Download Neuronal signaling and synapses

Neurotransmitters (L7)
Neuronal
signaling and
synapses
-incoming signals enter the neuron through synapses located mostly on neuronal
dendrites, specifically on dendritic spines
-combining their effects determines whether/how often to fire an action potential 
ability to compare & combine different inputs is responsible for the computational
power of the NS
-output signals travel by way of a single axon leaving the neuron  can be excitatory or
inhibitory
ELECTRICAL SYNAPSE
-direct spread of current from one neuron to another through gap junctions – relatively
rare in adult NS
-advantages  presynaptic signal is duplicated in postsynaptic cell; no delay in
transmission of signal; no need to synthesize vesicles & neurotransmitters
-disadvantages  partial loss of functional individuality in coupled neurons
-modulation
**found in horizontal cells of the retina
CHEMICAL SYNAPSES & NEUROTRANSMITTERS
-neurotransmitters  neuroactive chemical transmitters that allow communication
between two cells
*can be small molecules, larger peptides, or diffusible gases
*first chemical synapse to be described was the neuromuscular junction (a nervemuscle synapse in which the neurotransmitter is acetylcholine, or Ach)
-a single presynaptic terminal (usu. an axon) on the postsynaptic membrane (usu. A
dendrite) of another neuron, separated by a synaptic cleft
-transmitter vesicles & mitochondria are important to the excitatory or inhibitory
functions  transmitter substances released from the transmitter vesicles either excite
or inhibit the postsynaptic neuron depending on whether the neuron contains excitatory
receptors or inhibitor receptors, respectively
*mitochondria provide ATP that supplies energy for neurotransmitter synthesis
ELECTRICAL VS. CHEMICAL SYNAPSE
Neurotransmi -7 steps of synaptic transmission:
1.synthesis & storage
ssion
2.action potential & depolarization
3.activation of voltage-dependent Ca2+ channels
4.vesicle fusion & release
5.receptor binding
6.signal termination in the synaptic cleft
7.termination of postsynaptic intracellular signaling
Postsynaptic
effects of
neurotransmi
tters
Neuromuscul
ar junction
-receptor proteins contain  a binding component for the neurotransmitter that
protrudes into the synaptic cleft; a transmembrane component, either:
*an ion channel allowing passage of specific ion types OR a second messenger
activator that extends into the cell cytoplasm & activates one or more substances within
the postsynaptic neuron
-somatic neuron axons are myelinated by Schwann cells
-each motor axon terminal has clusters of vesicles filled with ACh  AP causes vesicles
to fuse with the terminal membrane
*diffuses across synaptic cleft and through the basal lamina to reach postsynaptic
receptors at troughs in the muscle surface across from vesicle clusters
-presynaptic ending at each neuromuscular junction contained about 1000 active zones
-a single AP in the motor axon  simultaneous release of hundreds of vesicles full of Ach
at closely spaced sites  large EPSP
-selective concentration of receptors on the postsynaptic membrane ensures that fast
PSPs are spatially localized/restricted
Receptors
-neurotransmitter removal – Ach is split into acetate & choline by acetylcholinesterase in
the synaptic cleft; choline is then transported back to the presynaptic ending for further
synthesis of ACh
-ionotropic receptors  fast-acting, transmitter-gated ion channels
-metabotropic receptors  slow synaptic transmission; binding of neurotransmitter
leads to altered concentrations of second messengers
*modulates channel conductance; most are G protein-coupled receptors
-the effect that a neurotransmitter has is determined by the receptor to which it binds
*there are multiple receptors for most neurotransmitters – thus each is capable of
different effects
*the many subtypes of receptors make it possible to design drugs that target specific
neuronal subsystems
-AChR is a ligand (transmitter) – gated channel on the postsynaptic membrane
-2 main categories of AChRs  nicotinic & muscarinic
-nicotinic (ionotropic receptor) only AChR found at neuromuscular junctions  can
produce muscle contraction (fast EPSP)
-muscarinic (metabotropic, G protein-coupled receptor) found on smooth & cardiac
muscle fibers & on many neurons  can produce a decrease in HR through increased
opening of K+ channels & slow IPSP
-ion channels  short-term effects (close within ms)  cation channels allow mainly
Na+ though (sometimes K+ and Ca2+)
*open cation channels excite the neuron; thus neurotransmitters that open cation
channels are excitatory
*anion channels allow mainly Cl- ions though  open anion channels inhibit the
neuron; opening anion channels are inhibitory
SECOND MESSENGER SYSTEMS
-four main types of changes can occur with the activation of metabotropic receptors
-opening specific ion channels through the postsynaptic cell member – e.g. opening of a
potassium channel (prolonged opening)
