[Murg] NEUROBIOLOGY: ON NEUROTRANSMITTERS

Wed Apr 27 17:44:54 EST 2005

http://scienceweek.com/2005/sw050429-2.htm

NEUROBIOLOGY: ON NEUROTRANSMITTERS

The following points are made by Steven E. Hyman (Current Biology 2005
15:R154):

1) The nervous system processes sensory information and controls behavior by
performing an enormous number of computations. These computations occur both
within cells and between cells, but it is intercellular information
processing, involving complex neural networks, that provides the nervous
system with its remarkable functional capacity. The principal cells involved
in information processing are neurons, of which there are hundreds, if not
thousands of individual cell types based on morphology, location,
connectivity and chemistry [1]. In addition to neurons, the other major kind
of cell in the nervous system is the glia, which play critical support roles,
but which are increasingly seen to function in some aspects of information
processing.

2) To provide some idea of the magnitude of the information processing
capacity of the human brain, its 10^(11) neurons make, on average, about 1000
connections or synapses, at which communication occurs with other neurons.
The range of synapses per cell is very large; the Purkinje cells of the
cerebellum may receive 100,000 contacts from input cells. Overall the human
brain may contain between 10^(14) and 10^(15) synaptic connections.

3) The diverse chemical substances that carry information between neurons are
called "neurotransmitters". Otto Loewi (1873-1961) discovered the first
neurotransmitter in 1926 when he demonstrated that acetylcholine carried a
chemical signal from the vagus nerve to the heart that slowed the cardiac
rhythm. Since that time, more than one hundred substances and a far larger
number of receptors have been implicated in synaptic transmission. Because of
the remarkably diverse effects of neurotransmitter-mediated signaling at the
receptor and post-receptor levels, the number of neurotransmitters, as large
as it is, vastly understates the complexity of signaling in the brain.

4) In the nervous systems of higher animals, only a small fraction of neurons
are directly involved in transducing sensory information or controlling
output cells, such as endocrine, smooth muscle or striated muscle cells. The
vast majority form what Nauta [2] called the great intermediate net, which
underlies the extraordinary computational power of the brain. The complex set
of neuronal networks interposed between input and output neurons form the
basis, inter alia, for learning complex motor sequences, for thought,
emotion, for "top down" behavioral control and, in humans, for such functions
as language, writing poetry and planning wars.

5) In addition to performing present-oriented computations, the nervous
system is plastic; it alters itself (forms memories) as it processes
information, so that it can respond more adaptively in the future. The
subtlety and complexity of the brain's outputs, along with its ability to
change in response to new information, is supported by a rich set of
mechanisms for cell-cell communication involving, at an anatomical level,
intricate but plastic local connections, larger scale neural circuits, and
overlying global regulatory systems; and at the chemical level, a large
number of neurotransmitters with highly diverse mechanisms for decoding their
informational content.[3-5]

References (abridged):

1. Masland, R.H. (2004). Neuronal cell types. Curr. Biol. 14, R497-R500

2. Nauta, W. (1986). Fundamental Neuroanatomy. (New York: Freeman)

3. Nestler, E.J., Hyman, S.E. and Malenka, R.J. (2001). Molecular
Neuropharmacology: Foundation for Clinical Neuroscience. (New York: McGraw
Hill)

4. Malenka, R.C. (2003). The long-term potential of LTP. Nat. Rev. Neurosci.
4, 923-926

5. Trachtenberg, J.T., Chen, B.E., Knott, G.W., Feng, G., Sanes, J.R.,
Welker, E. and Svoboda, K. (2002). Long-term in vivo imaging of
experience-dependent synaptic plasticity in adult cortex. Nature 420, 788-794

Current Biology http://www.current-biology.com

--------------------------------

Related Material:

NEUROBIOLOGY: ON SYNAPTIC VESICLES

The following points are made by W.J. Tyler and V.N. Murthy (Current Biology
2004 14:R294):

1) Chemical synapses provide the predominant form of fast functional
information transfer between neurons in the brain. Synaptic transmission is
initiated in a presynaptic neuron when neurotransmitter-containing vesicles
release their contents into the synaptic cleft that physically separates the
presynaptic and postsynaptic neurons. The released neurotransmitter molecules
then bind to their cognate receptors on the postsynaptic neuron, eliciting an
array of chemical and electrical changes. Early physiological studies made
profound contributions to our understanding of the discrete (quantal) nature
of neurotransmitter release and its calcium-dependence. Over the past two
decades, our knowledge of synapse operation has been advanced by molecular
biological, genetic and biochemical analyses

2) The presynaptic terminal is a compartment where
neurotransmitter-containing vesicles cluster near a highly specialized region
of the plasma membrane called the "active zone". From there, vesicles release
their contents during synaptic transmission. There are exceptions to this
general architecture -- for example, presynaptic specializations can occur in
dendrites rather than in axons and there are synapses specialized for
continuous release that do not have conventional active zones, but have
"ribbons". Before neurotransmitter release can occur from a given release
site, synaptic vesicles must be sorted, translocated to the active zone, dock
and be primed for fusion. Synaptic vesicle recycling is an integral feature
of presynaptic function.

