Inside the Neuron

Neurotransmitters are about outside the brain cell. Let's open up the hood.

Neuons, neurogenesis, and plasticity. In 2000, 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 two years earlier to 1998 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."

Soon after, 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. Earlier experiments by Robert Sapolsky PhD of Stanford found that animals subjected to stress resulted in dead or atrophied neurons in the hippocampus, as well as endangered neurons that were more likely to die when subjected to another stressful event.

Suppose that process could be reversed? 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 that these new cells and restored older cells established connections with existing neural systems. Depleted dendritic spines (responsible for receiving communications from other neurons) grew back. Weakened brain pathways became stronger.

I heard both Dr Duman and Dr Gage talk about their research in two separate lectures at the 2007 American Psychiatric Association annual meeting. 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 key "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.

As Dr Manji explained at the numerous conferences where I have heard him speak, neurons 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."

"You can mess all you want with serotonin and dopamine, etc," Dr Manji told one audience, "but if you don't have the appropriate [cell] circuitry in place it's not going to have any effect."

A Closer Look

Stress elevates cortisol, which in turn ups the excitatory neurotransmitter glutamate, which increases calcium influx into the neuron and activates certain calcium-dependent "death" enzymes. Cortisol may also reduce the neuron's capacity to take energy-sustaining glucose into the cell so it doesn't have the strength to deal with a subsequent crisis. Another casualty may be the glia, the "other" brain cell, once thought of as mere mind-glue but now recognized as an active partner of the neuron. One of its functions is thought to be clearing glutamate from the synapse.

Basically, the cells can't handle the load. One of the casualties inside the neuron is brain derived neurotrophic factor (BDNF), a protein that helps mediate neuron survival, inhibit cell death, and modulate synaptic neurotransmitter activity. Dr Duman and his team found that repeated antidepressant treatment "up-regulates" a signal pathway known as the cAMP-CREB cascade, which in turn acts on BDNF.

Meanwhile, experimenting with lithium and Depakote on brain cell tissue, Dr Manji and his colleagues found that these two completely different compounds indirectly affected some of the same cell pathways associated with cell survival and death. One protective protein that utilizes these pathways is Bcl-2, which in one experiment was doubled by lithium and Depakote administration. Subsequent experiments on rats found that lithium mitigated the effects of lab-induced stroke and led to the growth of new neurons in the hippocampus.

Putting the Pieces Together

The following PowerPoint presentation Dr Manji delivered at the 2011 9th International Conference on Bipolar Disorder helps guide us through a very confusing thicket. Never mind the complextites. Focus, instead, on the general picture:

Above: I’ve seen versions of 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. (See also in this section Psychiatry's Big Bang.)

Above: Here’s an overview of what happens when things go wrong. (See also Systems in Collapse.)

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.

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

Above: 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. Bcl-2 is a protective protein that regulates programmed cell death.

Above: Dr Manji's summary slide.

For how the inside-the-neuron "micro" view interacts with a brain systems "macro" view, see Systems in Collapse.

For a genetic overview, see Gene Quest.

First published 2000, latest update and revision Jan 17, 2012

McMan's Depression and Bipolar Web