Cholinergic Transmission in CNS An Overview
Vijaya Kumar 22/8/2014
History
• First to be identified as neurotransmitter
• Hunt-1907
• Henry Dale-1910
• Otto Leowi-1920
• Shute and Lewis- 1960
• ChAT antibodies-1980
• Receptor structure Sakmann-1984
• Neuronal excitability
• Influences synaptic transmission
• Induces synaptic plasticity and
• coordinates firing of groups of neurons
More than hundred years of research!!!
Techniques used for the study: • Acetylcholinersterase activity assay and histochemistry
• Choline acetyl transferase (ChAT) histochemistry
• Vesicular choline transporter
• Nicotinic and muscuranic receptor expressions and localization
• Nerve Growth factor-p75NGFR
• Cholinergic toxins-Ethylcholine mustard aziridinium ion (AF64A)
• Microdialysis
• Lesion studies
• Retrograde labelling studies
• Developmental disruption studies
• Electrophysiological Studies
• Knockout models
Newman et al, Frontiers in Behavioral Neuroscience;2012
Phylogeny and ontogeny of Cholinergic system
The evolution of the cholinergic system
Laurent Descarries & Kresimir Krnjevic (2004),Acetyl Choline in Cerebral cortex,Elsevier Publishers,Vol 145
Subventricular zone of the ganglionic eminence (GE) in an E14 rat
Laurent Descarries & Kresimir Krnjevic (2004),Acetyl Choline in Cerebral cortex,Elsevier Publishers,Vol 145
Spatiotemporal pattern of neurogenesis of cholinergic neurons in the rat
Laurent Descarries & Kresimir Krnjevic (2004),Acetyl Choline in Cerebral cortex,Elsevier Publishers,Vol 145
ChAT fibers in Rat Parietal cortex
Laurent Descarrie s& Kresimir Krnjevic (2004),Acetyl Choline in Cerebral cortex,Elsevier Publishers,Vol 145
Invitro and invivo induction of cholinergic phenotype by BMP-9
Ignacio Lopez-coviella et al, Science, 2000
Cholinergic receptors
• Muscarinic receptors
M1 & M2
M1 subtypes: m1, m3, m5 (Layer I, II)
M2 subtypes: m2, m4 (Layer III, V )
• Nicotinic receptors
α subunits (α2-10 )
β subunits (β 2-4 )
Sites of Nicotinic and Muscarinic Acetylcholine Receptors
Marina R. Picciotto et al, Neuron 76, 2012
Lesion studies
Barry J et al,Annual Review of Psychology; 1997
Outcome of lesion studies
Barry J et al,Annual Review of Psychology; 1997
Effects of Acetylcholine on Activity of Cortical Neurons
Marina R. Picciotto et al, Neuron 76, 2012
Laurent Descarrie s& Kresimir Krnjevic (2004),Acetyl Choline in Cerebral cortex,Elsevier Publishers,Vol 145
Effects of Acetylcholine on Hippocampal-Amygdala Stress Response
Marina R. Picciotto et al, Neuron 76, 2012
Cholinergic Route of Panic Disorder??
M Battaglia, Molecular Psychiatry (2002)
Effects of Acetylcholine on Activity of Dopamine Mesolimbic Circuit
Marina R. Picciotto et al, Neuron 76, 2012
Regulation of Brain states
Laurent Descarries & Kresimir Krnjevic (2004),Acetyl Choline in Cerebral cortex,Elsevier Publishers,Vol 145
Lesion studies of cholinergic nuclei
Laurent Descarries & Kresimir Krnjevic (2004),Acetyl Choline in Cerebral cortex,Elsevier Publishers,Vol 145
Intrinsic Thalamic circuitry
Laurent Descarrie s& Kresimir Krnjevic (2004),Acetyl Choline in Cerebral cortex,Elsevier Publishers,Vol 145
Laurent Descarries & Kresimir Krnjevic (2004),Acetyl Choline in Cerebral cortex, Elsevier Publishers,Vol 145
Laurent Descarrie s& Kresimir Krnjevic (2004),Acetyl Choline in Cerebral cortex,Elsevier Publishers,Vol 145
Vigilance states between wakefulness and sleep
S Graef et al, Psychopharmacology (2011)
Cholinergic transmission in Basal Ganglia
Laurent Descarrie s& Kresimir Krnjevic (2004),Acetyl Choline in Cerebral cortex,Elsevier Publishers,Vol 145
Role of Cholinergic neurons in Spinal cord
Ventral Horn Motor Neurons
Cholinergic interneurons around central canal
Paul Okwudiri, UCLA Electronic Theses and Dissertations,2013
Cholinergic functions in Hypothalamus
• Role in Thermoregulation
• Role in Feeding behavior
• Role in endocrine and metabolic function
• Sleep wake behavior
R. D. Meyers and M. B. Waller, J. Physiol. (1973)
Cholinergic system in Neurodevelopmental Disorders
Involvement of cholinergic system in schizophrenia
• Cognitive deficits are considered to be the most incapacitating aspect of schizophrenia.
• Social functioning correlates well with some cognitive deficits in patients with schizophrenia.
• Muscarinic and nicotinic receptors are implicated in the pathology of schizophrenia.
• A subgroup of people with schizophrenia have lost 75% of their cortical muscarinic receptors.
• Modulation of nicotinic or muscarinic receptors has produced modest improvements in symptoms associated with schizophrenia.
Muscarinic expression in schizophrenia
Elizabeth Scarr and Brian Dean, Expert Rev. Neurother. 9(1), 73–86 (2009)
Miwa et al, Neuron 70, 2011
Cholinergic receptor expression in Autism
Perry et al, The American Journal of Psychiatry; Jul 2001; 158
Cholinergic regulation of Inflammation
Kevin J Tracey,Journal of Clinical Investigation, 2007
Cholinergic Regulation of Cerebral Blood flow
Laurent Descarries & Kresimir Krnjevic (2004),Acetyl Choline in Cerebral cortex, Elsevier Publishers,Vol 145
Knock out models
• β2 and α 7 knock out models
• Autosomal-dominant nocturnal frontal lobe epilepsy (ADNFLE)
• caused by mis sense mutations in either the a4 or the b2 subunit.
• who use a nicotine patch or tobacco have fewer seizures
Thank you