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1012 neurons

In human brain
1013 glial cells
Signaling in Nerve Cells CNS: Oligodendrocytes Astrocytes

Chap. 7.7-7.8

Yi-Ping Hsueh PNS: Schwann Cell

Oct 5, 2006

Outline:
Albert Einstein
The Nobel Prize in Physics 1921 I. Structure and function of neuron
The brain of Albert Einstein has often
been a subject of research and speculation.
Einstein's brain was removed within 7 hours of II. Action potential
his death. The brain has attracted attention
because of Einstein's reputation for being one of
the foremost geniuses of the 20th century, and III.Molecular Properties of voltage-gated ion channel
apparent regularities or irregularities in the
brain have been used to support various ideas
about correlations in neuroanatomy with general
or mathematical intelligence. IV. Neurotransmitters, synapse and transmission
Einstein's brain contained 73 percent
more glial cells than the average brain. V. Neurotransmitter receptors

VI. Learning and memory

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Types of Neurons I. Structure and function of neuron
Specialized regions of neurons carry out different functions
1. Projecting neurons vs Interneurons
1. Cell body (Soma)
2. Dendrite
3. Axon hillock
4. Axon
5. Synapse
(Neuromuscular
junction, NMJ;
Neuronal
synapse;
dendritic spine)

2. Sensory neurons vs motor neurons Longer than 1 meter


Neurons are organized into circuits.

Synaptic connection
Chemical Synapse

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Presynaptic vs Postsynaptic Dendritic spine = excitatory synapse
> 90% of excitatory synapses in rat brain are located at
dendritic spines.

(spine)

(perikaryon)

* Neurotransmitter vesicles at presynaptic site.


* Electronic dense structure (PSD) at postsynaptic site.
* Asymmetric v.s. symmetric synapse.

Morphology of dendritic spine is regulated by developmental How Neuron Delivers Signal to Next Neurons?
process and synaptic activity. * Changes of membrane potential
* Release of neurotransmitters

Resting Action Neuro- Change of


potential Potential transmitter Membrane
(depolarization) release potential

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Patch clamps permit measurement of ion movements through single channels
Measurement of the electric potential across an membrane

Resting potential
is ~–60 mV

Oocyte expression assay Incoming signals must reach the threshold potential
To study the activity of normal and mutant channels using frog oocytes.
to trigger an action potential in a postsynaptic cells.

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Origin of the resting potential in a typical vertebrate neuron.
Resting potential = ~60 mV
The ionic compositions of
the cytosol and of the
Uneven distribution of ions across plasma membrane extracellular fluid are
different.

K+ is higher in the
cytosol.

Na+ is higher in the


extracellular fluid.

This gradient is
maintained by Na+-K+
ATPase.

All cells expend a large of fraction of the ATP they produce (up to 70% in
nerve cells) to maintain their required cytosolic Na+ and K+ concentrations.

Depolarization of the plasma membrane due to opening How does neuron generate
of gated Na+ channels. action potential?
-Voltage-gated cation channels.

Voltage-gated Na+ channels:


Open first but transiently by change
of membrane potential
Na+ influx,
results in depolarization

Non-gated K+ channel

During the time that the voltage-


Voltage-gated Na+ channel gated Na+ channels are closing,
voltage-gated K+ channels open.

K+ efflux,
results in re-polarization

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The action potential is a cycle of membrane depolarization,
hyperpolarization and return to the resting value. Operational model of the voltage-gated Na+ channel.

The Structure of the Potassium Channel:


Molecular Basis of K+ Conduction and Selectivity Structure of resting potassium channel from the bacterium
Declan A. Doyle, João Morais Cabral, Richard A. Pfuetzner, Anling Kuo,
Jacqueline M. Gulbis, Steven L. Cohen, Brian T. Chait, Roderick MacKinnon Streptomyces lividans
Science (1998) 280:69-77
2003 Nobel Laureate (1) A large aqueous cavity stabilizes an ion
(green) in the otherwise hydrophobic
Top view
membrane interior.
(2) Oriented helices point their partial
negative charge (carboxyl end, red) towards
the cavity where a cation is located.

All K+ channel proteins are tetramers comprising four identical subunits.

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Mechanism of ion selectivity in resting K+ channel Shaker type K+ channels:

Identified using Drosophila


mutant screening by Lily and
Yuh-Nung Jan

The shaker mutant flies exhibit an abnormally prolonged action


potential because of a defect in the voltage-gated K+ channel that is
required for normal repolarization.

Ball-and-chain model for inactivation of voltage-gated K+ channel


Proposed structural model of shaker voltage-gated K+ channel

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Ball and chain model for inactivation
Why Neurons conduct the action potential unidirectionally
along axon?

