Human Physiology, 14th edition (2016)

200 Chapter 7

During LTP, the insertion of AMPA receptors for gluta-
mate into the postsynaptic membrane is increased. As pre-
viously stated, glutamate binding to AMPA receptors can
produce the depolarization needed for activation of the NMDA
receptors (see fig. 8.16). Long-term depression (LTD) is a
related process involving the removal of AMPA receptors from
the postsynaptic membrane. A recent report showed that, with-
out the ability to remove AMPA receptors, LTD was impaired
and learning (in rodents) was diminished.
In LTD, the postsynaptic neurons are stimulated to release
endocannabinoids. The endocannabinoids then act as retrograde
neurotransmitters, suppressing the release of neurotransmitters
from presynaptic axons that provide either excitatory or inhibi-
tory synapses with the postsynaptic neuron. This suppression
of neurotransmitter release from the presynaptic axons can last
many minutes, and has been shown to occur in several brain
regions. A shorter-term form of this is depolarization-induced
suppression of inhibition (DSI). In DSI, the depolarization of a
postsynaptic neuron by excitatory input suppresses (via endo-
cannabinoids as retrograde neurotransmitters) the release of
GABA from inhibitory presynaptic axons for 20 to 40 seconds.
Long-term potentiation is produced experimentally by
stimulating the presynaptic neuron with a high frequency of
shocks. Long-term depression can be produced in a variety of
ways, most commonly by prolonged periods of low frequency
stimulation. Both LTP and LTD depend on a rise in Ca^2 1 con-
centration within the postsynaptic neuron. A rapid rise in the
Ca^2 1 concentration causes potentiation (LTP) of the synapse,
whereas a smaller but more prolonged rise in the Ca^2 1 concen-
tration results in depression (LTD) of synaptic transmission.
Synaptic plasticity also involves structural changes in the
postsynaptic neurons, including the enlargement or shrinkage
of dendritic spines (chapter 8; see fig. 8.17). For a discussion
of synaptic plasticity as it relates to memory and cerebral func-
tion, see chapter 8, section 8.2.

Synaptic Inhibition

Although many neurotransmitters depolarize the postsynap-

tic membrane (produce EPSPs), some transmitters do just the

opposite. The neurotransmitters glycine and GABA hyperpo-

larize the postsynaptic membrane; that is, they make the inside

of the membrane more negative than it is at rest ( fig.  7.34 ).

Because hyperpolarization (from 2 70 mV to, for example,

2 85 mV) drives the membrane potential farther from the

threshold depolarization required to stimulate action poten-

tials, this inhibits the activity of the postsynaptic neuron.

Hyperpolarizations produced by neurotransmitters are there-

fore called inhibitory postsynaptic potentials (IPSPs), as previ-

ously described. The inhibition produced in this way is called

postsynaptic inhibition. Postsynaptic inhibition in the brain is

produced by GABA; in the spinal cord it is mainly produced

by glycine (although GABA is also involved).

Excitatory and inhibitory inputs (EPSPs and IPSPs) to a

postsynaptic neuron can summate in an algebraic fashion. The

effects of IPSPs in this way reduce, or may even eliminate,

the ability of EPSPs to generate action potentials in the post-

synaptic cell. Considering that a given neuron may receive as

Figure 7.34 Postsynaptic inhibition. An inhibitory

postsynaptic potential (IPSP) makes the inside of the postsynaptic

membrane more negative than the resting potential—it

hyperpolarizes the membrane. Therefore, excitatory postsynaptic

potentials (EPSPs), which are depolarizations, must be stronger

to reach the threshold required to generate action potentials at

the axon hillock. Note that the IPSP and EPSP are recorded at the

axon hillock of the postsynaptic neuron.

See the Test Your Quantitative Ability section of the Review

Activities at the end of this chapter.

1

2

–85 mV

–55 mV

–70 mV

Inhibitory

neurotransmitter

from neuron 1 Excitatory

neurotransmitter

from neuron 2

IPSP

EPSP

Threshold for action potential

CLINICAL APPLICATION

Although glutamate activation of NMDA receptors to allow

the entry of Ca^2 1 is required for normal brain function and

memory formation, an excess of glutamate in the synaptic

cleft promotes excitotoxicity. In excitotoxicity, excessive

amounts of glutamate cause excessive entry of Ca^2 1 into

neurons, which leads to the activation of digestive protease

enzymes and the release of reactive oxygen species from

mitochondria. These trigger a cascade of events that result

in the apoptotic cell death of the neurons. Excitotoxicity is

responsible for neuron death in ischemic strokes (due to

obstructed arteries, which account for 80% of all strokes;

the remainder are hemorrhagic strokes due to ruptured blood

vessels). This occurs because ischemia impairs glutamate

uptake from the synapse. Excitotoxicity is also believed to

contribute significantly to neuron death in such neurodegen-

erative disease as Alzheimer’s, Parkinson’s, multiple sclero-

sis, amyotrophic lateral sclerosis ( ALS ), and others.