Introducing the brain: fine controls of synapses (Introduction)

by David Turell , Wednesday, January 03, 2024, 16:10 (323 days ago) @ David Turell

It is not goes go or not go, but nuances in between:

https://mail.google.com/mail/u/0/#inbox/FMfcgzGwJcXsSGKtbVTTXHGvGpdrMSWW

"Looks can be deceiving. In the brain, several types of proteins act as receptors for the neurotransmitter glutamate, exciting neurons by opening ion channels when the neurotransmitter binds. But one kind—so-called glutamate delta (GluD) receptors—don’t respond to glutamate at all, even though they look a lot like the ones that do. Now, neuroscientists have discovered that one of these receptors, called GluD1, actually binds a completely different neurotransmitter, and in doing so, has a dampening effect on neurons.

"Glutamate receptors are usually found at the synapses between neurons that predominantly use glutamate. So, researchers were puzzled to find GluD1 receptors at synapses dominated by the neurotransmitter GABA—which quiets neurons instead of exciting them. Further examination in mouse brain tissue revealed that these receptors bind GABA, and in doing so, play an unexpected role in dampening neuronal activity, as they report in the most recent issue of Science.

“'This challenges the dogmatic distinction between glutamate and GABA receptors and identifies GluD1 as a regulator of inhibitory signaling,” Ian Coombs and Mark Farrant note in an accompanying Perspective. The exact role of GluD1 in human brains needs further investigation, they say, especially given that mutations in the human version of the gene have been associated with neurological conditions, including schizophrenia and seizures."

From the article:

https://www.science.org/doi/10.1126/science.adf3406?utm_source=sfmc&utm_medium=emai...

"The high (10 mM) concentrations of neurotransmitter reached at fast chemical synapses after vesicular releas indicate substantial activation of GluD1 receptors by GABA despite their relatively low affinity for this agonist. The detailed mechanisms that couple GluD1 activation to the modulation of GABAAR activity, however, remain to be deciphered. The question of whether this previously unknown form of GABAergic synaptic plasticity interacts with other forms of inhibitory plasticity also remains open. Because GluD1 receptors are broadly expressed in the forebrain, including at inhibitory synapses in the neocortex, GABA signaling through GluD1 receptors likely represents a general mechanism that extends the computational rules of inhibitory plasticity with consequences on neuronal circuit function.

"In humans, GluD1 mutations are associated with susceptibility to autism and schizophrenia as well as major depressive disorders. With their dual ability to reside at excitatory and inhibitory synapses, GluD1 receptors are not only specially equipped to act as powerful regulators of synaptic circuits but are also vulnerable nodes of excitation-inhibition imbalance during neuropsychiatric disorders. In that context, our finding that GluD1 receptors are molecular machines with hybrid features—functionally GABAergic but structurally glutamatergic—opens fresh perspectives on GluD1-targeted neuropharmacology." (my bold)

Comment: all processes in living organisms have positive and negative influences as well as feedback loops to maintain a very delicate balance of fine control at all times.