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CHAPTER 5 Transmitting to Targets 91
driving force for sodium is much greater than the driving force for potassium.
Thus the majority of current through these ionotropic receptors will be a sodium
current that causes depolarization of the membrane potential and is excitatory.
One type of ionotropic glutamate receptor called the NMDA receptor, and one type
of acetylcholine receptor, the alpha 7 receptor, are also permeable to calcium ions.
Activation allows sodium and calcium levels to increase in the postsynaptic
neuron. Sodium inux depolarizes the membrane potential while calcium works
as a second messenger to regulate a number of processes.
Although glutamate and acetylcholine are generally associated with fast
excitatory synaptic transmission through ionotropic receptors, both also activate
metabotropic receptors. And serotonin has both ionotropic and metabotropic
receptors as well.
Inhibiting for control
The ionotropic receptors for GABA and glycine are ligand-gated chloride channels.
The chloride equilibrium potential for most neurons is just below the resting
potential. GABA or glycine opening of their ionotropic receptors typically leads to
chloride inux, which hyperpolarizes the membrane potential and is inhibitory. In
neurons, opening chloride channels also counteracts the depolarization caused by
opening excitatory ionotropic receptors by reducing membrane resistance. This
eect is called shunting inhibition.
In the same way that glutamate, acetylcholine, and serotonin all have both iono-
tropic and metabotropic receptors, GABA also activates a metabotropic receptor.
Metabotropic GABA receptors lead to opening of potassium channels via a
Gprotein in a process that also causes inhibition.
The most abundant excitatory ionotropic receptors in the mammalian nervous
system are those for glutamate and acetylcholine. Glutamate receptors are by far
the most numerous and important excitatory receptors in the CNS.In the periph-
eral nervous system excitatory synaptic transmission at the neuromuscular junc-
tion uses acetylcholine. In addition, metabotropic receptors for glutamate and
acetylcholine mediate other responses.
The most important inhibitory neurotransmitters in the CNS are GABA and
glycine receptors. Inhibitory ionotropic receptors are permeable to and conduct
chloride. For GABA, metabotropic receptors also exist. Interestingly, there are
few inhibitory neurotransmitters used in the peripheral nervous system.
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92 PART 1 Getting Started with Neurobiology
Meeting Metabotropic Receptors
Metabotropic receptors are the targets of all the monoamines and all the neuro-
peptides. Glutamate, GABA, and acetylcholine also have metabotropic receptors.
These sections describe how activation of metabotropic receptors produces slow
indirect synaptic transmission, often with longer lasting responses.
Working through G proteins
In contrast to ionotropic receptors, metabotropic receptors have no ion channel.
Instead, when they bind to a neurotransmitter, a conformational change in the
receptor activates a G protein inside the postsynaptic neuron. G proteins bind
guanosine triphosphate (GTP) or guanosine diphosphate (GDP). Metabotropic
receptors activate heterotrimeric G proteins formed by three subunits, called
alpha, beta, and gamma. An activated metabotropic receptor stimulates the bind-
ing of GTP to the alpha subunit. Alpha-GTP dissociates from the beta/gamma
subunits. The alpha subunit eventually hydrolyzes the bound GTP to GDP and then
alpha reassociates with beta/gamma.
Both the alpha and beta/gamma subunits can stimulate targets called eector
proteins in the plasma membrane. The eector is either an ion channel or an
enzyme that produces a second messenger. The second messenger may also
regulate an ion channel. Second messengers also activate protein kinase and
phosphatases and other actions. Downstream of second messengers there can be
eects on metabolism, the cytoskeleton, and/or gene expression. These eects
are called neuromodulation.
Numerous neurotransmitters function through activation of metabotropic recep-
tors and produce neuromodulatory responses. Second messenger cascades can
cause multiple actions. They may stimulate the opening or closing of ion chan-
nels. Second messengers can lead to the modulation of neuronal morphology,
metabolism, and/or gene expression. These eects tend to be slower and longer
lasting compared to the rapid eects of ionotropic receptors.
Metabotropic receptors activate G proteins, so these receptors are also referred to
as G protein-coupled receptors. Besides neurons, the majority of cells in the body
express receptors in this category. About a thousand dierent G protein-coupled
receptors have been identied in the human genome. Many of them are odorant
receptors expressed in olfactory receptor cells.
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CHAPTER 5 Transmitting to Targets 93
Activating second messengers
More than a thousand types of metabotropic receptors exist, but they use only a
limited number of second messenger pathways:
»
Cyclic adenosine monophosphate (cAMP) pathway: Some metabotropic
receptors activate an increase in cAMP.Other receptors lead to a decrease
in cAMP.
