Synaptic Integration Case File

Synaptic Integration Case File

EUGENE C.TOY, MD, RAHUL JANDIAL, MD, PhD, EVAN YALE SNYDER, MD, PhD, MARTIN T. PAUKERT, MD

CASE 6

An 18-year-old male was involved in a motor vehicle accident 2 years ago. At that time, he sustained a Chance fracture at T11 and a complete spinal cord injury at that level. The fracture was repaired surgically and the patient was eventually discharged from the hospital.

He presents to the physical medicine and rehabilitation clinic for routine assessment. The patient is sitting in his wheelchair with obvious scissoring of his legs. There is normal muscle bulk, but complete loss of voluntary movements. There is a marked increase in tone to his legs with passive movement, increased patellar reflexes, and upgoing toes bilaterally. He has a no sensation below his umbilicus. There is also evidence of developing contractures in his distal lower extremities.

• Which descending tracts account for the loss of voluntary motor movement?
• Which tracts account for the loss of sensation at the umbilicus?
• The loss of what type of postsynaptic potential on lower motor neurons might account for the increased tone in the lower extremities?

ANSWERS TO CASE 6: SYNAPTIC INTEGRATION

Summary: An 18-year-old paraplegic male following a severe spinal cord injury at T11.

• Descending tracts: Corticospinal tracts, rubrospinal tracts, and reticulospinal tracts.
• Sensory ascending tracts: Spinothalamic tract and dorsal columns.
• The loss of inhibitory postsynaptic potential (IPSP) on lower motor neurons might account for the increased tone in the lower extremities. In the absence of IPSPs, the lower motor neurons will only be innervated by excitatory postsynaptic potentials (EPSPs), making muscle contraction more likely.

CLINICAL CORRELATION

It has been estimated that in the United States, there are 50,000 spinal column injuries every year. The cervical spine is the most common location followed by the thoracolumbar spine. The thoracolumbar spine is particularly susceptible to injury because of its location at the transition zone from the rigid, kyphosis of the thoracic spine to the mobile, lordosis of the lumbar spine. This region serves as a fulcrum between the thoracic and lumbar spine and places it in a relatively neutral position, resulting in the application of maximal stress to this region during any traumatic event. Up to half of all thoracolumbar spine fractures result in some type of neurological injury. These can be divided into complete and incomplete spinal cord injuries (SCIs). In a complete SCI, there is complete loss of all motor, sensory, and autonomic function below the level of the injury. Incomplete SCIs have preservation of some neurological function, however minimal it may be. Initially, a complete thoracolumbar SCI presents as a flaccid paralysis with loss of all sensation. As time progresses, the flaccid paralysis is replaced by the characteristic upper motor neuron findings in the lower extremities because of loss of the descending motor tracts. Lower motor neuron findings are generally because of injury to the peripheral nerves (Table 6-1). The spastic weakness and increased muscle stretch reflexes associated with upper motor neuron lesions result from the loss of the descending motor tracts to the alpha motor neurons in the ventral horn of the spinal cord. This leads to a condition known as hyperreflexia. The 1a axons, found in a muscle fiber’s muscle spindle, keep track of how fast a muscle stretch changes. Additionally, they innervate interneurons within the spinal cord which modulate the activity of the alpha motor neurons. Some of these interneurons result in inhibitory synapses on the alpha motor neurons of antagonist muscles. Supraspinal tracts also synapse with interneurons to help modulate the activity of the alpha motor neurons. With loss of the supraspinal influences, the system becomes underdamped and the response to the muscle stretch reflex is out of proportion to the stimulus. The alpha motor neurons are in a more hyperpolarized state resulting in the exaggerated responses

seen during testing of the monosynaptic reflex response (MSR).

APPROACH TO SYNAPTIC INTEGRATION

Objectives

1. Describe the excitatory synaptic pathway.
2. Describe the inhibitory synaptic pathway.
3. Know how the length constant and the time constant affect postsynaptic potentials (PSPs).
4. Describe how a neuron integrates excitatory and inhibitory synapses to form a single response.

