Integration of Neural Information Transfer

Communication between neurons is not always a one-to-one event as we have been describing. Frequently, the axon of a presynaptic neuron branches, and its collaterals (branches) synapse on multiple target neurons. This pattern is known as divergence (Fig. 8.22a). On the other hand, when a group of presynaptic neurons provide input to a smaller number of postsynaptic neurons, the pattern is known as convergence (Fig.  8.22b).

Combination of convergence and divergence in the CNS may result in one postsynaptic neuron with synapses from as many as 10,000 presynaptic neurons (Fig. 8.22c). For example, the Purkinje neurons of the CNS have highly branched dendrites so that they can receive information from many neurons (Fig. 8.22d).

In addition, we now know that the traditional view of chemical synapses as sites of one-way communication, with all messages moving from presynaptic cell to postsynaptic cell, is not always correct. In the brain, there are some synapses where cells on both sides of the synaptic cleft release neurotransmitters that act on the opposite cell. Perhaps more importantly, we have learned that many postsynaptic cells “talk back” to their presynaptic neurons by sending neuromodulators that bind to presynaptic receptors. Variations in synaptic activity play a major role in determining how communication takes place in the nervous system.

The ability of the nervous system to change activity at synapses is called synaptic plasticity {plasticus, that which may be molded}. Short-term plasticity may enhance activity at the synapse (facilitation) or decrease it (depression). For example, in some cases of sustained activity at a synapse, neurotransmitter release decreases over time because the axon cannot replenish its neurotransmitter supply rapidly enough, resulting in synaptic depression.

Sometimes changes at the synapse persist for significant periods of time (long-term depression or long-term potentiation). In the sections that follow, we examine some of the ways that communication at synapses can be modified.

Postsynaptic Responses May Be Slow or Fast

A neurotransmitter combining with its receptor sets in motion a series of responses in the postsynaptic cell (Fig. 8.23). Neurotransmitters that bind to G protein-coupled receptors linked to second messenger systems initiate slow postsynaptic responses.

Some second messengers act from the cytoplasmic side of the cell membrane to open or close ion channels. Changes in membrane potential resulting from these alterations in ion flow are called slow synaptic potentials because the response of the second messenger pathway takes longer than the direct opening or closing of a channel. In addition, the response itself lasts longer, usually seconds to minutes.

Slow postsynaptic responses are not limited to altering the open state of ion channels. Neurotransmitters acting on GPCRs may also modify existing cell proteins or regulate the production of new cell proteins. These types of slow response have been linked to the growth and development of neurons and to the mechanisms underlying long-term memory.

Fast synaptic responses are always associated with the opening of ion channels. In the simplest response, the neurotransmitter binds to and opens a receptor-channel on the postsynaptic cell, allowing ions to move between the postsynaptic cell and the extracellular fluid. The resulting change in membrane potential is called a fast synaptic potential because it begins quickly and lasts only a few milliseconds.

If the synaptic potential is depolarizing, it is called an excitatory postsynaptic potential (EPSP) because it makes the cell more likely to fire an action potential. If the synaptic potential is hyperpolarizing, it is called an inhibitory postsynaptic potential (IPSP) because hyperpolarization moves the membrane potential away from threshold and makes the cell less likely to fire an action potential.

Pathways Integrate Information from Multiple Neurons

When two or more presynaptic neurons converge on the dendrites or cell body of a single postsynaptic cell, the response of the postsynaptic cell is determined by the summed input from the presynaptic neurons. Figure 8.24c shows the three-dimensional reconstruction of dendritic spines of a postsynaptic neuron, with numerous excitatory and inhibitory synapses providing input. The summed input from these synapses determines the activity of the postsynaptic neuron.

The combination of several nearly simultaneous graded potentials is called spatial summation. The word spatial {spatium, space} refers to the fact that the graded potentials originate at different locations (spaces) on the neuron.

Figure 8.24d illustrates spatial summation when three presynaptic neurons releasing excitatory neurotransmitters (“excitatory neurons”) converge on one postsynaptic neuron. Each neuron’s EPSP is too weak to trigger an action potential by itself, but if the three presynaptic neurons fire simultaneously, the sum of the three EPSPs is above threshold and creates an action potential.

