most As things in Neuroscience, it all
begins with Santiago Ramon y Cajal
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1852-1934
Nobel Prize 1906
But Cajal could not have done it without
Camilo Golgis staining method
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1852-1934
1843-1926
Nobel Prize 1906
Nobel Prize 1906
Otto Loewi discovered neurotransmission
(1873-1961)
Nobel 1936
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Bernard
Katz
(1911-2003)
Nobel 1970
The neuromuscular junction
is the synapse made between a
motor neuron and a muscle fiber
and is a very large synapse.
The synaptic region on the muscle
fiber has a special name, the
END-PLATE
Basallamina
From Wes Thompson
Stimulation of the nerve always excites skeletal muscle fibers. It generates a
synaptic potential that is so large, that it always exceeds threshold and
generates an AP in the muscle fiber
The synaptic
potential at the
neuromuscular
junction is called
an end-plate
potential (EPP).
Katz discovered miniature end-plate
potentials
Stimulate nerve
Trial 1
Spontaneous
miniature
end plate
potentials
(mepp)
Trial 2
Etc.
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No stimulation:
Record spontaneous
Miniature endplate potentials
(MEPPS)
Evoked endplate potentials
from muscle bathed in very
low Ca++ solution
Distribution of sizes of
evoked endplate potentials
from muscle bathed in very low Ca++
Poisson distribution:
independent events, low
frequency of occurrence.
Distribution of sizes of
miniature endplate potentials (MEPPS)
recorded from muscle fiber
when nerve was not stimulated
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Synapse-specific variation in amount
of transmitter release
Hundreds of vesicles are released at the NMJ in
order that the postsynaptic cell (the muscle) reaches
threshold for an action potential.
One or a few synaptic vesicles are released at
synapses in the brain so that the inputs can be
averaged and the neuron can decide whether to
make an action potential or not.
Transmitter is loaded in and released from
presynaptic vesicles
Pre
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Post
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cleft
Vesicles fusing with
presynaptic membrane
figure
Calcium channels are adjacent to presynaptic
vesicles
Fusing vesicles
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Calcium channels
Freeze fracture of presynaptic face
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Calcium channels
Calcium levels fall-off rapidly a few microns
away from the channel: calcium microdomains
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Ca2+ channel
The steep fall-off is often aided by Ca2+ buffering proteins such as
parvalbumin, calbindin that capture and shuttle away unbound Ca2+.
Calcium levels fall-off rapidly a few microns
away from the channel: calcium microdomains
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Snare proteins are critical for vesicle docking
and release.
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Why do bacteria make toxins that block
synaptic transmission?
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Why do bacteria make toxins that block
synaptic transmission?
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Clostridium tetani
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Clostridium botulinum
Anaerobic bacteria that live in the soil
Why do bacteria make toxins that block
synaptic transmission?
Zakons hypothesis: protection from bacteriophagic nematodes?????
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Fusion of synaptic vesicles make use of a
phylogenetically ancient mechanism
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Exocytosis (yeast)
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Fusion of endosomes
(mammalian cells)
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Fusion of vacuolar
vesicles (yeast)
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Life cycle of a synaptic vesicle
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AP180 promotes the formation of homogeneously-sized vesicles
Clathrin Cages Assembled
in vitro Without AP180
Clathrin Cages Assembled
in vitro With AP180
Ye & Lafer, J. Neurosci. Res. 41, 15-26, 1995.
Synaptic Vesicles in Drosophila
Lacking Fly AP180 Gene lap
Synaptic Vesicles in Wild Type Drosophila
Containing Fly AP180 Gene lap
Zhang et al., Neuron 21, 1465-75, 1998.
Synaptic vesicles are
specialized cellular vesicles
Clathrin and other proteins assure uniform
vesicle size: beneficial for quantal
transmission at central synapses.
Calcium-dependent fusion: slower
constituitive cycling of vesicles within cells
does not depend on Ca2+. Regulated by
neural activity.
Categories of Neurotransmitters
Small
molecules (including monoamines)
DA (dopamine), NE*, E*, 5-HT (5-hydroxytryptamine), ACh
*adrenaline=epinephrine, noradrenaline=norepinephrine
Amino acids and their derivatives
Glu, Asp, GABA, Glycine, Histamine
Neuropeptides (~100)
Leu-enkephalin (ENK), met-ENK, -endorphin (END), -END,
Sub P, somatostatin, thyrotropin release hormone (TRH),
lutenizing hormone release hormone (LHRH), angiotensin,
vasopressin, oxytocin, cholecystokinin (CCK), vasoactive
intestinal peptide (VIP), Neuropeptide Y, Neurotensin (NT),
Bombesin, endocannabinoids, etc.
Soluble gases
Nitric oxide, carbon monoxide
Purines
adenosine, ATP
Why so many transmitters?
Why so many transmitters?
Define functional circuits: i.e.--oxytocin activation
of uterine muscles and central control of maternal
behavior.
Generate variation in postsynaptic response
magnitude or duration.
Allows greater complexity of cellular integration.
What are the most common
neurotransmitters in the brain?
What are the most common
neurotransmitters in the brain?
Glutamate is the most common excitatory
transmitter in the brain.
GABA is the most common inhibitory
transmitter (the major inhibitory transmitter in
the brainstem and spinal cord is glycine).
Hormones vs neuromodulators vs
neurotransmitters.
Hormones released at a distance; travel via blood.
Neuromodulators released in vicinity without postsynaptic sites
nearby; diffuse in extracellular fluid to reach target.
Neurotransmitters released right onto postsynaptic sites.
presynaptic
hormone
modulator
transmitter
postsynaptic
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Ionotropic vs metabotropic
Ionotropic receptor: receptor and channel are part
of the same molecular structure, transmitter rapidly
gates channel open, transmitter leaves receptor
and channel closes.
Metabotropic receptor: receptor is separate
molecular entity than channel, receptor initiates
second messenger cascade to activate channel,
response is usually long lasting.
Ionotropic
transmitter
ions
Metabotropic
transmitter
ions
Divergence and convergence
of neurotransmitter receptors
Divergence: An ancestral receptor has diversified
into the GABA, glycine, serotonin (5HT3), and
nicotinic acetylcholine receptor superfamily.
Same receptor evolved binding sites for different
ligands.
Convergence: GABA, serotonin, acetylcholine,
glutamate have both ionotropic and metabotropic
receptors. That is, binding sites for these
neurotransmitters have evolved independently in
each receptor family.
Acetylcholine Receptor
Serotonin Receptor
Dent, 2006
Histamine Receptor, invertebrate
GABA Receptor
Glycine Receptor
Dent, 2006
Many neurotransmitters have both
ionotropic and metabotropic receptors.
Same transmitter
ions
Most neurotransmitters have both
ionotropic and metabotropic receptors
Glutamate
GABA
Serotonin
Acetylcholine
Histamine (vert receptors are
metabotropic, invertebrate receptors are
ionotropic)
Purinergic (ATP)
What to know
Classes of neurotransmitters.
Life cycle of classical neurotransmitter.
Life cycle of synaptic vesicles.
Calcium and transmitter release.
Synaptic vesicles are specialized (Ca2+-dependent)
cellular vesicles.
Ionotropic vs metabotropic receptors
Convergence and divergence of neurotransmitter
receptors.