Transcript Cholinergic neuronal “Growth factors”

Cholinergic synapses - physiology
and pharmacology
1. Autonomic ganglia
2. Nicotinic and muscarinic ACh receptors
3. The cholinergic system in brain
•role in cognitive function and learning
•effects of cholinergic drugs
•treatment of Alzheimer’s disease
See: www.dns.ed.ac.uk/teaching.html
(use Internet Explorer on a PC)
The autonomic nervous system
The sympathetic and parasympathetic divisions of the autonomic nervous
systems have contrasting effects on a variety of end-organs. Sympathetic
activity elicits ‘flight-or-fight’ responses (increased heart rate, decreased gut
motility, reduced gastrointestinal secretions), whereas Parsympathetic
activity is associate with a sense of satisfaction and well-being (increased
gastrointestinal secretions and motility; slow steady heart rate, etc).
Organisation of autonomic ganglia
Both Sympathetic and parasympathetic divisions employ
cholinergic preganglionic neurones to signal between the CNS
and autonomic ganglia. The signals relayed to the tissues from
postganglionic neurones employ ACh and other
neurotransmitters, such nor-adrenaline, peptides and nitric
oxide.
Recordings from autonomic ganglia
show complex responses.
Intracellular recordings from sympathetic ganglia reveal complex
synaptic responses mediated by ACh and other
neurotransmitters. The Fast EPSP, Slow IPSP, Slow EPSP are
all responses to ACh. The differences are due to the types of
receptors that expressed in the ganglion cell membranes. (The
Late Slow EPSP - lower right - is mediated by a peptide
neurotransmitter, not acting on ACh receptors).
Nicotinic ACh
Receptors
Nicotinic ACh receptors are responsible for Fast EPSP’s in the cholinergic sysem,
including the EPPs produced at the neuromuscular junction. All these receptors are
made up of 5 sub-units surrounding a central pore. Each sub-unit comprises a
polypeptide that spans the membrane 4 times, and the N- and C- terminals are
outside the cell. The number alpha sub-units varies. Nicotine is an agonist and either
hexamethonium or tubocurarine are antagonists for all these types of receptor.
Muscarinic
ACh Receptors
Muscarinic ACh receptors are responsible for Slow EPSP’s and Slow IPSP’s in the
cholinergic sysem. All these receptors are made up of a single sub-unit and there is
no channel directly associated with the receptor. The receptor comprises a
polypeptide that spans the membrane 7 times, and the N-terminus is outside and
the C- terminus is inside the cell. The inside contains a G-protein binding site, which
is activated when ACh binds to the receptor. Muscarine is an agonist and atropine is
an antagonists for all types of muscarinic ACh receptor.
Muscarinic ACh Receptors utilise
G-proteins to effect a response
Activation of the G-proteins associated with muscarinic ACh receptors has diverse
effects. The sub-units of the G-protein dissociate, and one of the sub-units can
directly activate potassium ion channels, leading to inhibition of cell firing. Other Gprotein sub-units activate enzymes in the cell, including protein kinases, and release
of Ca ions. Phosphorylation or Ca-activation of ion channels by these kinases can
lead to either depolarisation, hyperpolarisation, or metabolic changes in the cells.
Two alternative signalling pathways
follow muscarinic receptor activation
A more detailed view of the alternative mechanisms that are activated after ACh
binds to muscarinic receptors. Other neurotransmitters act on specific receptors
which have similar ‘metabotropic’ properties.
Muscarinic agonists:
Muscarinic antagonists:
The nature of the cholinergic receptor mediating an excitatory or inhibitory response can
be most easily distinguished pharmacologically. Muscarine or oxotremorine have no effect
on nicotinic ACh receptors. Likewise atropine blocks the response to ACh or ACh agonists
by muscarinic, but not nicotinic receptors. Pirenzepine blocks the M1 sub-type of
muscarinic receptor (found in the gut, for example) whereas gallamine (which also blocks
nicotinic receptors at the NMJ) has no effect on M1 receptors but blocks M2 muscarinic
receptors in the heart.