Spatial summation is not always excitatory. If summation prevents an action potential in the postsynaptic cell, the summation is called postsynaptic inhibition. This occurs when presynaptic neurons release inhibitory neurotransmitter. For example, Figure 8.24e shows three presynaptic neurons, two excitatory and one inhibitory, converging on a postsynaptic cell. The neurons fire, creating one IPSP and two EPSPs that sum as they reach the trigger zone. The IPSP counteracts the two EPSPs, creating an integrated signal that is below threshold. As a result, no action potential is generated at the trigger zone.

Temporal Summation

Summation of graded potentials does not always require input from more than one presynaptic neuron. Two subthreshold graded potentials from the same presynaptic neuron can be summed if they arrive at the trigger zone close enough together in time. Summation that occurs from graded potentials overlapping in time is called temporal summation {tempus, time}. Let’s see how this can happen.

Figure 8.24a shows recordings from an electrode placed in the trigger zone of a neuron. A stimulus (X1) starts a subthreshold graded potential on the cell body at the time marked on the x-axis. The graded potential reaches the trigger zone and depolarizes it, as shown on the graph (A1), but not enough to trigger an action potential. A second stimulus (X2) occurs later, and its subthreshold graded potential (A2) reaches the trigger zone sometime after the first. The interval between the two stimuli is so long that the two graded potentials do not overlap. Neither potential by itself is above threshold, so no action potential is triggered.

In Figure 8.24b, the two stimuli occur closer together in time. As a result, the two subthreshold graded potentials arrive at the trigger zone at almost the same time. The second graded potential adds its depolarization to that of the first, causing the trigger zone to depolarize to threshold.

In many situations, graded potentials in a neuron incorporate both temporal and spatial summation. The summation of graded potentials demonstrates a key property of neurons: postsynaptic integration. When multiple signals reach a neuron, postsynaptic integration creates a signal based on the relative strengths and durations of the signals. If the integrated signal is above threshold, the neuron fires an action potential. If the integrated signal is below threshold, the neuron does not fire.

Concept Check

  1. In Figure 8.24e, assume the postsynaptic neuron has a resting membrane potential of −70 mV and a threshold of −55 mV. If the inhibitory presynaptic neuron creates an IPSP of −5 mV and the two excitatory presynaptic neurons have EPSPs of 10 and 12 mV, will the postsynaptic neuron fire an action potential?

  2. In the graphs of Figure 8.24a, b, why doesn’t the membrane potential change at the same time as the stimulus?

Synaptic Activity Can Be Modified

The examples of synaptic integration we just discussed all took place on the postsynaptic side of a synapse, but the activity of presynaptic cells can also be altered, or modulated. When a modulatory neuron terminates on a presynaptic cell, the IPSP or EPSP created by the modulatory neuron can alter the action potential reaching the axon terminals of the presynaptic cell and modulate neurotransmitter release. In presynaptic facilitation, input from an excitatory neuron increases neurotransmitter release by the presynaptic cell.

If modulation of a neuron decreases its neurotransmitter release, the modulation is called presynaptic inhibition. Presynaptic inhibition may be global or selective. In global presynaptic inhibition (Fig. 8.24f), input on the dendrites and cell body of a neuron decreases neurotransmitter release by all collaterals and all target cells of the neuron are affected equally.

In selective modulation, one collateral can be inhibited while others remain unaffected. Selective presynaptic alteration of neurotransmitter release provides a more precise means of control than global modulation. For example, Figure 8.24g shows selective presynaptic modulation of a single collateral’s axon terminal so that only its target cell fails to respond.

Synaptic activity can also be altered by changing the target (postsynaptic) cell’s responsiveness to neurotransmitter. This may be accomplished by changing the structure, affinity, or number of neurotransmitter receptors. Modulators can alter all of these parameters by influencing the synthesis of enzymes, membrane transporters, and receptors. Most neuromodulators act through second messenger systems that alter existing channels, and their effects last much longer than do those of neurotransmitters. One signal molecule can act as either a neurotransmitter or a neuromodulator, depending upon its receptor (Fig. 8.23).

