Tag Archives: dopamine

A totally unsuspected information processing mechanism in the brain

This is pretty hard core stuff for the neurophysiology, neuropharmacology and  neuroscience cognoscenti.  You can skip it if you’re satisfied with our understanding of how the brain works, and our current treatments for neurological and psychiatric disease.  You aren’t?  Join the club and read on.

We thought we pretty much understood axons.  They were wires conducting nerve impulses (action potentials) from the cell body to their far away ends, where the nerve impulses released neurotransmitters which then affected other neurons they were connected to by synapses.

We knew that there were two places on the axon where receptors for neurotransmitters were found, allowing other neurons to control what the axon did.  The first was the place where axon leaves the cell body, called the axon initial segment (AIS).  Some of them are controlled by the ends of chandelier cells — interneurons with elaborate specialized synapses called cartridges.   The second was on the axon terminals at the synapse — the presynapse.  Receptors for the transmitter to be released were found (autoreceptors) and for other neurotransmitters (such as the endocannabinoids (( our indigenous marihuana)) released by the presynaptic cell.

Enter a blockbuster paper from Science (volume 375 pp. 1378 – 1385 ’22) science.abn0532-2.pdf.  It shows (in one particular case) that the axons themselves have receptors for a particular transmitter (acetyl choline) which partly can control their behavior.  I sure people will start looking for this elsewhere. The case studied is of particular interest to the neurologist, because the axons are from dopamine releasing neurons in the striatum.  Death of these neurons causes parkinsonism.

The work used all sort of high technology including G Protein Coupled Receptors (GPCRs) highly modified so that when dopamine hit them a fluorescent compound attached to them lit up, permitting the local concentration of dopamine to be measured in the living brain.  Another such GPCR was used to measure local acetyl choline concentration.

The dopamine axons contain a nicotinic type receptor for acetyl choline.  Stimulation of the interneurons releasing acetyl choline caused a much larger release of dopamine (in an area estimated to contain 3 to 15 million dopamine axon terminals.  The area covered by dopamine release was 3 times larger than the area covered by acetyl choline release, implying that the acetyl choline was causing the axons to fire.

The cell body of the dopamine neuron had nothing to do with it, as the phenomenon was seen in brain slices of the striatum (which have no input from the dopamine cell bodies.

They could actually study all this in living animals, and unsurprisingly, there were effects on movement with increased striatal dopamine and acetyl choline being associated with movement of the animal to the opposite side.

So this is an entirely novel mechanism for the control of neural activity.  How widespread such a mechanism is awaits further study, as is whether it is affected in various diseases, and whether manipulation of it will do any good (or harm).

Exciting times.



What Cassava Sciences should do now

Apparently someone important didn’t like the way Cassava Sciences analyzed their data and their stock tanked again today..  Unfortunately all of this seems to be behind a paywall, and the someone important isn’t named.  I’d love a link if any reader knows of one — just put it in as a  comment below.

I’m not important, but I thought Cassava’s results were quite impressive.  They had enough cases and enough time for the results to be statistically significant

For one thing,  Cassava dealt with severely impaired people (see below) who would be expected to show greater neuronal dropout, senile plaques and neurofibrillary tangles, than recently diagnosed patients.   Neuronal loss is not reversible in man, despite hoards of papers showing the opposite in animals.

Since everything turns on ADAS-CoG, here is a link to a complete description along with some discussion — https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5929311/

On a slide from Cassava’s presentation yesterday the ADAS-CoG average of the 50 patients on entry 9 months ago was 16.6.  With a perfect score of 70, it’s clear that these people were significantly impaired (please look at the test items to see how simple the tasks in ADAS-CoG actually are).    So an improvement of 3 points at 9 months  is significant, particularly since a drop of 5 points is expected each year — yes I’ve seen plenty of Alzheimer patients with ADAS-CoG scores of zero or close to it.

So an increase of 3 points in this group is about a16% improvement.

Here’s what Cassava should do now.  Their data should be re-examined as follows.  Split the ADAS-CoG scores into 3 groups: highest middle and lowest. Quartiles are usually used, but I don’t think 50 patients is enough to do this.  Then examine the median improvement in each of the three.  I’d use median rather than average as with small numbers in each group, a single outlier can seriously distort things — think of the survival of Stephen Hawking in a group of 12 ALS patients.

If the patients with the highest ADAS-CoG scores have the highest median improvement, there is no reason mildly impaired individuals should have a less than 16% improvement in their scores.  This means that a person with ADAS-CoG of 60 should achieve a perfect score of 70,  e.g. return to normal.

This would be incredibly useful for early Alzheimer’s disease.

There is a precedent for this.  Again it’s Parkinson’s disease.

As I mentioned in an earlier post, I was one of the first neurologists in the USA to use L-DOPA for Parkinsonism.  All patients improved, and I actually saw one or two wheelchair bound Parkinsonians walk again (without going to Lourdes).  They were far from normal, but ever so much better.