-activation of cAMP or cGMP in the neuron can activate metabolic processes that result
in changes in cell structure that alter long term excitability
-activation of one or more intracellular enzymes
-activation of gene transcription can initiate formation of new proteins within the
neuron that change the metabolic activity or structure
**on activation by a nerve impulse, the alpha portion of the G-protein separates from
the beta & gamma portions and is free to move within the cell cytoplasm
Neuronal
plasticity
-ability to alter neuronal connections d/t experience  existing synapses can be altered
for long periods (hours/days) and maintained; new synaptic connections can form
-learning & memory
-repetitive stimulation of neuronal synapses can alter the strength of synaptic
connections
*short-term increases in strength are known as facilitation or potentiation
*short-term decreases in strength includes depression, which can occur d/t highfrequency stimulation, and habituation (a slowly progressing decrease as a result of lowfrequency activation)
Long-term
potentiation
(LTP)
-establishment and modification of neuronal networks (through both excitatory &
inhibitory synaptic transmission) are vital for normal brain functioning
-potentiation  elevated Ca2+ increases the odds of vesicle exocytosis the next time an
AP arrives at the terminal
-LTP  repetitive stimulation of a particular synapse eventually leads to an increase in
the strength of the synaptic connection
*first discovered in hippocampus
*learning & memory
*depends on activation of glutamate receptor
*can involve long-term increases in transmitter release, postsynaptic sensitivity (# of
receptors), or both
-neurons that fire together, wire together
-strong candidates for synaptic changes in learning & memory
-spines are connected to the dendrite by a narrow neck  small changes to diameter of
neck could lead to large changes in a spine’s electrical properties, ability to maintain
altered concentrations of second messengers
Long-term
depression
-shapes & numbers of dendritic spines change when learning occurs
-specific synaptic connections are weakened
-can result from  strong synaptic stimulation (e.g. purkinje cells in the cerebellum;
motor learning); persistent (low-frequency) weak synaptic stimulation (as in the
hippocampus)
-LTD thought to result from decrease in postsynaptic receptor density; also decrease in
presynaptic neurotransmitter release
*e.g. high-frequency bursts of APs can delete the synaptic vesicle pool, thereby
decreasing the odds of synaptic vesicle exocytosis to the synaptic cleft
Modulatory
systems
-together, LTD & LTP affect neuronal plasticity
*LTD selectively weakens specific synapses to optimize synaptic strengthening caused
by LTP (otherwise, LTP might go unchecked, increasing to a maximum level and hinder
encoding of new information)
-systems of neurons influence the excitability states of other networks within the CNS &
alternations in modulatory systems produce a wide range of psychiatric disorders
-neuropeptides (neuroactive peptides) usu. stored & released froim the same neurons as
Large
one of the small neurotransmitters
molecule
neurotransmi
-metabolically expensive; present and effective at low concentrations
tters
-endorphins (endogenous substance with morphine-like actions)
-substance P  originally described as a smooth muscle relaxant isolated form gut, has
been localized in synaptic endings in basal ganglia & DRG
-enkephalins  prominent role in pain-control circuitry
-small neurotransmitters are each stores & released by separate sets of neurons and
Small
include:
molecule
*amino acids – glutamate, GABA, & glycine
neurotransmi
*biogenic amines – acetylcholine, serotonin, histamine, dopamine, norepinephrine,
tters
epinephrine
*purine derivatives – ATP  found in many neurons and other cell types; they can be
released as a co-transmitter with other neurotransmitters
Synaptic
communicati
on
-variation in communication
-use of different neurotransmitters
-presence of several different types of receptors
-activation of different down-stream pathways via these receptors
-difference in time course of synaptic interaction
Cholinergic
pathway
-cholinergic  acetylcholine, Ach, mediates rapid, point-to-point transmission in PNS
*mainly excitatory effect, sometimes inhibitory
-cholinergic neurons of the CNS are brainstem, basal forebrain, and basal ganglia 
regulate general activity level of CNS neurons, particularly during phases of sleep-wake
cycle and during learning
Monoamines
Noradrenergi -norepinephrine = noradrenaline, noradrenergic projection system
c pathways
-norepinephrine affects entire CNS
*NE activates mostly excitatory receptors, some inhibitory receptors
*secreted by postganglionic neurons of the sympathetic nervous system  fight or
flight; arousal, attention, stress/panic
-main locations of neurons that (cell bodies) produce NE; locus ceruleus, lateral