Concept Check

  1. Why are axon terminals sometimes called “biological transducers”?

Long-Term Potentiation Alters Synapses

Two of the “hot topics” in neurobiology today are long-term potentiation (LTP) {potentia, power} and long-term depression (LTD), processes in which activity at a synapse brings about sustained changes in the quality or quantity of synaptic connections. Many times changes in synaptic transmission, such as the facilitation and inhibition we just discussed, are of limited duration. However, if synaptic activity persists for longer periods, the neurons may adapt through LTP and LTD. Our understanding of LTP and LTD is changing rapidly, and the mechanisms may not be the same in different brain areas. The descriptions below reflect some of what we currently know about long-term adaptations of synaptic transmission.

A key element in long-term changes in the CNS is the amino acid glutamate, the main excitatory neurotransmitter in the CNS. As you learned previously, glutamate has two types of receptor-channels: AMPA receptors and NMDA receptors. The NMDA receptor has an unusual property. First, at resting membrane potentials, the NMDA channel is blocked by both a gate and a Mg2+ ion. Glutamate binding opens the ligand-activated gate, but ions cannot flow past the Mg2+. However, if the cell depolarizes, the Mg2+ blocking the channel is expelled, and then ions can flow through the channel. Thus, the NMDA channel opens only when the receptor is bound to glutamate and the cell is depolarized.

In long-term potentiation, when presynaptic neurons release glutamate, the neurotransmitter binds to both AMPA and NMDA receptors on the postsynaptic cell (Fig. 8.25 ). Binding to the AMPA receptor opens a cation channel, and net Na+ entry depolarizes the cell . Simultaneously, glutamate binding to the NMDA receptor opens the channel gate, and depolarization of the cell creates electrical repulsion that knocks the Mg2+ out of the NMDA channel . Once the NMDA channel is open, Ca2+ enters the cytosol .

FIG. 8.25 Long-term potentiation

The Ca2+ signal initiates second messenger pathways . As a result of these intracellular pathways, the postsynaptic cell becomes more sensitive to glutamate, possibly by inserting more glutamate receptors in the postsynaptic membrane [up-regulation, p. 51]. In addition the postsynaptic cell releases a paracrine that acts on the presynaptic cell to enhance glutamate release .

Long-term depression seems to have two components: a change in the number of postsynaptic receptors and a change in the isoforms of the receptor proteins. In the face of continued neurotransmitter release from presynaptic neurons, the postsynaptic neurons withdraw AMPA receptors from the cell membrane by endocytosis [here], a process similar to down-regulation of receptors in the endocrine system [here]. In addition, different protein subunits are inserted into the AMPA receptor proteins, changing current flow through the ion channels.

Researchers believe that long-term potentiation and depression are related to the neural processes for learning and memory, and to changes in the brain that occur with clinical depression and other mental illnesses. The clinical link makes LTP and LTD hot topics in neuroscience research.

Concept Check

  1. Why would depolarization of the membrane drive Mg2+ from the channel into the extracellular fluid?

Disorders of Synaptic Transmission Are Responsible for Many Diseases

Synaptic transmission is the most vulnerable step in the process of signaling through the nervous system. It is the point at which many things go wrong, leading to disruption of normal function. Yet, at the same time, the receptors at synapses are exposed to the extracellular fluid, making them more accessible to drugs than intracellular receptors are. In recent years, scientists have linked a variety of nervous system disorders to problems with synaptic transmission. These disorders include Parkinson’s disease, schizophrenia, and depression. The best understood diseases of the synapse are those that involve the neuromuscular junction between somatic motor neurons and skeletal muscles. One example of neuromuscular junction pathology is myasthenia gravis. Diseases resulting from synaptic transmission problems within the CNS have proved more difficult to study because they are more difficult to isolate anatomically.

Drugs that act on synaptic activity, particularly synapses in the CNS, are the oldest known and most widely used of all pharmacological agents. Caffeine, nicotine, and alcohol are common drugs in many cultures. Some of the drugs we use to treat conditions such as schizophrenia, depression, anxiety, and epilepsy act by influencing events at the synapse. In many disorders arising in the CNS, we do not yet fully understand either the cause of the disorder or the drug’s mechanism of action. This subject is one major area of pharmacological research, and new classes of drugs are being formulated and approved every year.