Cholinergic neurotransmission

Question 1

Central cholinergic pathways

Answer 1

Cholinergic projection neurons are restricted to 8 clusters.
Medial septal group: clusters Ch1-4 in the basal forebrain target cortical and limbic structures involved in attention, learning and memory.
Pontine cholinergic system: clusters Ch5-6 in the caudal midbrain target the thalamus, midbrain and cerebellum → sleep, arousal and motor function.
Clusters Ch7-8 in the midbrain target the brainstem and midbrain, involved in motor and sensory function.

Question 2

Peripheral cholinergic pathways

Answer 2

Preganglionic neurons have their cell bodies in the brain and spinal cord of the CNS. They synapse with neurons in an autonomic ganglion located near or in the effector organs.
Parasympathetic neurons are longer than sympathetic ones.
Postganglionic neurons have their cell bodies in the ganglion and synapse on the effector.
These can stimulate or inhibit muscle contraction.

Question 3

ACh synthesis, storage, release and recycling

Answer 3

Choline acetyltransferase (ChAT) transfers an acetyl group from acetyl-coenzyme A (Acetyl-CoA) to choline, forming acetylcholine.
Vesicular ChT loads 10,000 ACh molecules into each 40-50 nm vesicle.
ACh is metabolised to choline and acetate by acetylcholinesterase (AChE) in the synaptic cleft within microseconds.
80% of choline is taken up by presynaptic neurons and recycled. This occurs via an energy-dependent cotransport channel with Na+.

Question 4

Nicotinic AChRs

Answer 4

Ionotropic
Pentameric, contain at least two α subunits which each bind one molecule of ACh.
11 different subtypes
Mediate fast neurotransmission in the PNS, and excitation/neuromodulation in the CNS.
Muscle-types receptors at the neuromuscular junction (N1 or Nm)
- embryonic form (α1, β1, δ, and γ subunits)
- adult form (α1, β1, δ, and ε subunits) – higher conductance, shorter opening time.
Neuronal subtypes (N2 or Nn) - combination of twelve different nicotinic receptor subunits: α2−α10 and β2−β4.

Question 5

Muscarinic AChRs

Answer 5

Muscarinic receptors are metabotropic G-coupled receptors, so they use intracellular 2nd messengers.
There are 5 subtypes, M1-5. All are found in the CNS and types 1-4 are also found in the PNS.
These can be excitatory M1-type (M1,3,5), coupled to Gq signalling, or inhibitory M2-type (M2,4), coupled to Gi signalling.
M1-type activation leads to an increase in PLC, IP3 and DAG, intracellular calcium, and MAPK.
M2-type activation leads to a decrease in cAMP, increase in GIRK channel conductance and inhibition of calcium channels
M1 receptors are found in the CNS, M2 in the heart and M3 in smooth muscle.

Question 6

Brain effects

Answer 6

Nicotinic and muscarinic receptors are highly expressed in the cortex and hippocampus.
They play a neuromodulatory role in increasing (nicotinic) or decreasing (M2-like muscarinic) synaptic release probability.

Question 7

Cognitive performance

Answer 7

Manipulation of ACh levels affects attention, learning and memory.
ACh depletion contributes to normal age-related cognitive decline.
AChEIs prevent ACh degradation and increase ACh levels at the synapse. Reversible inhibitors improve cognitive function in Alzheimer’s disease (e.g. Donepezil). However, irreversible inhibitors are toxic as they cause excitotoxicity.
AChR antagonists produce memory impairments as in AD, e.g. scopolamine and atropine. These can be prescribed for peripheral issue such as urinary incontinence or nausea and vomiting.

Question 8

Vigilance tasks

Answer 8

Vigilance tasks require sustained attention.
Scopolamine decreases ACh signalling and impairs vigilance task performance - slower responses, more errors. Scopolamine induces transient memory impairments, so it is used as a model of cognitive deterioration in mice.
Nicotine improves vigilance task performance - faster responses, less errors

Question 9

Transmission in disease

Answer 9

Schizophrenia - smoking unusually prevalent, may be due to mutations in the nicotinic α7 receptor, which increases the chance of developing SCZ.
Parkinson’s - dopaminergic activity is heavily regulated by both muscarinic and nicotinic receptor activity
Epilepsy - mutations in nicotinic receptors associated with Autosomal Dominant Nocturnal Frontal Lobe Epilepsy.
Addiction - nicotine activates mesolimbic DA pathways resulting in addiction. Deleting excitatory M5Rs on dopaminergic neurones reduces reinforcement and withdrawal related behaviours.
Alzheimer’s - neurological and psychiatric impairments are linked to disruption of the Cholinergic system. AChE-inhibitors are one of the only available treatment options.