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