Husseini Manji and Neural and Synaptic Plasticity

One of the featured speakers at the 9th International Conference on Bipolar Disorder was Husseini Manji, former chief of the Mood and Anxiety Disorders unit at the NIMH, now Global Therapeutic Head of Neuroscience at J&J. It was Dr Manji who opened my eyes to brain science way back in 2000, when I was first getting started in mental health journalism. I have heard him speak and interviewed him countless times, and have read no end of articles he has authored.

I did not catch the last day of the Conference, when Dr Manji gave his presentation, but thanks to his PowerPoint slides, I think I can give you an appreciation for some of his pioneering work in the brain science of bipolar. These sample slides represent a taste from a much more complex talk. Never mind the complexities. Let’s focus on the general picture.



Above. I’ve seen this slide displayed by other scientists from the NIMH. “Alleles” in the first caption refers to genetic variations. Genes switch on proteins that regulate cellular activity. Cells are organized into systems, which in turn influence behavior.



Above. Here’s an overview of what happens when things go wrong.















Above. “Plasticity” is the operative word, here. When neurons are compromised in their capacity to maintain cellular function, grow, and connect to new neural networks, bad things happen.




Above. Here are some of the candidate genes that may affect plasticity.


Above. Maybe you can see where Dr Manji is going with this. We are not talking about “bipolar genes” or “schizophrenia genes”. We are talking about genes that affect particular brain functions, which in turn influence how we think and behave. Note the overlap between the various mental illnesses. Note how mood and cognition and psychosis are not restricted to any particular diagnosis. “Phenotype” is the traditional way of looking at mental illness, as symptom clusters. “Endophenotype” looks at what else may be going on (such as a breakdown in neural plasticity).


Above. This is a representation of various signaling cascades inside the neuron that regulate neuroplasticity. If the receptors that feed neurotransmission into the cell aren’t functioning right, intracellular signaling is compromised. If intracellular signaling is compromised, the neuron atrophies and may die. This in turn compromises the neuron’s ability to connect with other neurons (through neurotransmission). Whole neuronal networks (synaptic plasticity) are in turn compromised.



Here we see a representation of a healthy neural network and an unhealthy one. Think of a shriveled tree with few branches.


The anterior cingulate, dentate gyrus (part of the hippocampus), and the striatum are all prime suspects when things go wrong with us. The anterior cingulate plays a major role in modulating brain function and in neural connectivity. The hippocampus is where memories are laid down and where new brain cells grow. The striatum is intimately tied to the dopamine system. Note the differences in neural density in these regions with the administration of lithium.


Above. Dr Manji's summary slide.

Rerun - Of Mice and Neurons

Two of my recent blog pieces offered a "macro" systems view of the brain experiencing breakdown. Here's a complementary "micro" cellular view I first published in March ...

I simply love reporting on brain science. Perhaps it's because the degree of difficulty is so high that nailing the landing, so to speak, has a way of setting off my dopamine in a highly pleasurable way.

Or maybe it's simply the fact that I love dealing with smart people working on really cool stuff.

About eight or nine years ago, I came across a journal article about how a research team led by Ron Duman PhD at Yale found that antidepressants caused brain cells to grow in the hippocampus.

Brain cells can actually grow? I thought. Then I asked: What the hell's a hippocampus?

We need to go back a year or two earlier when Fred Gage PhD of the Salk Institute discovered that we are not, in fact, stuck with the brain cells we are born with, that new brain cell growth takes place in an area of the brain known as the hippocampus.

The hippocampus is a tiny region in the limbic system of the brain that is involved in learning and memory, as well as complicit in regulating the stress response and in modulating dopamine's reward and motivation systems. New brain cell growth and regeneration is called "neurogenesis."

Around the same time, Husseini Manji MD and his team at the NIMH found that lithium increased brain cell growth. At first, I thought the fact that psychiatric meds could act as brain fertilizer was the story.

No, Dr Manji told me. Sure, the fact that the brain could grow new cells was important, but the real story, he said, was in how these new and regenerated brain cells connected to other brain cells. Let's return to Dr Duman's research:

In his experiments, Dr Duman and his team exposed lab rats to repeated foot shocks to induce behavioral helplessness equating to depression. When the rats were "depressed," neurogenesis was virtually shut down. But when the animals were treated with different classes of antidepressants, the process was reversed. Neurogenesis cranked up and the little guys were happy again.

Subsequent studies found these new cells and restored older cells established connections with existing neuronal systems. In other words, weakened brain pathways became stronger. The brain functioned better.

I had the pleasure of hearing both Dr Duman and Dr Gage talk about their research in two separate lectures two years ago at the American Psychiatric Association annual meeting in San Diego.

Think of it this way: Under the old way of thinking, psychiatry assumed that all we had to do was squirt serotonin or other neurotransmitters at a neuron and - poof! - no more depression. They even had a name for this: the monoamine hypothesis.

But suppose whole brain systems are off-line, that brain cells aren't talking to one another. That vital "be happy" and "get excited" messages get lost in the mail. What then?

Well, the serotonin may work, but it's going to take time. First, the individual brain cells need to boot up. Both Drs Manji and Duman have been pioneering in figuring out which "signal transduction pathways" and their constituent proteins inside the neuron play key roles in the booting up and other processes.

I have heard Dr Manji at numerous conferences explain that if we can develop treatments that directly target the proteins in these specific pathways we may be able to, in effect, get atrophied neurons booting up much quicker, and thus expeditiously bring entire brain systems back online.

This would translate into quick and safe and effective treatments for depression and bipolar and other mental illnesses.

Today I came across an article in the March 1 Biological Psychiatry that illustrated how Dr Duman's team has been dialing in their research. Their latest study used the same foot shock techniques as their earlier ones. This time, postmortem examination (that's right, they killed the poor guys after torturing them) using electron microscopy in the brain tissue revealed loss in the hippocampal neuron spines.

These dendritic spines play a key role in neurotransmitter traffic, that is in neurons connecting to other neurons.

The study also found that six days of antidepressant treatment reversed the process. In other words, the spines grew back.

Thus, in the entire depression-recovery cycle, we are beginning to see - actually see - the structural changes taking place in the brain and understand the significance of these changes. This particular study represents but a jigsaw puzzle piece in the overall scheme of things, but a picture is forming, one that is changing how we think about mental illness.

Further reading from mcmanweb:

Inside the Neuron

Dr Manji explained how for the last three decades, neurotransmitters have been the focus of mental health research. But recently, he went on to say, we have been learning that mental illness is much more complicated than that. Nerve cells communicate with each other through neurotransmitters, but do not actually go inside the nerve cell. Rather, they are merely the keys that unlock what is going on inside the neuron, "where all the action is." ...

Tooting from Pittsburgh II

It's going on 10 PM. I'm just about to get some serious sleep after a full day at the Eighth International Conference on Bipolar Disorder taking place in Pittsburgh. The image comes from a PowerPoint presentation in a morning talk by Husseini Manji on the fine points of BAG-1, a protein which seems to prevent glucocorticoid receptors from migrating to the nucleus of the neuron, if you know what I mean.

Let's put it this way, when glucocorticoid succeeds in its migration bad things happen.

It was heavy duty on the brain science this morning. We're not talking "imbalance of chemicals of the brain," Dr Manji reminded his audience. Instead, think of mood disorders as "impairments of synaptic and neural plasticity."

Don't worry if you don't understand any of this. I'm just giving you a feel for how my day went. Take my word for it, this is brain science 6.0. I'll be better able to break it down for you when I have a clear brain. To bed ...

This is John McManamy, live - well, actually brain dead - from Pittsburgh.