CNS cholinergic system
Introduction
The cholinergic system innervates areas of the CNS associated with learning & memory. It includes magnocellular neurons of the nucleus basalis of Meynert projecting to the cerebral cortex & amygdaloid nucleus & medial septal neurons projecting to the hippocampus.
- nucleus basalis of Meynert
- medial septal nucleus
- vertical limb of diagonal band of Broca
- amygdala
- intrinsic cholinergic interneurons of the caudate nucleus[3]
- pedunculopontine nucleus in the brainstem[3]
* The primate cerebral cortex does not contain intrinsic cholinergic neurons. In contrast, the rodent cerebral cortex contains intrinsic cholinergic interneurons, which may supply up to 30% of the local cholinergic innervation.[1]
Cholinergic innervation shows regional variability, with the amygdala & hippocampus showing the highest density of cholinergic axons & the occipital cortex showing the lowest density. Cholinergic projections from the basal forebrain (nucleus basalis) synapse in all layers of the cortex with highest density in layers 1 & 2 & upper regions of layer 3.
Cholinergic neurons are characterized by the presence of choline acetyltransferase (ChAT) which catalyzes formation of the neurotransmitter acetylcholine. Acetylcholine is stored in presynaptic vesicles & released into the synaptic cleft in response to axonal depolarization. Muscarinic receptors on post synaptic neurons bind acetylcholine resulting in a modulating rather than mediating effect. Acetyl & butyryl- cholinesterases hydrolyze acetylcholine within the synaptic cleft for recyle by presynaptic neurons.
Muscarinic cholinergic receptors transduce extracellular (neurotransmitter) signals via G-proteins. The muscarinic M1 receptor is the most abundant muscarinic receptor in the cerebral cortex; it is also found in the dentate gyrus, hippocampus, anterior olfactory nucleus, olfactory tubercle & nucleus accumbens. The M2 muscarinic receptor is a presynaptic autoreceptor which down-regulates release of acetylcholine from presynaptic terminals. The muscarinic M1 receptor appears to induce a facilitory response in postsynaptic neurons, through a prolonged reduction in K+ conductance, thus making the post-synaptic neuron more susceptible to excitatory input.[1] By this means cholinergic neurons may to learning & memory through facilitation of synaptic remodeling[4].
Nicotinic cholinergic receptors use ligand-gated ion channels for signal transduction in a mediating rather than modulating effect. They are most abundant in the thalamus, periaqueductal gray matter & substantia nigra.
In the mammalian CNS, 9 different nicotinic alpha subunits (2-10) & 3 different beta subunits (2-4) have been described. It is assumed that most receptors are heteropentameric structures, with various combinations of alpha & beta subunits, but some receptors may form as homopentamers, notably alpha-7. These alpha-7 homopentamers along with those containing alpha-4 & beta-2 subunits are the most abundant in brain.[5]
Within the brain, nicotinic receptors function as ligand-gated ion channels linked to rapidly desensitizing Ca2+ influx. They are both presynaptic & postsynpatic, & most likely on glia. An important role in modulation of release of several neurotransmitters ( glutamate, GABA & dopamine), mediating &/or modulating synaptic transmission, plasticity, & neurodegeneration is suggested.[5]
The cholinergic system is disrupted during the course of Alzheimer's disease (AD), especially the hippocampus & cortical association areas. Changes become apparent on autopsy with moderate stage dementia. Primary somatosensory areas are not affected until late in the course of AD. Other disorders affecting the CNS cholinergic system include Parkinson's disease & diffuse Lewy body disease (see diseases affecting the CNS cholinergic system).
More general terms
Additional terms
- amygdala
- choline-0-acetyltransferase (choline acetylase, choactase, ChAT, CAT)
- cholinergic receptor
- cholinesterase inhibitor
- diseases affecting the CNS cholinergic system
- medial septal nucleus
- nucleus basalis of Meynert
References
- ↑ 1.0 1.1 1.2 Mesulam M. The cholinergic lesion of Alzheimer's disease: pivotal factor or side show? Learn Mem. 2004 Jan-Feb;11(1):43-9. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/14747516
- ↑ The Human Nervous System, George Paxinos, Academic Press, San Diego CA 1990
- ↑ 3.0 3.1 3.2 Hansen L., Dementia with Lewy bodies, In: Alzheimer's Disease, 2nd ed, Terry RD et al ed, Lippincott, Williams & Wilkins, Philadelphia, 1999
- ↑ 4.0 4.1 Greenfield's Neuropathology, 5th ed., 1992 p.1328
- ↑ 5.0 5.1 5.2 Fabian-Fine R, Skehel P, Errington ML, Davies HA, Sher E, Stewart MG, Fine A. Ultrastructural distribution of the alpha7 nicotinic acetylcholine receptor subunit in rat hippocampus. J Neurosci. 2001 Oct 15;21(20):7993-8003. PMID: https://www.ncbi.nlm.nih.gov/pubmed/11588172
- ↑ UniProt http://www.uniprot.org/uniprot/P36544.html