Monday, June 13, 2011

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.


Lizabeth said...

Wow oh wow. Well I'm not pretending to understand all of this but I do know its a looong was from what I was taught in nursing school about 20 years ago. That was pre SSRIs, this hopefully will take us post SSRIs. How do they know this stuff tho---is it theory, or do they have empiracal data, experiments, MRIs, repeatable stuff to back it up? With Dr. Husseini Manji moving to J&J one hopes for the latter, espcecially the post SSRI part.

John McManamy said...

Hey, Lizabeth. Dr Manji has done a lot of studies on tissue samples using gene array technology. The breakthrough occurred about 10 years ago when these samples were treated with lithium and Depakote, and the gene array pointed to certain proteins involving neuroplasticity the neuron's signaling pathways. At about the same time, Fred Gage discovered neurons grow in the hippocampus and Ron Duman found antidepressants enhance their growth. Mor4e neuroplasticity stuff. Also, around the same time, the evidence came in loud and clear on how genetic vulnerability effects our reactions to stress. Bang! The stress reaction screws up neuroplasticity. So now we're connecting the dots.