»
Phospholipase C pathway: Inositol triphosphate/diacylglycerol (IP3/DAG)
pathway.
»
PI 3-kinase and ERK MAPK pathways: Phosphoinositide 3-kinase and
extracellular signal-regulated kinase/mitogen-activated protein kinase
pathways.
SIGNALING IN PATHWAYS
One group of metabotropic receptors activate a G protein called Gs to stimulate
adenylyl cyclase, its eector. This, in turn, converts ATP in the cytoplasm into the second
messenger cyclic AMP (cAMP), which diuses within the cytoplasm. cAMP can bind to
and open specic ion channels from the inside. cAMP also activates protein kinase A
(PKA). Protein kinases add phosphate groups (phosphorylation) to regulate ion channels,
cytoskeletal proteins, receptors, and transcription and translation factors.
Another group of metabotropic receptors activate the G protein Gq, which stimulates
the eector phospholipase C (PLC). PLC produces two second messengers called
diacylgycerol (DAG) and inositol trisphosphate (IP3). DAG activates a protein kinase
called protein kinase C (PKC). IP3 binds to and opens calcium channels on the
endoplasmic reticulum (ER). This allows calcium ions to ow out of the ER and
increasesthe cytoplasmic calcium levels.
Calcium ions bind to an adaptor protein called calmodulin. Calcium/calmodulin has
numerous targets, one of which is the calmodulin-dependent protein kinase
CaMKII.Similar to PKA and PKC, CaMKII is a protein kinase that has hundreds of
substrates in neurons, including metabolic enzymes, channels, receptors, transporters,
cytoskeletal proteins, and transcription and translation factors.
There are two other ways that neurons can increase their intracellular calcium:
•
By activation of voltage gated calcium channels that are also expressed in dendrites
•
Through NMDA receptor activation (NMDA receptors are permeable to both
sodium and calcium)
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94 PART 1 Getting Started with Neurobiology
Co-expressing receptor types
At some synapses, both ionotropic and metabotropic receptors can be co-expressed.
In dendritic spines for example, ionotropic receptors are often localized across
from the presynaptic active zone while metabotropic receptors are located outside
the synapse in perisynaptic areas. In response to neurotransmitter release, both
fast, direct, and slow, indirect transmission can occur at the same synaptic region.
Both types of receptors may also be located at the presynaptic membrane and
serve as autoreceptors to provide feedback control of neurotransmitter release.
In some cases, neurotransmitters activate both ionotropic and metabotropic
receptors at the same synaptic region. In other cases, neurotransmitters activate
ionotropic receptors in some neural circuits and metabotropic receptors in others.
Getting Back to Rest
After neurotransmitter release, neurotransmitter molecules must be removed so
the neuron can return to its resting state and cycles of synaptic transmission can
continue. In addition, the fused synaptic vesicle membrane must be retrieved so
presynaptic membrane area can be controlled. The next sections describe these
processes in more detail.
Ending neurotransmitter responses
Three main mechanisms remove the neurotransmitter molecules:
»
Diusion: The neurotransmitter may diuse away from the synaptic cleft.
Insome cases, the neurotransmitter may then activate receptors outside the
synapse in volume transmission.
»
Degradation: Enzymes within the synaptic cleft degrade the neurotransmitter.
Anexample is the degradation of acetylcholine by acetylcholinesterase.
»
Reuptake: Plasma membrane transporters take up the neurotransmitter.
Thetransported neurotransmitter can be repackaged and released again. This is
how glutamate, GABA, glycine, and the monoamines are removed. Transporters
can be located in the presynaptic and postsynaptic neurons and nearby astro-
cytes. In a few neurons, these transporters may work in the opposite direction
torelease neurotransmitters.
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CHAPTER 5 Transmitting to Targets 95
Recycling membranes by endocytosis
In some cases, a synaptic vesicle only partially fuses with the presynaptic mem-
brane, called kiss and run, before the vesicle membrane is quickly taken back in by
endocytosis. In this case the synaptic vesicle remains intact and can be relled
with neurotransmitter.
Other synaptic vesicles undergo full fusion with the presynaptic membrane. When
this occurs, the transmembrane proteins and lipids from both membranes mix
before endocytosis. The endocytic vesicles trac to the early endosome where
they’re sorted, and new synaptic vesicles bud o. The endocytosis and recycling of
synaptic vesicles is an important process for synaptic transmission.
Closing in on Electrical Synapses
In addition to chemical synapses, the other rarer type of synapse is an electrical
synapse that doesn’t involve neurotransmitters or receptors. In an electrical syn-
apse, protein channel subunits on the presynaptic axon form a complex with the
same channel subunits expressed on the postsynaptic cell in a process called a gap
junction. Gap junctions occur between some neurons and also between many types
of cells, including astrocytes, liver cells, and secretory cells. These sections look at
the characteristics of gap junctions and electrical synapses.