However,  treated mildly impaired Parkinsonians became indistinguishable from normal, to the extent that I wondered if I’d misdiagnosed them. These results were typical.   For a time, in the early 70s neurologists thought that we’d actually cured the disease.  It was a very heady time.  We were masters of the neurologic universe — schizophrenia was too much dopamine, Parkinsonism not enough. Bring on the next neurotransmitter, bring on the next disease.

We hadn’t cured anything of course, and the underlying loss of dopamine neurons in the substantia nigra continued.  Reality intruded for me with one such extremely normal appearing individual I’d diagnosed with Parkinsonism a few years earlier. He needed surgery, meaning that he couldn’t take anything by mouth for a while.  L-DOPA could only be given orally, and he looked quite Parkinsonian in a day or two.

If reanalysis of the existing data shows what I hope, Cassava Sciences should start another study in Alzheimer patients with ADAS-CoG scores of over 50.  If I’m right the results should be spectacular (and lead to immediate approval of the drug).

A little blue sky.  Sumafilam will then come to be known as intellectual Viagra, as all sorts of oldsters (such as yrs trly) will try to get it Alzheimer’s or no Alzheimer’s.

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.


Just when you thought you understood neurotransmission

Back in the day, the discovery of neurotransmission allowed us to think we understood how the brain worked. I remember explaining to medical students in the early 70s, that the one way flow of information from the presynaptic neuron to the post-synaptic one was just like the flow of current in a vacuum tube — yes a vacuum tube, assuming anyone reading knows what one is. Later I changed this to transistor when integrated circuits became available.

Also the Dale hypothesis as it was taught to me, was that a given neuron released the same neurotransmitter at all its endings. As it was taught back in the 60s this meant that just one transmitter was released by a given neuron.

Retrograde transmission was just a glimmer in the mind’s eye back then. We now know that the post-synaptic neuron releases compounds which affect the presynaptic neuron, the supposed controller of the postsynaptic neuron. Among them are carbon monoxide, and the endocannabinoids (e. g. what marihuana is trying to mimic).

In addition there are neurotransmitter receptors on the presynaptic neuron, which respond to what it and other neurons are releasing to control its activity. These are outside the synapse itself. These events occur more slowly than the millisecond responses in the synapse to the main excitatory neurotransmitter of the brain (glutamic acid) and the main inhibitory neurotransmitter (gamma amino butyric acid — aka GABA). Receptors on the presynaptic neuron for the transmitter it’s releasing are called autoreceptors, but the presynaptic terminal also contains receptors for other neurotransmitters.

Well at least, neurotransmitters aren’t released by the presynaptic neuron without an action potential which depolarizes the presynaptic terminal, or so we thought until [ Neuron vol. 82 pp. 63 – 70 ’14 ]. The report involves a structure near and dear to the neurologist the striatum (caudate and putamen — which is striated because the myelinated axons of the internal capsule go through its anterior end giving it a striated appearance).

It is the death of the dopamine containing neurons in the substantial nigra which cause Parkinsonism. They project some of their axons to the striatum. The striatum gets input elsewhere (from the cortex using glutamic acid) and from neurons intrinsic to itself (some of which use acetyl choline as their neurotransmitter — these are called cholinergic interneurons).

The paper makes the claim that the dopamine neurons projecting to the striatum also contain the inhibitory neurotransmitter GABA.

The paper also says that the cholinergic interneurons cause release of GABA by the dopamine neurons — they bind to a type of acetyl choline receptor called nicotinic (similar but not identical to the nicotinic receptors which allow our muscles to contract) in the presynaptic terminals of the dopamine neurons of the substantial nigra residing in the striatum. Isn’t medicine and neuroanatomy a festival of terms? It’s why you need a good memory to survive medical school.

These used optogenetics (something I don’t have time to explain — but see http://en.wikipedia.org/wiki/Optogenetics ) to selectively stimulate the 1 – 2% of striatal neurons which use acetyl choline as a neurotransmitter. What they found was that only GABA (and not dopamine) was released by the dopamine neurons in response to stimulating this small subset of neurons. Even more amazing, the GABA release occurred without an action potential depolarizing the presynaptic terminal.

This literally stands everything I thought I knew about neurotransmission on its ear. How widespread this phenomenon actually is, isn’t known at this point. Clearly, the work needs to be replicated — extreme claims require extreme evidence.

Unfortunately I’ve never provided much background on neurotransmission for the hapless chemists and medicinal chemists reading this (if there are any), but medicinal chemists must at least have a smattering of knowledge about this, since neurotransmission is involved in how large classes of CNS active drugs work — antidepressants, antipsychotics, anticonvulsants, migraine therapy. There is some background on this here — https://luysii.wordpress.com/2010/08/29/some-basic-pharmacology-for-the-college-student/