(missing the ball)


Oocyte
expression
assay

Unidirectional conduction of an action potential due to Neurotransmitters


transient inactivation of voltage-gated Na+ channels.
ATP,
Adenosine,
Neuropeptides
…….

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Cycling of Neurotransmitters and of Synaptic Vesicles
in Axon Terminals The Functional Anatomy of Neurotransmitter Release
Started in 1986
The strategies were:
1. To purify and clone the various protein
at presynaptic termini.
2. To study their structures.
3. To analyze their functions by knocking
them out in mice.
Tom Sudhof

~20 protein families were identified.

Neurotransmitter receptors Neurotransmitter receptors:

One transmitter Several different types of receptors 1. Ligand-gated ion channels


2. G-protein-coupled receptors

Ligand-gated ion channel


Functional type Ligand/receptor Ion channel

Excitatory receptors Acetylcholine/Nicotinic receptor Na/K


Glutamate/NMDAR Na/K and Ca
Glutamate/non-NMDAR Na/K
Serotonin/5-HT receptor Na/K

Inhibitory receptors GABA/GABA-A class receptor Cl


Glycine Cl
Original finding by different types of agonists

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AMPAR:
Ion Channels: Responds to
glutamate
1. Non-gated ion channel:
constitutively open NMDAR:
non-gated K+ channel….. 1. Depolarization
2. The presence of
2. Voltage-gated ion channel: glutamate
triggered by change of membrane potential
voltage-gated Na+ or K+ channels…….
Ca influx
3. Ligand-gated ion channels Enhances the
ligand binding induces channel open response of
AMPAR, NMDAR……. postsynaptic
cells.

G-Protein Signaling

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Neurotransmitter receptors: Learning and memory
1. Ligand-gated ion channels
Fast synapses
Change membrane potential within 0.1-2 ms
2000 Nobel Laureate
2. G-protein-coupled receptors Senior Investigator of HHMI,
Slow synapses Columbia University College of
Mediated by second messengers (Ca and cAMP) Physicians and Surgeons
Modify the ion conductance of a linked ion channel.

Eric R. Kandel

Learning and memory Learning and memory

Eric R. Kandel Eric R. Kandel


Science (2001) 294:1030

Aplysia punctata
A simple learned behavior:

1. Gill withdrawal reflex


A light touch to the siphon causes the siphon to contract and the gill
to withdraw.

2. Sensitization
A noxious stimulus to another part of the body, such as tail, enhances
the withdrawal reflex of both the siphon and the gill.

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1. Serotonin secreted Long-Term Memory Requires Protein synthesis.
by an activated
facilitator neuron
binds to the G-
protein-coupled
receptor, leading to
an increase of cAMP.
2. Protein
phosphorylation
prevents opening of K
channel and prolong
depolarization.
3. Prolonged
depolarization leads
to enhanced
secretion of the Enlarge
neurotransmitter existing
New synapses
glutamate, which synapses
stimulate the motor
neuron

Hebb’s hypothesis for synaptic modification


Neurons are organized into circuits.
1. When the presynaptic axon is active and at the same time the
postsynaptic neuron is strongly activated under the influence of
Brain function Neuronal connection other input, then the synapse formed by the presynaptic axon is
strengthened.
Synaptic interaction Neurons that fire together wire together.
2. When the presynaptic axon is active and at the same time the
Stronger synaptic interaction, postsynaptic neuron is weakly activated by other inputs, then
the synapse formed by the presynaptic axon is weakened.
better connection.
Neurons that fire out of sync lose their link.
More synaptic interaction
between two neurons, stronger
connection between these two
neurons.

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Long-term potentiation
Learning Induces Long-Term Potentiation in Hippocampus
Whitlock, J.R., Heynen, A. J., Shuler, M. G., Bear, M. F.
A burst of stimulation of a postsynaptic neuron makes it Science 313: 1093 (2006)
more responsive to subsequent stimulation by presynaptic
neurons.
After animal enters the dark side,
close the door and apply a
Inhibitory Avoidance (IA) electrical shock.
IA training creates a stable
memory trace in a single trial
and causes substantial
changes in gene expression in
area CA1 of dorsal
hippocampus, which suggests
that this is a site of robust
synaptic plasticity

Learning and Memory

IA training results in an
enhancement of fEPSPs in Outline:
area CA1 of the hippocampus
in vivo.
I. Structure and function of neuron

II. Action potential

III.Molecular Properties of voltage-gated ion channel

IV. Neurotransmitters, synapse and transmission

V. Neurotransmitter receptors
IA trained
control
VI. Learning and memory

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References:

1. Molecular Cell Biology, fifth edition, by Lodish, Berk, Zipursky, Photographs of Albert
Matsudaira, Baltimore and Darnell. Chapter 7. Einstein's brain, taken in
2. Neuroscience Exploring the Brain, second edition, by Bear, Connors 1955. The original caption
and Paradiso. Chapter2, 3, 5 and 6. indicated that: "A, superior;
B, left lateral; C, right lateral;
3. Science (1998) 280:69-77.
D, inferior; E, midsagittal view
4. Cell (2003) 112: 519-33. of the left hemisphere. The
5. JBC (2002) 277:7629-32. arrow in each hemisphere
6. Science (2001) 294:1030 indicates the posterior
7. Science (2006) 313: 1093 ascending branch of the
Sylvian fissure as it runs into
(is confluent with) the
postcentral sulcus.
Consequently, there is no
parietal operculum in either
hemisphere. Scale bar, 1 cm."

Albert Einstein's brain


Study by the Team at McMaster University

However, in 1999, further analysis by a team at McMaster University in Ontario revealed that Einstein's parietal operculum region was missing. The operculum is part of the inferior
frontal gyrus of the frontal lobe in the brain. The inferior frontal gyrus borders the lateral sulcus (Sylvian fissure) below. The Sylvian fissure was partially absent from Einstein's
brain. Researchers at McMaster University believe this may have enabled neurons in this part of his brain to communicate better. "This unusual brain anatomy…(the missing part of the
Sylvian fissure)… may explain why Einstein thought the way he did," said Professor Sandra Witelson who led the research published in the Lancet. Einstein himself claimed that he
thought through images rather than verbally. As of now this is unproven. Professor Laurie Hall of Cambridge University says, "To say there is a definite link is one bridge too far, at
the moment. So far the case isn't proven. But magnetic resonance and other new technologies are allowing us to start to probe those very questions." [citation needed]

Scientists are currently interested in the possibility that physical differences in brain structure could determine different abilities. [6] [7]One famous part of the operculum is
Broca's area which plays an important role in speech production (see below for discussion relating to Einstein's difficulties with language). To compensate, the inferior parietal lobe
was 15 percent wider than normal [8]. The inferior parietal region is responsible for mathematical thought, visuospatial cognition, and imagery of movement. Einstein's brain also
contained 73 percent more glial cells than the average brain.
[edit]

Study by the Team of Marion C. Diamond

In the 1980s, University of California, Berkeley professor Marion C. Diamond persuaded Thomas Harvey to give her samples of Einstein’s brain. She compared the ratio of glial cells in
Einstein’s brain with that in the preserved brains of 11 men. Her laboratory made thin sections of Einstein’s brain, each 6 micrometers thick. They then used a microscope to count the
cells. Einstein’s brain had more glial cells relative to neurons in all areas studied, but the difference was statistically significant only in the left inferior parietal area. This area is part
of the association cortex, regions of the brain responsible for incorporating and synthesizing information from multiple other brain regions. Diamond admits a limitation in her study is
that she had only one Einstein to compare with 11 normal men. S. S. Kantha of the Osaka BioScience Institute in Japan criticized Diamond’s study, as did Terence Hines of Pace
University. [9]

Diamond and Joseph Altman (then of Purdue University) had already both discovered that rats with enriched environments developed more glial cells for each neuron. Rats in
impoverished environments had fewer glial cells relative for each neuron. [10] A lifetime studying difficult mathematical and physical problems may have enriched Einstein’s
environment.
[edit]

Speculation on Autism

“A post-mortem study of Einstein’s brain may provide clues as to the cerebral processes underlying genius (Witelson et al 1999). There was significant enlargement of the gyri
comprising the parietal association cortices, suggesting variation at some early stage of cerebral ontogeny. The authors conclude that this may reflect an extraordinarily large expanse
of highly integrated cortex within a functional network—a notion consistent with Cajal’s speculation that variation in axonal connectivity may be a neuronal correlate of intelligence
(Cajal 1989).” [11]

The Sylvian fissure was partially absent from Einstein's brain. It appears that in normal brains the Sylvian fissure is involved in processing language. '"Cortical areas that may be
implicated in impaired language functioning include the Sylvian fissure." (Leonard, 2001). Einstein did not start talking until he was three and he frequently repeated sentences
obsessively up to the age of seven. As an adult his lectures were notoriously confusing. Further abnormalities in the Sylvian fissure could possibly be associated with autism. [12]

During his education Einstein was very successful at Physics and mathematics but did less well in some other subjects. At 16 he failed history and language examinations for the Swiss
Federal Institute of Technology. This can demonstrate science ability with poorer language skills. [13]

Isaac Newton showed similar genius and similar difficulties to Einstein. Suggesting similar causes is speculative as there is no knowledge of the physiology of Newton’s brain. Some
have considered a post-mortem diagnosis of autism for Einstein (see people speculated to have been autistic).

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