Flowing through gap junctions
The gap junction is a connexon channel, which has a pore that links the cytoplasm
of the presynaptic axon to the cytoplasm of the postsynaptic cell. The pore in the
gap junction is larger and less selective than a typical ion channel. It’s permeable
to ions, including sodium, potassium, and chloride ions and small organic mole-
cules less than a kilodalton.
Electrical (ionic) currents pass through the connecting gap junctions from one cell
to the other. These currents make the postsynaptic cell respond in a manner sim-
ilar to the presynaptic cell. The advantages of this type of synapse are speed and
synchronicity because the postsynaptic cell follows the presynaptic cell inlock-
step. Figure5-2 shows a gap junction at high magnication.
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96 PART 1 Getting Started with Neurobiology
Comparing chemical and electrical
Although transmission at electrical synapses is faster, chemical synapses are
more adaptable. By activating numerous receptors, a response at a chemical
synapse can be enhanced. By activating dierent types of the receptors, the post-
synaptic response at a chemical synapse can be depolarizing and excitatory or
hyperpolarizing and inhibitory. By activating receptors that produce second mes-
sengers at a chemical synapse, responses can be widespread and longer lasting.
In addition, each step in chemical transmission represents a place that can be
modied and regulated by gene expression.
Integrating Postsynaptic Responses
Most neurons in the CNS can receive thousands of synaptic inputs. The
responsesproduced by ionotropic and metabotropic receptors will be integrated.
Integration is essential to control the output signal, the action potentials from
the neuron. Here we discuss how synaptic responses are integrated in the
postsynaptic neuron.
FIGURE5-2:
Gap junction
synapses.
© John Wiley & Sons, Inc.
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CHAPTER 5 Transmitting to Targets 97
Summating the potentials
Both temporal and spatial summation occur continuously throughout the neuron
to integrate the incoming electrical responses. When the integrated membrane
potential reaches threshold at the initial segment of the axon, the action potential
will be generated and then conducted along the axon. The action potential output
frequency and pattern is dependent on continuous spatial and temporal summa-
tion of all the excitatory and inhibitory synaptic inputs.
Changing synapses in plasticity
One of the most intriguing recent advances in neurobiology is the understanding
that synaptic transmission isn’t xed, but changes in synapses occur in response
to pre- and postsynaptic ring patterns. This is called synaptic plasticity, a type of
neuroplasticity that occurs in both the developing and adult nervous systems.
Synaptic plasticity is well accepted as one of the mechanisms involved in learning
and memory and as a potential mechanism in recovery following injury.
Synaptic plasticity occurs during development in sensory, motor, and cognitive
systems. Synaptic plasticity also occurs at synapses in the adult brain. Several
types of synaptic plasticity have been characterized, including short-term plas-
ticity, lasting a few seconds to minutes, and long-term plasticity, lasting minutes
to hours and longer. Both increases and decreases in synaptic ecacy can occur.
Synaptic plasticity depends on activity and the timing of inputs, as well as the
prior history of activity at the synapse and activity of nearby synapses. Each has
computational functions.
This chapter highlights presynaptic and postsynaptic activities involved in
synaptic transmission. Several of these mechanisms can be modulated in synaptic
plasticity. Chapter15 describes proposed mechanisms and functions of synaptic
plasticity.
Dividing and Conquering: Circuits
Understanding the function of a neural circuit or brain area can be dicult for
neurobiologists because for most neurons in the middle of the brain we don’t
know exactly what the input is, where the output goes, or what the output does.
Several schemes have been proposed for analyzing the functions of neurons in
large circuits.
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98 PART 1 Getting Started with Neurobiology
Analyzing the functions
One instructive way to analyze the function question was proposed by David Marr
and Tomaso Poggio of the MIT Articial Intelligence Laboratory. They suggested
that function in the nervous system could be approached at three levels:
»
Computational level: What is the overall task of the system? For example,
the autopilot in an airplane has the task of keeping the plane on the correct
heading at the right altitude, among other things.
»
Algorithmic/representational level: How does the system operate? For the
autopilot, algorithms compute how much elevator change in degrees should
be made for a particular altitude error.
»
Physical implementation level: What’s the actual hardware? Autopilots can be
digital or analog, controlling the plane with wires, hydraulics, or electric motors.
Researchers investigate nervous system function at all three levels. This is typi-
cally easiest to do for parts of the nervous system close to sensory input or motor
output, where you can observe the correlation between the circuit and its result.