Definitions

PSPs: Local potentials developed on the postsynaptic membrane following binding of neurotransmitter to its specific receptor.

EPSPs: Potentials leading to the depolarization of the postsynaptic membrane.

IPSPs: Potentials leading to the hyperpolarization of the postsynaptic membrane.

Spatial summation: The total potential resulting from multiple, simultaneous PSPs.

Temporal summation: The total potential resulting from consecutive PSP at one site.

DISCUSSION

Neurons in the central nervous system receive synapses from multiple other neurons on their dendrites and soma, which form local currents that spread throughout the neuron. These PSPs can be either excitatory or inhibitory, depending on the type of neurotransmitter and receptor. Whether a synapse is excitatory or inhibitory depends less on the type of neurotransmitter released by the presynaptic terminal and more on the type of ligand-gated ion channel that opens as a result of binding by the neurotransmitter. The PSP from all of the various synapses travels to the axon hillock. If the sum of all of the excitatory and IPSP is sufficient to depolarize the voltage-gated ion channels to threshold at the axon hillock, an action potential is generated and propagated down the axon.

Glutamate is the predominant excitatory neurotransmitter in the brain and spinal cord. There are two types of glutamate-gated channels, inotropic glutamate receptors and metabotropic glutamate receptors. Once opened, the glutamate-gated ion channels are permeable to both Na+ and K+ ions. Since the electrochemical gradient for K+ is close to the resting membrane potential (RMP), there is less flow of K+ ions through the channel. There is a significant difference in the electrochemical gradient for Na+ and RMP, however, resulting in a larger Na+ conductance. As the ion currents reach equilibrium, the membrane potential approaches 0 mV resulting in an EPSP. When glutamate binds to the metabotropic receptors, a second messenger system is activated in the neuron which indirectly gates an ion channel.

The predominant inhibitory neurotransmitters in the central nervous system are the amino acids glycine and gamma aminobutyric acid (GABA). GABA receptors are more prevalent than glycine receptors. Binding to their respective receptors leads to the generation of an IPSP in the neuron.

A single neuron can receive upward of 10,000 different synapses. Depending on the size and location of these synapses, they can have a strong or weak influence on the neuron. The amplitude and shape of the PSP diminishes as the electrical distance from the synapse to the axon hillock increases. The amount a PSP decreases as it spreads passively is determined by the length constant of the neuron and can be determined mathematically by the following formula:

where λ is the length constant, d is the diameter of the neuron, Rm is the membrane resistance, and Ri is the internal resistance of the axon. The longer the length constant, the less the signal diminishes as it travels through the neuron. In a process called spatial summation, multiple PSP originating from different presynaptic neurons are summed to determine the cumulative effect on the postsynaptic neuron.

Like the length constant, the time constant is an intrinsic property of a neuron. It is determined by the relationship of the capacitance and resistance of the membrane and is determined by the following formula:

where t is the time constant, Rm is the membrane resistance, and Cm is the membrane capacitance. The time constant helps determine the cumulative effects of consecutive PSP from the same site on the postsynaptic neuron in a process called temporal summation. Conduction velocity is proportional to [1/Cm] × √[d/(4RmRi)] so that increasing the diameter or reducing the capacitance increases velocity of transmission. Myelin decreases the membrane capacitance to increase velocity.

Whether a synapse is excitatory or inhibitory is related to its location. Postsynaptic sites on the dendrites are often excitatory, while sites on the cell body tend to be inhibitory. This localization is owing to the greater effect inhibitory Cl_ channels can have at the base of the dendrite and on the cell body than on the distal dendrite. The open Cl_ channels act as a sink for positive current flowing from the dendrites to the axon hillock via the cell body. Presynaptic sites on the axon terminal often modulate the amount of neurotransmitter released by the presynaptic neuron.

