Glutamate · Grey Matter

Glutamate is the main excitatory neurotransmitter of the brain: released by pyramidal cells, it opens channels on the next neuron that let positive ions in and push that neuron toward firing.

Glutamate. Glutamate is the main excitatory neurotransmitter of the brain: released by pyramidal cells, it opens channels on the next neuron that let positive ions in and push that neuron toward firing.

It acts through several receptors, and two ion-channel receptors do most of the fast work at cortical synapses. AMPA receptors open within a millisecond of glutamate binding and let mostly sodium in; they produce the quick depolarisation that most excitatory signalling consists of. NMDA receptors bind the same glutamate but, at resting voltage, their pore is plugged by a magnesium ion. Only when the membrane is already depolarised (usually by the AMPA current) does the magnesium leave, and the channel then admits calcium as well as sodium.

The NMDA receptor is a coincidence detector. It passes current only when the presynaptic cell has released glutamate and the postsynaptic cell is depolarised at the same moment, which is the cellular form of the rule that cells firing together strengthen their link.

The calcium that enters through NMDA receptors is a signal as well as a charge. It switches on the enzymes that make a synapse stronger or weaker, so NMDA receptors are the entry point of most forms of synaptic plasticity.

Glutamate has to be removed fast. Left in the extracellular space it keeps receptors open and depolarises the tissue; transporters, mostly on astrocytes, take it up within milliseconds, and too much glutamate for too long damages neurons (excitotoxicity).

Glutamate also acts on slower metabotropic receptors that work through G proteins; they tune excitability over longer times and are left to a later card.

Glutamate is the accelerator of the cortex, and the NMDA receptor is the part that learns.

The same molecule that drives every excitatory signal also decides, through calcium, which connections are kept.

Questions: What do glutamate and GABA each do to the same neuron's membrane? Glutamate opens AMPA channels that let sodium in, so the membrane moves toward threshold within a millisecond; if the cell is already depolarised, NMDA receptors also lose their magnesium block and admit calcium. GABA works the other way: GABA-A receptors open chloride channels that hold the membrane at or below rest and short-circuit excitatory currents, and GABA-B receptors, more slowly, open potassium channels through G proteins. The neuron fires or stays silent according to the running sum of the two, which is why the same cell can be pushed either way within a few milliseconds. How much glutamate does one synaptic vesicle hold? Thousands of molecules, with estimates that depend on the method. Biochemical analyses of isolated vesicles gave about 2,000 to 4,000, models fitted to the response of postsynaptic receptors gave about 5,000 to 9,000, and a direct electrochemical count in single vesicles found about 8,000. Release happens in these packets (quanta), so the smallest signal a synapse can send is one vesicle's worth. What removes glutamate after it is released, and why does the speed matter? There is no enzyme that destroys glutamate in the cleft; it is pumped away, mostly into astrocytes, whose transporters (GLT-1 carries about 90 % of the uptake in the adult forebrain) sit on the fine processes wrapped around synapses. The astrocyte turns it into glutamine and returns that to neurons to be made into transmitter again. Fast clearance keeps each signal short and private to its synapse; when uptake slows, glutamate lingers, spills to neighbouring synapses and keeps receptors open, and altered astrocyte transporters are a common finding in epileptic tissue. Why is the AMPA current over within a few milliseconds of glutamate release? Glutamate in the cleft reaches a high concentration for only about a millisecond before it diffuses away and is taken up by transporters, and AMPA receptors bind it with low affinity, so they let go quickly. Those that stay bound close anyway within milliseconds by desensitising. The current therefore decays with a time constant of roughly one to a few milliseconds, and below a millisecond at some fast synapses onto interneurons. The brevity is what lets AMPA synapses carry precise timing, while the slower NMDA current beside them integrates over a hundred milliseconds or so.