For example, you can shine light on a photoreceptor and observe its electrical
response. In the upcoming sections, we apply each of these three levels to look at
dierent nervous system functions.
Recent technical progress in physiological measurement and neural response
manipulation has expanded understanding into the middle of the brain— where
the greatest mysteries remain.
Pooling sensory input
One place in the nervous system where considerable work has been done at the
circuit level is the retina. On the computational level, the retina’s job is to allow
you to see. On the algorithmic level, the retina allows you to see using ve major
cell types arranged in two synaptic layers that extract and transmit specic
aspects of the visual world to the brain. On the physical implementation level, the
information sent to the brain goes over the axons of about 30 dierent ganglion
cell classes, each of which has a representative at almost every point in the retina.
Neural convergence occurs when the inputs from many sources are pooled and
transmitted in the output of fewer neurons. For example, the retinas of animals
that are at least partially nocturnal have large numbers of the photoreceptors
called rods. Rods can operate in light levels where only a few photons per second
are available to be captured. The rods have multiple photopigment molecules that
capture photons and multiple rods that connect to downstream cells. Pooling
inputs sacrices preserving information about exactly where the photon was
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CHAPTER 5 Transmitting to Targets 99
absorbed to increase sensitivity. Pooling is common in sensory system relays to
the brain, and commonly deals with sensitivity-eciency trade-os.
Coordinating motor output
Walking or swimming to get somewhere (computational) requires multiple mus-
cles in multiple limbs to coordinate with each other in time and space. This coor-
dination involves neural sensors that report limb position and forces and neural
integrating circuits that coordinate and sequence limb movements (algorithmic).
A hierarchy of controllers work together to coordinate these sequences, starting
with simple reex controllers in the spinal cord, to spinal cord cyclic pattern gen-
erators, to error generation in the cerebellum that interact with the thalamus,
basal ganglia, and motor cortex (implementation).
The superior colliculus is a good example of a controlled motor output for
whichthe neural basis is known. This midbrain structure receives a large input
from theretina, so it has cells in its supercial layers that respond to visual input.
But the function (computational) of the superior colliculus appears to be to code
eye movements — saccades— for orienting your attention (algorithmic). This
happens by a projection from the superior colliculus to the pulvinar and frontal
lobe areas of the brain, leading to eye movement. Shocking a given area on the
colliculus produces an eye movement toward a particular visual eld position.
Thus, higher-than-normal activity somewhere in the periphery may cause an eye
movement to occur to place central vision at that area to resolved greater detail.
Comparing brains to computers
The computational theory of mind (also called computational theory of cognition) holds
that the mind is a computational system like a computer. This computer metaphor
draws an analogy between the mind as software and the brain as hardware.
One of the hottest topics in neuroscience is comparing the computational power
of the brain with that of computers. But how do you compare the two? You know
that human and animal brains can do things — such as recognize complex
patterns— that are extremely dicult to program computers to do. Of course,
computers can do things like calculate the value of π to thousands of decimal
places in a few milliseconds, which humans can’t do.
Brains and computers compute in fundamentally dierent ways, even when doing
the same task (same computation, probably dierent algorithms, and certainly
dierent implementations). Only the human brain uses neurons. However,
articial intelligence uses what’s called deep learning where hundreds of layers of
hundreds of simulated neuron-like elements are used for pattern recognition and
generation and language processing.
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100 PART 1 Getting Started with Neurobiology
Given what is known about how neurons work, how do they do computations
andwhat sort of computations do they do? If you think of a very simple case where
a neuron has two inputs, each of which by itself is above the threshold (more
properly, the voltage at the soma due to the net synaptic current produced by
those inputs is above the threshold), then the neuron is like an OR gate (it res if
either one or the other input is active).
But if the somatic response to each of the two input neurons (inputs A and B) is a
bit less than half as much as the threshold, the neuron becomes an AND gate. That
is, the output neuron is active only if both A and B inputs are active.
Because the output of neurons can also be inhibitory, they can function as
inverters, or NOT gates. The combination of OR, AND, and NOT is more than suf-
cient for the nervous system to implement the same logical power as present in
digital computer circuits.
In trying to compare the computing power of brains to computers, several prob-
lems remain. Most digital computers are serial devices, executing one instruction
at a time. The brain is massively parallel, however, potentially executing billion
of actions simultaneously. Individual synapses in neurons can also execute
complex analog computations such as multiplication, division, and logarithmic
transforms that make them more like analog than digital computers. Neurobiolo-
gists clearly need to know more about how neurons actually work in neural
circuits. (Chapter20 briey discusses some techniques that neurobiologists use
to study neurons and the nervous system.)
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