The brain also contains a network of cholinergic
neurones. Those with cell bodies in the basal forebrain
project to areas of the brain concerned with cognitive
function, memory and learning. Degeneration of
neurones in the cholinergic system occurs in presenile
dementia (Alzheimer’s disease) and this may contribute
to impaired cognitive function and learning,
characteristics of the disease
Cholinergic receptors are involved
in ‘spatial learning’
Morris Water maze
Evidence that cholinergic neurones play a role in memory and learning has been
obtained in behavioural experiments on rodents. These animals learn to navigate in
the Morris Water Maze - named after Richard G.M. Morris (Professof Neuroscience
at Edinburgh University) who devised the method - where the task is to find a
hidden platform (red arrow). The map(top right) shows a typical path adopted after
several trials at the task. But they take much longer to learn the location of the
platform after being given atropine, the muscarinic antagonist. The hippocampus is
strongly implicated as the region of the brain responsible for managing this form of
learning.
Cholinergic receptors are involved in
transmission in the hippocampus - a learning
centre in the brain
Donepezil
(Aricept)
Intracellular recordings from neurones in the hippocampus show a component of
their synaptic responses that is cholinergic. The synaptic potential is prolonged by
the anticholinesterase inhibitor physostigmine, and blocked by the muscarinic
antagonist atropine.
Donepezil (proprietary name Aricept) is a mild anticholinesterase acting on specific
for forms of cholinesterase expressed in the brain. It has been reported to have
mildly beneficial effects on the progression of Alzheimer’s disease.
Cholinergic neuronal “Growth factors”
Neurotrophins
NGF
BDNF
NT-3
NT-4
Cytokines
CNTF
FGF
GDNF
IGF
Growth factors are polypeptides which promote cell survival and stabilisation of
synapses. Different neurones express receptors for the different types of growth
factors. Those listed above have been reported to delay cell degeneration when
administered to cholinergic neurones from the brain, either in tissue culture or in
vivo. Neurotrophins are a related family whose members have homologous amino
acid sequences. NGF was the first “Nerve Growth Factor’ to be discovered.
Nerve growth factor treatment of old animals improves
survival of cholinergic neurones and enhances learning.
Old
Old-NGF treated Young
Backman et al. · Systemic Administration of OX-26-NGF Reverses Age-Related Cognitive Dysfunction
J. Neurosci., September 1, 1996, 16(17):5437–5442
In this report, NGF (coupled to a carrier that enabled it to be transported fron the
blood into the brain) was demonstrated to both prevent age-related degeneration in
cholinergic neurones in the basal forebrain, and to improve Water Maze learning in
aged animals. One application of such growth factor research may be the
development of rational treatments for degenerative diseases of the nervous system
such as Alzheimers Disease.
Summary
1. Acetylcholine is an important neurotransmitter in both
the peripheral nervous system (PNS: skeletal and
smooth muscle, autonomic sympathetic and
parasympathetic ganglia), and in the central nervous
system (CNS).
2. Cholinergic responses are mediated by
nicotinic receptors (giving EPSPs) and muscarinic
receptors (giving either EPSPs or IPSPs). Nicotinic
receptors are ligand-gated ion channels; muscarinic
receptors are metabotropic, utilising G-proteins and
intracellular signalling to activate channels elsewhere in
the cell.
3. Nicotinic receptors are activated by carbachol and
generally blocked by tubocurarine and/or
hexamethonium. Muscarinic receptors are also activated
by carbachol but generally blocked by atropine.
3. The cholinergic system in brain is important in
cognitive function and learning. Impaired cognition and
learning can be alleviated by stimulating cholinergic
transmission using anticholinesterases or growth
factors.
4. Attempts to treat Alzheimer’s disease, a form of
dementia in which cognitive function and learning are
impaired, with anticholinesterases or growth factors
have met with limited success.