Do glia think?

Do glia think Dr. Gonatas?  This was part of an exchange between G. Milton Shy, head of neurology at Penn, and Nick Gonatas a brilliant neuropathologist who worked with Shy as the two of them described new disease after new disease in the 60s ( myotubular (centronuclear) myopathy, nemaline myopathy, mitochondrial myopathy and oculopharyngeal muscular dystrophy).

Gonatas was claiming that a small glial tumor caused a marked behavioral disturbance, and Shy was demurring.  Just after I graduated, the Texas Tower shooting brought the question back up in force —

A recent paper [ Neuron vol. 105 pp. 954 – 956, 1036 – 1047 ’20] gives good evidence that glia are more than the janitors and the maintenance crew of the brain.

Glia cover most synapses (so neurotransmitter there doesn’t leak out, I thought) giving rise to the term tripartite synapse (presynaptic terminal + postsynaptic membrane + glial covering).

Here’s what they studied.  The cerebral cortex projects some of its axons (which use glutamic acid as a neurotransmitter) to a much studied nucleus in animals (the nucleus accumbens).  This is synapse #1. The same nucleus gets a projection of axons from the brainstem ventral tegmental area (VTA) which uses dopamine as a neurotransmitter.  However, the astrocytes (a type of glia) covering synapse #1 have the D1 dopamine receptor (there are 5 different dopamine receptors) on them.  It isn’t clear if the dopamine neurons actually synapse (synapse #2) on the astrocytes, or whether the dopamine  just leaks out of the synaptic cleft to the covering glia.

Optogenetic stimulation of the VTA dopamine neurons results in an elevation of calcium in the astrocytes (a sign of stimulation). Chemogenetic activation of these astrocytes depresses the presynaptic  terminals of the neurons projecting the nucleus accumbens  from the cerebral cortex .  How does this work?  Stimulated astrocytes release ATP or its produce adenosine.  This binds to the A1 purinergic receptor on the presynaptic terminal of the cortical projection.

So what?

The following sure sounds like the astrocyte here is critical to brain function.  Activation of the astrocyte D1 receptor contributes to the locomotor hyperactivity seen after an injection of amphetamine.

Dopamine is intimately involved in reward, psychosis, learning and other processes (antipsychotics and drugs for hyperactivity manipulate it).  That the humble astrocyte is involved in dopamine action takes it out of the maintenance crew and puts it in to management.

A final note about Dr. Shy.  He was a brilliant and compelling teacher, and instead of the usual 1% of a medical school class going into neurology, some 5% of ours did.  In 1967 he ascended to the chair of the pinnacle of American Neurology at the time, Columbia University.  Sadly, he died the month he assumed the chair.  Scuttlebut has it that he misdiagnosed his own heart attack as ‘indigestion’ and was found dead in his chair.

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  • Peter Shenkin  On March 23, 2020 at 10:59 pm

    This is somewhat peripheral – but not entirely.

  • luysii  On March 24, 2020 at 1:52 pm

    Ah Kinky Friedman. A fellow resident settled in Texas after being assigned there in the service ’68 – ’70. I couldn’t believe what he told me about Kinky. Texans loved him and he made a semi-serious run for governor. Kinky took antisemitism and ran with it — his band was called Kinky Friedman and the Texas Jewboys

  • Mark Thorson  On April 2, 2020 at 9:35 pm

    Do Paramecia think? One of the strangest things I was taught in school is that Paramecia can be trained. Dip a wire in a bacteria broth, then dip it in the Paramecia culture, and they will swim to it and feast on the bacteria. Do it enough times, and you’ll be able to dip a plain wire with no bacteria, and they swim to that too.

    How can a unicellular organism remember anything? With all the previously ignored small RNA and peptides now being implicated to be non-junk and possibly quite important, I’d suggest it may be time to revive chemical memory theory (formerly called RNA memory). A criticism of the Planaria experiments that were used to support RNA memory theory was that Planaria have nervous systems. Chunks of trained neural networks might be transplanting themselves into new hosts when the trained Planaria are chopped up and fed to the untrained Planaria. I think experiments like these should be redone with Paramecia to rule that out. If someone could demonstrate a memory factor that can transfer memory from a trained unicellular organism to an untrained organism, that would be strong evidence for chemical memory. I’d suspect a memory peptide, small RNA, or peptide/RNA complex would be strongly conserved, and it may still exist in humans. That might be the target that needs to be hit to treat memory diseases like Alzheimer’s.

    • luysii  On April 3, 2020 at 1:50 pm

      Interesting. There was a whole genre of research back in the 70s and they even had their own journal facsimile called (I think) The Worm Runners Quarterly

  • Mark Thorson  On April 3, 2020 at 9:04 pm

    Here’s something relevant to the mind/glia problem:

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