Craviso: CNS Neurotransmission Flashcards
T/F: Average neuron forms ~ 1000 synaptic connections and receives even more
True
What is the activity of a neuron dependent on?
the ratio of excitatory to inhibitory inputs to that neuron
What are the small molecules involved in CNS functioning?
serotonin norepi dopamine ACh histamine
neurotransmitter; sleep, arousal, mood, appetite
serotonin
neurotransmitter; mood, arousal, appetite
norepi
neurotransmitter; movement (motor control), behavior, mood, perception
dopamine
neurotransmitter; arousal, cognition (memory and learning)
ACh
neurotransmitter; wakefulness, equilibrium
histamine
Excitatory amino acid neurotransmitter
glutamate (glutamic acid)
Inhibitory amino acid neurotransmitters
GABA
glycine
Neuropeptides involved in pain transmission
methionine
leucine enkephalin
substance P
Endocannabinoids involved in memory, cognition, and pain perception
anandamide
2-arachidonylglycerol
**post-synaptic neurons make endocannabinoids and they are retrograde NTs
Pattern of neuronal connectivity: Transmission is highly sequential and interconnected neurons are related to each other in a hierarchical fashion - e.g., primary sensory and motor pathways
Pain transmission!
long-hierarchical (relay)
Pattern of neuronal connectivity:
Neurons from a single anatomical location extend multiple, divergent connections to target cells outside the region in which the neurons originate
non-hierarchical, projecting
ex: serotonin, norepi, dopamine, ACh, 5HT
Where do serotonin neurons project from?
raphe nucleus
Functions of 5HT (serotonin)
sleep, arousal, mood behavioral changes hallucinations feeding behavior vomiting
Where do norepinephrine neurons project from?
locus coeruleus
Functions of norepinephrine
arousal and mood (frontal cortex)
appetite (hypothalamus)
cardiovascular control
Where do dopamine neurons project from?
midbrain
striatum
hypothalamus
Functions of dopamine
mood behavioral changes motor control (nigrostriatal pathway) neuroendocrine function vomiting
Where do ACh neurons project from?
forebrain and brainstem
Functions of ACh
arousal
learning and memory (think of Alzheimer’s disease)
motor control (nigrostriatal pathway)
The effects of cholinergic neurons can be via (blank) (GPCR) receptors or (blank) (ionotropic) receptors located presynaptically
muscarinic; nicotinic
Where do histamine neurons project from?
hypothalamus
Functions of histamine
arousal and wakefulness
equilibrium
effects on synthesis, storage, release, reuptake and/or degradation of neurotransmitters; agonist or antagonist activity at nerve terminal autoreceptors
pre-synaptic mechanisms by which neurotransmitters are modulated
receptor agonist, antagonist or modulatory activity; degradation of neurotransmitters
post-synaptic mechanisms by which neurotransmitters are modulated
**ACh is inactivated by degradation
With these receptors, responses occur within several hundreds of milliseconds and last for seconds and even minutes
GPCRs (metabotropic receptors)
Some metabotropic receptors (GPCRs)
all alpha and beta adrenergic receptors (norepi receptors)
dopamine
muscarinic ACh
histamine
neuropeptide and endocannabinoid receptors
most 5HT receptors (except those involved in vomiting)
metabotropic glutamate and GABA receptors
How to GPCRs work?
- neurotransmitter binds
- activates G-protein
- G-protein intracellular messengers modulate ion channels
- ion channels open
- ions flow across membrane
Ionotropic receptors are also called (blank)
ligand-gated ion channels
Where are most ionotropic receptors found?
at neuromuscular junctions
With these receptors, responses occur within a few milliseconds and last for only MILLISECONDS
ionotropic receptors
Which receptors DEPOLARIZE cells? What ion is involved?
AMPA *Na ion channel kainate *Na ion channel NMDA *Ca++ and Na nicotinic ACh receptors 5HT3 receptors (vomiting) *Na
**Na+ or Ca++ are involved
Which receptors HYPERPOLARIZE cells? What ion is involved?
GABA-A and glycine receptors
**Cl- ion channels
How do ionotropic receptors work?