As a neuron receives innervation from multiple presynaptic sites, the EPSP and IPSP from these synapses travel through the neuron to the axon hillock and are combined in a process termed neuronal integration. As we learned previously, this region of the neuron has the highest concentration of voltage-gated Na+ channels. If the cumulative effect of all of the signals depolarizes the neuron to threshold, an action potential is generated. This represents the most fundamental decision-making process of the central nervous system.

COMPREHENSION QUESTIONS

[6.1] A patient comes to your office with a diagnosis of multiple sclerosis (MS), a disease that results in demyelination of central nervous system (CNS) neurons. Since the function of the myelin sheath is to decrease the capacitance of the neuronal membrane (Cm), how would you expect this demyelination to alter the time constant of the neuron?

A. Increase the time constant

B. Decrease the time constant

C. No change in the time constant

[6.2] In studying the response of a CNS neuron to various neurotransmitters, you note that the application of neurotransmitter X to the area around the soma virtually eliminates all action potentials generated by the neuron, no matter how much excitatory input is given to the neuron. X is most likely which neurotransmitter?

A. Acetylcholine (ACh)

B. GABA

C. Glutamate

D. Glycine

[6.3] Still studying the response of a CNS neuron to various stimuli, you note that when stimulated by a single excitatory input, there is no action potential generated. However, when stimulated by three pulses from the same excitatory input in rapid succession, an action potential is generated. This is an example of what principle?

A. Spatial summation

B. Temporal summation

C. Excitatory neurotransmission

D. Inhibitory neurotransmission

Answers

[6.1] A. Increasing the capacitance of a membrane increases its ability to store charge, which increases its time constant and therefore increases temporal summation. In vivo, however, the removal of myelin does very little to affect temporal summation, because for the most part dendrites are not myelinated. Demyelination primarily affects axonal propagation in the CNS, where an increase in the time constant results in slower action potential propagation, accounting for the pathology of MS.

[6.2] B. X is most likely to be GABA. Since the application of X around the soma eliminates most action potentials, we can conclude that X induces IPSPs in the neuron. Since this is a CNS neuron, the two most common inhibitory neurotransmitters are GABA and glycine. GABA is a more common inhibitory neurotransmitter than glycine, so it is more likely that the neuron in question has GABA receptors than glycine receptors. Glutamate is an excitatory neurotransmitter, so cannot account for the changes seen. ACh can have various postsynaptic responses, depending on the specific receptor, but in the CNS, it primarily acts as an excitatory neurotransmitter.

[6.3] B. The situation described is an example of temporal summation of PSPs. The excitatory input is not strong enough to cause the postsynaptic neuron to reach threshold, but if subsequent inputs reach the axon hillock before the subthreshold depolarization has decayed to the resting potential, they build on the prior partial depolarization, further depolarizing the postsynaptic cell until threshold is reached. Spatial summation is the combination of different inputs received simultaneously at different sites on the postsynaptic neuron. Excitatory and inhibitory neurotransmission are combined in special and temporal summation to result in the net effect on the neuron.

NEUROSCIENCE PEARLS ❖ The sum of all the excitatory and IPSPs converging at the axon hillock must exceed the threshold in order to generate an action potential. ❖ Glutamate is the predominant excitatory neurotransmitter, while glycine and GABA are the predominant inhibitory neurotransmitters in the central nervous system. ❖ Postsynaptic sites on the dendrites are often excitatory, while sites on the cell body tend to be inhibitory.

REFERENCES

Bear MF, Connors B, Paradiso M, eds. Neuroscience: Exploring the Brain. 3rd ed. Baltimore, MD: Lippincott Williams & Wilkins; 2006. 

Kandel E, Schwartz J, Jessell T, eds. Principles of Neural Science. 5th ed. New York: McGraw-Hill; 2000. 

Zigmond MJ, Squire LR, Bloom FE, Landis SC, Roberts JL, eds. Fundamental Neuroscience. 2nd ed. San Diego, CA: Academic Press; 1999.

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