3) The presynaptic terminal contains all the necessary molecular machinery
that permits it to function as an autonomous, subcellular compartment highly
specialized for local vesicle trafficking and recycling. In fact, when axons
are severed from their soma, the terminals are capable of remaining
functional for quite some time. In addition to synaptic vesicles, the
presynaptic terminal is enriched with components required for both exocytosis
and endocytosis: these include specialized neurotransmitter transporters to
repackage empty vesicles; endosome organelles that might mediate some aspects
of vesicle recycling; elements of smooth endoplasmic reticulum that may
regulate intracellular Ca2+; mitochondria to meet the energy demands placed
on the vesicle cycle; and a matrix of cytoskeletal elements and scaffolding
proteins thought to facilitate synaptic vesicle sorting. A large number of
cytoplasmic and plasma membrane proteins that appear to play regulatory roles
are also found in synapses.

4) Typical presynaptic terminals in the mammalian forebrain contain about 200
synaptic vesicles. Under resting conditions, less than half of these vesicles
participate in synaptic transmission. It is unclear why the remaining
vesicles do not participate in the synaptic vesicle cycle. A subset of the
recycling vesicles -- about 10 typically -- are in apparent contact with the
active zone and are called "docked vesicles". Whereas docked vesicles can
only be observed through ultrastructural examination, they are thought to be
the morphological correlate of a physiologically defined "readily releasable
pool". Members of the readily releasable pool are the first vesicles to
undergo fusion upon invasion of an action potential into the presynaptic
terminal.(1-5)

References:

1. Ceccarelli, B., Hurlbut, W.P., and Mauro, A. (1973). Turnover of
transmitter and synaptic vesicles at the frog neuromuscular junction. J. Cell
Biol. 57, 499-524

2. Heuser, J.E. and Reese, T.S. (1973). Evidence for recycling of synaptic
vesicle membrane during transmitter release at the frog neuromuscular
junction. J. Cell Biol. 57, 315-344

3. Murthy, V.N. and De Camilli, P. (2003). Cell biology of the presynaptic
terminal. Annu. Rev. Neurosci. 26, 701-728

4. Rettig, J. and Neher, E. (2003). Emerging roles of presynaptic proteins in
Ca++-triggered exocytosis. Science 298, 781-785

5. Royle, S.J. and Lagnado, L. (2003). Endocytosis at the synaptic terminal.
J. Physiol. 553, 345-355

Current Biology http://www.current-biology.com

--------------------------------

NEUROBIOLOGY: ON SYNAPTIC NEUROTRANSMITTER RELEASE

The following points are made by S.O. Rizzoli and W.J. Betz (Nature 2003
423:591):

1) Synaptic transmission -- the transfer of information between nerve cells
-- is the most important aspect of brain function. Roughly speaking, it works
as follows. When electrical impulses propagate to the end of a neuron, they
evoke the release of chemicals called "neurotransmitters". These diffuse to a
nearby neuron and trigger further electrical activity. The neurotransmitters
are stored inside the neuron in small, membrane-bounded vesicles(1) -- rather
like a soap bubble within a larger soap bubble -- and they are released en
masse through a pore that forms when the vesicle membrane fuses with the
neuron's surface membrane. It is well established that the vesicle membrane
can then collapse into and coalesce with the surface membrane; after that, it
can reform and be reused.

2) But the retrieval of membrane components from collapsed vesicles is
complex(2), and a different theory, called "kiss-and-run", envisions no
vesicular collapse at all; instead, a fusion pore flickers open and then
closes. Although the economy of this concept holds considerable intuitive
appeal(3), and it is known to occur in secretory processes in other cells(4),
solid quantitative evidence of kiss-and-run fusion at conventional synapses
has been virtually absent -- until recently. Gandhi and Stevens(5) used
different fluorescent markers to track the fate of individual synaptic
vesicles, following a single electric shock, in living neurons from the
hippocampal region of rat brains. The evidence is that a large fraction of
neurotransmitter-release events involve kiss-and-run, not vesicle collapse.

3) Gandhi and Stevens(5) studied these events by using genetic tools to load
synaptic vesicles with synaptophluorin, a pH-sensitive fluorescent protein
that is attached to a protein in the vesicle membrane. In resting vesicles,
the pH is low and the fluorescence of synaptophluorin is quenched. But upon
exocytosis -- vesicle fusion with the surface membrane -- the interior of the
vesicle becomes open to the solution outside the neuron, allowing protons to
escape and so raising the pH. Synaptophluorin then fluoresces brightly, and
does so until vesicle retrieval (endocytosis) and reacidification occur.

References (abridged):

1. Katz, B. The Release of Neural Transmitter Substances (Liverpool Univ.
Press., 1969)

2. Heuser, J. E. & Reese, T. S. J. Cell Biol. 57, 315-344 (1973)

3. Ceccarelli, B. & Hurlbut, W. P. Physiol. Rev. 60, 396-441 (1980)

4. Alvarez de Toledo, G., Fernandez-Chacon, R. & Fernandez, J. M. Nature 363,
554-558 (1993)

5. Gandhi, S. P. & Stevens, C. F. Nature 423, 607-613 (2003)

Nature http://www.nature.com/nature

ScienceWeek http://scienceweek.com 

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