Sunday, May 6, 2012

Electrically coupled cells make a connection

Inside our brains are billions of neurons, which communicate to each other via chemical messengers called neurotransmitters.  Neurotransmitters are released from one cell and bind to receptors on a neighbor cell, creating a chemical synapse between the two neurons.  Precise connections between neurons create microcircuits made up of multiple cells, which are responsible for processing sensory information or controlling motor output.  Our brains contain an outer cortex that has 6 layers of cells (you can think of it as 6 layers of an onion peel with layer 6 being the closest to the center).  Between the layers are functional columns made up of neurons that all serve a similar function and connect to each other in a microcircuit.  In other words, cells in layer 1 connect to layer 2 and layer 3 cells and so on, until there is a circuit of inter-connected neurons spanning all 6 layers. 

Diagram of the 6 cortical layers. From, an excellent neuroscience primer
What’s interesting is that cells right next to each other in one layer may not form chemical synapses with each other at all, opting instead to synapse with a neuron in another layer.  What’s so special about the neurons in other layers?  How do neurons decide with which cells to make a chemical synapse? 

Another interesting thing about these microcircuits that make up the columns is that the interconnected neurons were “born” from the same stem cell.  During the development of an organism, there are many stem cells (also known as progenitor cells) that divide to make mature cells.  When a progenitor cell divides, it makes one copy of itself, as well as one cell that will mature to become an adult cell, which is no longer capable of dividing.  What’s interesting about this process in the brain is that one progenitor cell will end up making many “sister” neurons and these are the neurons that make synapses with each other, forming the microcircuits.  We can now refine our initial questions to ask: How do sister neurons find each other in the brain, through multiple layers, and then make chemical synapses with each other?  How do they know they were made from the same progenitor cell?

The answer is: sister neurons are electrically coupled with each other early in development, which promotes the formation of chemical synapses.  This process was described recently by Yu et al. in the online version of Nature.  Before we look at the experiments, we need to understand what it means to be “electrically coupled”.

Electrical vs chemical synapses
I mentioned already how neurons are functionally connected to each other through chemical synapses.  Packages of neurotransmitters, a type of chemical, are released from one cell to tell a neighbor cell to become activated (or inactivated).  This is sort of an indirect way for cells to communicate since it requires a chemical messenger as a mediator. 

There are also more direct connections between neurons called electrical synapses.  In this case, a tube of proteins, called a gap junction, acts as a tunnel between two neurons.  When one neuron gets activated, positive ions rush into the cell.  These ions can go through the gap junction and enter the second neuron, also activating it.  In this way, the two neurons are electrically coupled, because an activating current can easily spread from one cell to another in an instant.  In the adult nervous system, most of our synapses are chemical synapses, but one prominent example of electrical synapses occurs in the heart.  A small group of muscle cells, called the pacemaker, set the heart rate.  When they become activated, they quickly spread the electric signal to the rest of the cells in the heart because they are all directly connected to each other through gap junctions.  The message sent through an electrical synapse is less likely to fail than a chemical synapse, so that’s one reason why it’s important for our heart cells to be electrically coupled.
From University of Tokyo, Life Science web textbook
Electrically coupled sister neurons
The researchers set out to show that sister neurons, borne of the same progenitor cell, form electrical synapses with each other shortly after they are made.  They found a way to label sister neurons with a fluorescent protein.  They then stuck recording electrodes into two labeled sister neurons and two other nearby neurons that came from other progenitors.  All four neurons were overlapping, so they could easily form synapses with each other if they wanted.  They then injected current into one cell and found that the current traveled to the sister neuron, but not into the other nearby neurons.  What does this tell us?  There are electrical synapses between sister neurons but not between other cells.  The authors go on to show that the electrical synapses are only present during the first few days of life.  By the 6th day after birth, the sister neurons are no longer electrically coupled.

What’s the benefit of being electrically coupled early on in development?  It allows the neurons to be activated in synchrony.  Another important aspect of neuronal signaling is that there is a minimum threshold necessary for a cell to become activated.  A small amount of ion flow (i.e. current) will dissipate and the neuron will not be active or send signals to other cells.  Once the current reaches a certain threshold, though, the cell fires what we call an “action potential”.  Basically the neuron will get super positive inside really quickly and it will release chemical signals to other neurons.  This is what I mean when I say a neuron is “active”.  So if two cells are electrically coupled, a subthreshold current in one cell, plus another subthreshold current in the second cell will add up to push the neurons into the active state.  Thus both neurons will fire an action potential at the same time.

Okay, so now we have one last question: sister neurons are electrically coupled, so they fire action potentials together in synchrony, so what? 

“Neurons that fire together wire together”
It’s been shown that neurons that are active at the same time are more likely to form chemical synapses.  This finding has been used to explain how neurons can form new synapses during the process of learning (see: Hebbian plasticity).  If we apply this theory to development, then it would follow that the electrically coupled sister neurons are active together, which leads to the formation of chemical synapses between them.

To prove this hypothesis, the authors created mice that had defective gap junctions and therefore no electrical synapses (only in one region of the brain).  They found that in these mice, sister neurons no longer formed chemical synapses with each other.  The electrical coupling between sister neurons is necessary for these neurons to form chemical synapses later on in development.

Let’s review
            1) Progenitor cell divides many times to make sister neurons
            2) Early in development, sister neurons form electrical synapses
            3) Sister neurons are active in synchrony (they “fire” together)
            4) Synchronous activity leads to chemical synapse formation
            5) The electrical synapses go away later in development, leaving behind a microcircuit 
                of sister neurons connected via chemical synapses

Yay for electrical synapses… no longer a footnote in Neuroscience textbooks!

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