperation between neurons and astrocytes is therefore essential for the production of glutamate and GABA.

Upon release into the synaptic cleft only a small portion of glutamate is re-uptaken into the presynaptic neuron; most of it is transported via glutamate transporters EAAT1 and EAAT2(Excitatory Amino Acid Transporter) into astrocytes.

Glutamate is transformed into glutamine inside an astrocyte, which reaction requires ATP and ammonia and is catalysed by glutamine synthetase. Glutamine is then exported into neurons hence completing the cycle.

Clinical correlation:

Some diseases such as liver failure may cause an elevation of blood ammonia levels. Ammonia as an uncharged species easily traverses the blood-brain barrier and in the presence of glutamate it can be converted into glutamine while consuming ATP. If there is too much ammonia, neuronal ATP may be depleted and at the same time two major neurotransmitter systems will be dysregulated – glutamate and GABA. This condition is called liver encephalopathy. Elevated blood ammonia is one factor by which liver disease may influence CNS function.

One may ask why astrocytes recycle glutamate in such a complicated manner instead of handing it over to neurons directly. One possible explanation is that an uncontrolled release of glutamate into the extracellular fluid could excite neighbouring neurons. to prevent this glutamate is first converted to glutamine. Latest research shows that astrocytes can indeed release glutamate but do so in a highly controlled manner.

There are several types of glutamate receptors categorised according to their specific pharmacological agonists:

1) AMPA receptors

2) NMDA receptors

3) Kainate receptors

4) Metabotropic receptors (mGluR1-8)

1) AMPA receptors (AMPARs)

These are ligand-gated ion channels, i.e. ionotropic receptors. Their opening allows the influx of calcium and sodium and the efflux of potassium. They close soon after opening.

2) NMDA receptors (NMDARs)

These are also ionotropic receptors increasing the permeability for calcium, sodium and potassium. The opening of NMDA receptors requires in addition to a conformational change the removal of a magnesium ion, which blocks the pore. Magnesium leaves the channel only if the membrane is sufficiently depolarised (e.g. via AMPARs), which alteration of the electric field repulses the cation.

NMDARs allow a calcium influx sufficient for the activation of calcium-dependent enzymes, which can then regulate properties of the postsynaptic density, receptor density in the membrane, etc. These processes are very important for synaptic plasticity.

3) Kainate receptors

Kainate receptors are also ionotropic and functionally similar to AMPARs.

4) Metabotropic receptors

There are 8 known types of metabotropic receptors labelled as mGluR1-8. They are fond, e.g. on presynaptic neurons, where they attenuate their activity or increase the turnover of phosphatidylinositol.