Photolysis of Caged Glutamate for Use in the Central Nervous System (CNS)

Glutamate As a Neurotransmitter

The nervous system involves in the regulation and controlling of various physiological activities through neural signals. Generally, neural signals are divided into electrical signals and chemical signals, of which electrical signals are transmitted to neurons in the form of action potentials, whereas chemical signals are transmitted between neurons in the form of neurotransmitters. Until now, a variety of neurotransmitters have been identified, which are categorized into excitatory neurotransmitters and inhibitory neurotransmitters according to their physiological functions. And based on the chemical structures, neurotransmitters mainly include choline, monoamines, amino acids, neuropeptides.

Glutamate, the ionic form of glutamic acid, is a kind of amino acid neurotransmitter, which is the most abundant excitatory neurotransmitter in the brain. As a nonessential amino acid, glutamate is critical to protein synthesis and metabolism in organisms, playing important roles in the development of the brain, and other organs. As a neurotransmitter, glutamate has a role in synaptic plasticity by activating several receptors, such as AMPA receptors, NMDA receptors, and metabotropic glutamate receptors, widely involving in cognitive functions.

Fig.1 Glutamatergic neurotransmission and excitotoxicity. (Lin, 2012)

What is Caged Glutamate and Photolysis?

The concept of caged compounds was born in 1978, which refers to small biomolecules that are encapsulated into an inactive form by being bound to an inert compound (namely the “cage” moiety). Once exposed to irradiated light, the covalent bonds break, releasing small bioactive molecules to exert their functions, the process of which is named photolysis. Caged neurotransmitters, especially caged glutamates, are widely used for neuroscience research. Several caged glutamates have been synthesized and published, such as α-carboxy-ortho-nitrobenzyl glutamate (CNB-Glu), bromo-hydroxycoumarin (Bhc-Glu), and 4-methoxy-7-nitroindolinyl glutamate (MNI-Glu).

Fig.2 Structures of caged glutamates. (Ellis-Davies, 2019)

Photolysis of Caged Glutamates for Neurological Research

• Photolysis of caged glutamates for modeling in vitro

It has been demonstrated that caged glutamate could induce seizure discharge in the hippocampal neurons once photolysis by ultraviolet light. This can be used for in vitro epilepsy modeling for further exploration of the molecular pathogenesis of seizures.

• Photolysis of caged glutamates for synaptic plasticity research

The repeated photoactivation of clavicular glutamate around a single dendritic spine resulted in an increased current on the dendrite, and a continuous increase in the volume of the dendritic spine. This confirmed the synaptic plasticity at the level of single dendritic spines through photolysis of caged glutamate.

• Photolysis of caged glutamates for other related neurological studies

Photolysis of caged glutamates also has been applied for study on signal integration mechanism of dendrites, glutamate receptor mapping, transmitter dynamics, local neuronal functions, and so forth.

Fig.3 Uncaging caged glutamate at single spines evokes uncaging (u) EPSPs. (Mitchell, 2019)

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References

1. Lin, C.L.G.; et al. Glutamate transporter EAAT2: a new target for the treatment of neurodegenerative diseases. Future Medicinal Chemistry. 2012, 4(13), 1689-1700.
2. Mitchell, D.E.; et al. Probing single synapses via the photolytic release of neurotransmitters. Frontiers in Synaptic Neuroscience. 2019, 11: 19.