tegmental area, reticular formation of the brainstem  alertness, mood
-medulla oblongata area of the brainstem also contains adrenaline containing neurons
(C1-C3); these neurons have very few projections into higher brain regionals & play a
role on descending transmission & the autonomic nervous system
LOCUS CERULEUS
-meaning the dark blue spot, a named derived from its blue appearance in unstained
brain tissue
-the color is d/t light scattering from melanin in noradrenergic (producing or activated by
norepinephrine) nerve cell bodies
-involved with physiological response to stress & panic
-principal site for brain synthesis of norepinephrine (noradrenaline)
Dopaminergic -dopamine-containing neurons are scattered throughout the CNS
pathways
-substantia nigra – midbrain; projects to the striatum (caudate & putamen) facilitating
voluntary movement  degeneration of dopaminergic cells in the substantia nigra
produces Parkinson’s disease
-ventral tegmental area – midbrain; projects to part of the forebrain (prefrontal cortex)
and parts of the limbic system  implicated in neural systems that mediate
reinforcement or reward as well as aspects of drug addiction and psychiatric disorders
(schizophrenia)
-members of the class of antipsychotic drugs called neuroleptics are antagonists of
certain dopamine receptors
-substantia nigra
Substantia Nigra
DOPAMINERGIC AGENTS
-cocaine blocks reuptake of norepinephrine & dopamine
-amphetamine causes enhanced neurotransmitter release (norepinephrine & dopamine)
Serotongergic -serotonergic raphe neurons associated with mood control  LSD exerts effects through
serotonergic systems
pathways
-depression
*SSRIs used to treat (Prozac) block serotonin reuptake, prolonging serotonin effect in
the brain
-MAOIs prevent breakdown of serotonin
-serotonin projections also reach cranial blood vessels within the brain & pia mater
where it cause vasoconstriction
*also go to the thalamus (sensory integration) & hypothalamus (eating, sleeping,
temperature)
-SSRIs  block reuptake into presynaptic terminal, keeping serotonin in the synapse
longer
-MAOIs  monoamine oxidase inhibitors; inhibit the activity of the monoamine oxidase
enzyme family, preventing breakdown of serotonin
Histaminergic -VLPO – ventrolateral proptic nucleus of the hypothalamus is the contral center for
arousal & sleep
pathways
-histamine regulates autonomic & neuroendocrine activities such as feeding, drinkin, &
temperature; it can also regulate behavoris such as locomotion and arousal
Excitation vs.
inhibition
-modulatory synapses  neuromodulator + membrane receptor + G-protei 
intracellular signal cascade
-excitatory synapses  glutamate binds to fast, ligand-gated cation channels to
generate and EPSP
-inhibitory synapses  GABA or glycine binds to ligand-gated anion channels to
generate IPSPs
-fast excitatory
*PNS – Ach (nicotinic receptors)
*CNS – glutamate
-fast inhibitory
*GABA (GABAA, mostly in brain)
*glycine (mostly in spinal cord)
Glutamate &
GABA
-glutamate  the major transmitter for fast, brief, excitatory synaptic events in CNS
*one of the transmitters at about 90% of CNS synapses
*acts on 4 major types of receptors, 1 metabotropic *G-protein coupled) and 3
ionotropic (AMPA, NMDA, & kainite)
*NMDA – responsible for some forms of long-term potentiation (LTP)
-GABA (ʏ-aminobutyric acid) & glycine  the major transmitters for fast, brief,
inhibitory synaptic events in CNS
*glycine localized to spinal cord; GABA everywhere
**NMDA (N-methyl-D-aspartate)
**AMPA (a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)
EXCITOTOXICITY
-normally, glutamate is rapidly taken back up into presynaptic terminal or surrounding
glia so that postsynaptic exposure is minimized
-prolonged exposure to glutamate (through excessive release or deficient reuptake) can
injure or kill neurons – excitotoxicity
*initiated by excessive Ca2+ entry through NMDA receptors
-brain damage in stroke may involve release of toxic amounts of glutamate in response
to anoxia
GABA RECEPTORS
-GABAA  ionotropic receptors permeable to CL-b/c of the need for control of inhibition, GABAA receptors have other binding sites for
different chemicals
*the probable natural modulators of GABAA receptor are the metabolites of
progesterone, corticosterone, & testosterone
*benzodiazepines (i.e. diazepam- Valium) increase the frequency of channel opening &
can increase the Cl- conductance of the GABAA receptor
*barbiturates (i.e. phenobarbital) increase the duration of channel opening
- GABAA receptor  G-protein coupled metabotropic receptor  linked to either the
opening of K+ or suppression of Ca2+ channels
Key concepts
-steps in chemical synaptic transmission & Ca2+ involvement
-neuromuscular junctions & Ach
-ionotropic & metabotropic receptors
-cholinergic, noradrenergic, dopaminergic, serotonergic, histaminergic, projection
systems (primary locations of cell bodies, functions, & drugs that act on these systems)
-glutamate & GABA
-any clinically relevant details