- neurotransmitter binds directly to channel
- channel opens
- ions flow across membrane
So, which occur more quickly, metabotropic or ionotropic receptor reactions? Which have longer lasting effects?
ionotropic are faster; metabotropic last longer
Amino acid neurotransmitters mediate major excitatory inputs via (blank) and inhibitory inputs via (blank)
glutamate; GABA
Excitatory transmission is balanced by feed-forward and recurrent inhibitory actions of (blank) released from interneurons
GABA
Inputs to neurons are paired to achieve a coordinated balance between excitatory and inhibitory events, but (blank) neuro-transmission predominates
inhibitory
T/F: Interference of the relationship b/w excitatory and inhibitory neuro-transmission is highly disruptive
True
**can cause two extremes - comatose or seizures
synthesized from glutamate, by glutamic acid decarboxylase that requires pyridoxal phosphate
GABA
What is GABA metabolized by in the mitochondria of neurons and glial cells?
GABA-amino transferase
What is unique about endocannabinoid transmission?
retrograde transmission - synthesized in post synaptic neuron
What does GABA bind to?
metabotropic receptors in nerve terminal which can modulate GABA release
ionotropic GABA receptors postsynaptically, they will enhance the actions of GABA
There is a high conc of these receptors in the spinal cord
GABA-B receptors
an agonist at GABAB receptors, is used for treating spasticity (involuntary and abnormal muscle contractions) in individuals with amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS)
Baclofen (Lioresal)
When GABA binds, you are conducting (blank)
Cl-
What does GABA do to cells?
hyperpolarizes
The majority of GABAs effects are mediated by (blank) receptors
GABA-A
Contrast phasic and tonic neurotransmission
tonic - continuous activation of extra-synaptic receptors
phasic - rapid, synchronous opening of channels in synaptic cleft; resolves in time and space
What is this?
GABA gets released, and diffuses outside the synaptic cleft - binds to high affinity receptors and causes continuous activation of extra-synaptic receptors
tonic inhibition
Glycine are (blank) conducting ion channels
Cl-
occurs in nature in certain seeds; an ingredient in rat poison; an antagonist of glycine neurotransmission and a powerful convulsant!
strychnine
**causes seizures when you block inhibitory neurotransmitters
What happens to glutamate after its release?
reuptake occurs via transporters present on nerve terminals and astrocytes (mostly astrocytes) - glutamate is converted to glutamine
These cells are responsible for much of the uptake and regulation of glutamate
glial cells
2 types of non-NMDA glutamate receptors
AMPA receptors
Kainate receptors
primarily Na+ - conducting ion channels; some receptors also permeable to Ca2+
mediate the majority of excitatory synapses
play a major role in neural plasticity
AMPA receptors
primarily Na+ - conducting ion channels; some receptors also permeable to Ca2+
Located both pre- and post-synaptically
physiologic role not known but play a role in neural plasticity
Kainate receptors
Ionophores that conduct primarily Ca2+; also conduct Na+
Are essential mediators of neural plasticity and are capable of converting specific patterns of neuronal activity into long-term changes in synapse structure and function (e.g., play a role in learning and memory)
NMDA glutamate receptors
What is an essential co-agonist necessary for NMDA receptors to be activated by glutamate?
glycine!!!
What blocks the NMDA channels and must be overcome with a strong depolarizing stimulus to activate the NMDA receptors?
magnesium
What two things must happen for NMDA receptors to be activated?
- simultaneous binding of two agonists (glutamate and glycine)
- strong enough depolarization to overcome Mg2+ block
What is neural plasticity?
the constant pruning and altering of neuronal dendritic connections; mostly due to the actions of glutamate
Increases sensitivity of post-synaptic neurons to glutamate
long-term potentiation
Decreases sensitivity of post-synaptic neurons to glutamate
long-term depression
How do NMDA receptors mediate neural plasticity?
If NMDA receptors are being activated more frequently, the number of AMPA receptors will increase and will cause a stronger, quicker response. Also, with increasing Ca++ due to activation of NMDA receptors, genes will be turned on that can change the synapse structure and make for stronger synaptic connections
If NMDA receptors are not being activated frequently, AMPA receptors will be internalized and there will be weaker synaptic connections
Excessive activation of NMDA glutamate receptors causes (blank)
excitotoxicity
What is excitotoxicity?
too much activation of NMDA –> too much Ca++ coming in –> activates a lot of cellular processes –> NO and other free radicals build up –> leads to death of neurons
