The neuron is the functional unit of our nervous system. Neurons only make up a tiny fraction of the cells found in the central nervous system, but are the reason for the existence of all the cells around them. The astrocytes, ependymal cells, microglia, Schwann cells and oligodendrocytes (collectively known as the glia) exist only to support, protect, and serve the neurons. Neurons form the basis of thought, emotion, motion, sensation and every interaction that we have with or environment, and even our own bodies. They comprise our communication network, our sensory network, our processing center, and memory. But how do they work? You have probably heard that they are electrical in nature, but it's not the same thing as copper wire and solder. They are a lot more complicated, and require an introduction of a few concepts from cell biology. In the first installment of a three part series, I will talk about some of these basic concepts. From there, we can move on to a discussion of how signals get transmitted in the brain, and how certain drugs may affect that signaling.
The anatomy of a neuron
The classic neuron consists of three main parts : the soma, or cell body, the axon, and the dendrites. The soma is similar to the main cell body of any other cell in the body, except for the presence of synapses, which are discussed in the next edition. The cell body supports the rest of the cell, manufacturing proteins and peptides, shunting energy sources and waste products, and providing a genetic control center (the nucleus). Primary cell functions take place in the nucleus. The dendrites are are fingerlike projections that provide the input for the neuron. These receive input from other neurons, or in the case of sensory neurons, from the outside world. They can transmit this information in the form of electrical impulses to he cell body for transmission along the axon. A given neuron will have a very large number of dendrites, from dozens to thousands. The axon is a long, single, bifurcating projection from the neuron. This is the output. Only one axon leaves a neuron, but nearly all bifurcate into multiple treelike telodendria, which can also number in the thousands. Each telodendrite will terminate at an effector cell of another neuron. These connections are commonly in the form of a synapse, a point at which the two structures come exceptionally close, but do not actually touch. This synapse may be with an effector cell, such as a muscle or a gland, or with another neuron. In the brain, each neuron will receive input from, on average, 2000 synaptic endings. For an estimated 10^11neurons in the human brain, this means 200 trillion connections. By raw complexity, this outpaces the Pentium 4 processor by about six orders of magnitude.
The membrane potential
We are all familiar with diffusion, I hope. And we can all recall the high school biology class where we talked about semipermeable membranes, and the establishment of a concentration gradient. Well, every cell in out body has a concentration gradient set up of several different ions. The important ones for this discussion are sodium (Na), chloride (Cl), potassium (K), and calcium (Ca). Chloride is negatively charged. The rest are positive. Throughout our bodies, the levels of Na, Cl, and Ca are higher outside the cells than in. Potassium is higher inside. We are all aware of the tendency of these ions to move down their concentration gradient, or their chemical gradient, but many of us are probably not familiar with the idea of an electrical gradient. These ions are charged, and therefore set up an electrical potential across the membrane, which is determined by the small region of space directly on either side of the membrane. This thin region is known as the dipole layer. Ions outside this layer do not influence the membrane potential. By convention, the extracellular space is referenced as zero. Relative to that, the inside of a neuron is about -90mV when resting. This can change very easily, however, by altering the permeability of the membrane to certain ions. By regulating the flow of ions macros the membrane, you can transiently affect the voltage across the membrane. These changes are commonly referred to as hypopolarization (a decrease in the magnitude of the membrane potential), hyperpolarization (an increase in the magnitude of the membrane potential) and depolarization, which will be discussed in the next section. Remember: hypopolarization will actually be an increase in the potential. The resting potential is negative, so it must increase (become more positive) to approach zero.
So, how is this done? There are specific proteins in the membranes of cells called ion channels. These are controlled, or gated, in different ways. Some are opened by interaction with another molecule, either from outside or inside the cell. These are called ligand gated ion channels. Others are opened by mechanical forces. Many sensory neurons use these mechanically gated ion channels. Still others open in response to changes in the membrane potential, and are referred to as voltage gated ion channels. Recall the relative concentrations of ions. If a cell has a ligand gated sodium channel, and it is opened, positively charged sodium will flow into the cell, altering the electrochemical makeup of the dipole layer in that region, making it more positive. This will be a hypopolarization, or, in the case of a neuron, an excitatory potential. Alternatively, if a ligand gated chloride channel is opened, it will allow an influx of negatively charged chloride into the cell. This will result in a hyperpolarization of the membrane. To change things around a bit, imagine that a potassium channel opens. This would result in efflux of positively charged potassium from the cell, again hyper polarizing the cell.
Remember the voltage gated ion channels? Most of these are sodium and potassium channels, and are found scattered along the axons of neurons. These typically open when the membrane potential reaches about -65mV, but this threshold can be modulated by the action of some neurotransmitters. When a local region of the membrane reaches or crosses this threshold, the voltage gated sodium channels in that region open rapidly. The resulting influx of sodium completely depolarizes the membrane, and the potential enters the positive domain. Some ions will diffuse along the membrane, altering the voltage in the neighboring regions. More voltage gated ion channels open in this region, depolarizing that region as well. This causes a cascade all the way down the axon.
Voltage gated sodium channels have two gates, one on the extracellular face and another on the intracellular face. In the resting state, the outer gate is closed and the inner gate is open. Upon crossing the threshold, the outer gate opens very rapidly, and the inner gate begins to close, but comparatively slowly. As a result, the gate remains open for only a short period of time, without the need for an additional outside force to act on the channel. The closing of the sodium channels prevents further influx of sodium, and the sodium that has flowed in begins to diffuse away from the membrane, deeper into the cell. Once the ions have left the dipole layer, they no longer influence the membrane potential and the potential can return to resting. Additionally, the same voltage that opens sodium channels stimulates a delayed opening of potassium channels. These do not fully open until the sodium channels have already begun to close, so they do not affect the membrane potential during this phase. Once they do open, they allow the efflux of potassium, which contributes to the reestablishment of the resting potential. Diffusion of sodium out of the dipole layer begins a slow repolarization, and the opening of the potassium channels initiates a rapid repolarization. The result is a sudden increase, then reestablishment of the membrane potential in one area, and this wave of depolarization propagates down the axon to the synapse.
One last feature of the sodium channels : the observant reader may have noticed that this should result in a continual series of action potentials, as that sodium from the next segment will diffuse in both directions. Sodium ions flowing backwards from the second segment to the first should raise the membrane potential there back to the threshold, reactivating the voltage gated sodium channels and repeating the depolarization. This, however, does not happen. Once a voltage gated sodium channel has been activated, it is no longer in its resting state. It now sits with its inner gate closed and its outer gate open, and it must be retooled. Anterograde propagation is prevented by the necessity of the channel to retool; it can only do so at the resting potential of -90mV. By the time the membrane returns to this potential, the action potential has propagated well beyond the range at which its sodium ions could affect the now responsive sodium channels.
So how is the membrane depolarized in the first place? This discussion begins with the assumption that a region of the membrane has crossed the -65mV threshold. How does this region of the membrane get to that potential? This is the function of the synapse : to control the membrane potential in a local region of the neuron via regulation of ion channels. This is the receptor potential, and we will discuss this in the next installment of the series.