Tag Archives: Serotonin

Why don’t serotonin neurons die like dopamine neurons do in Parkinson’s disease

Say what ?  “This proportion will likely be higher in rat dopaminergic neurons, which have even larger axonal arbors with ~500,000 presynapses, or in human serotonergic neurons, which are estimated to extend axons for 350 meters” – from [ Science vol. 366 3aaw9997 p. 4 ’19 ]

I thought I was reasonably well informed but I found these numbers astounding, so I looked up the papers.  Here is how such statement can be made with chapter and verse.

“The validity of the single-cell axon length measurements for dopaminergic and cholinergic neurons can be independently checked with calculations based on the total volume of the target territory, the density of the particular type of axon (axon length per volume of target territory), and the number of neuronal cell bodies giving rise to that type of axonThese population analyses are made possible by the availability of antibodies that localize to different types of axons: anti-ChAT for cholinergic axons (also visualized with acetylcholine esterase histochemistry), anti-tyrosine hydroxylase for striatal dopaminergic axons, and anti-serotonin for serotonergic axons.

The human data for axon density and neuron counts have been published for forebrain cholinergic neurons and for serotonergic neurons projecting from the dorsal raphe nucleus to the cortex, and cortical volume estimates for humans are available from MRI analyses; forebrain cholinergic neuron data is also available for chimpanzees. These calculations lead to axon length estimates of 107 m and 31 m, respectively, for human and chimpanzee forebrain cholinergic neurons, and an axon length estimate of 170–348 meters for human serotonergic neurons.”

H. Wu, J. Williams, J. Nathans, Complete morphologies of basal forebrain cholinergic neurons in the mouse. eLife 3, e02444 (2014). doi: 10.7554/eLife.02444; pmid: 24894464

How in the world can these neurons survive as long as they do?

Not all of them do–  At birth there are 450,000 neurons in the substantia nigra (one side or both sides?), declining to 275 by age 60.  Patients with Parkinsonism all had cell counts below 140,000 [  Ann. Neurol. vol. 24 pp. 574 – 576 ’88 ]. Catecholamines such as dopamine and norepinephrine are easily oxidized to quinones, and this may be the ‘black stuff’ in the substantia nigra (which is latin for black stuff).

Here are the numbers for serotonin neurons in the few brain nuclei (dorsal raphe nucleus) in which they are found.  Less than dopamine.  A mere 165,000 +/- 34,000 — https://www.ncbi.nlm.nih.gov › pubmed

So being too small to be seen with a total axon length of a football field, they appear to last as long as we do.  Have we missed a neurological disease due to loss of serotonin neurons?

Why should the axons of dopamine, serotonin and norepinephrine neurons be so long and branch so widely?  Because they release their transmitters diffusely in the brain, and diffusion is too slow, so the axonal apparatus must get it there and release it locally into the brain’s extracellular space, no postsynaptic specializations are present in volume neurotransmission — that’s the point.  This is one of the reasons that a wiring diagram of the brain isn’t enough — https://luysii.wordpress.com/2011/04/10/would-a-wiring-diagram-of-the-brain-help-you-understand-it/.

Just think of that dopamine neuron with 500,000 presynapses.  Synthesis and release must be general, as the neuron couldn’t possibly address an individual synapse.

The more we know the more remarkable the brain becomes.

 

Apologies to Hamlet

Apologies to Shakespeare and Hamlet.  Serotonin does “more things in heaven and Earth, Horatio, than are dreamt of in your philosophy.”  How about chemically modifying histones?We all know about serotonin and depression (or at least we think we know).  Block serotonin reuptake by the releasing neuron and bingo you’ve  cured depression (sometimes).  Do not ask the lecturer which of the 15 known serotonin receptors in the brain the increased serotonin actually binds to and what effects the increased levels produce after binding (and which are important for the alleviation of depression).The two body organs producing the most serotonin are the brain and the gut.  Chemical modification of proteins by serotonin has been known for 10 years.  The enzyme responsible is transglutaminase2, it takes the NH2 group of serotonin and replaces the NH2 of glutamine with it — forming an isopeptide bond.

Interestingly, the serotonylation of histones is quite specific.  Only glutamine #5 on histone H3 is modified this way.  For the reaction to occur lysine #4 on histone H3 must be trimethylated (H3K4Me3) — now you can begin to see the combinatorial possibilities of the various histone modifications known.  Over 130 post-ranslational modifications of histones were known by 2013 [ Cell vol. 155 p. 42 ’13 ].

The H3K4Me3Q5Ser is enriched in euchromatin and correlates with permissive gene expression.  Changing glutamine #5 to something else so it can’t be serotonylated changes the transcription pattern, and deficits in cellular differentiation.  You can read more about it in Nature vol. 567 pp. 464 – 465, 535 – 539 ’19 ]