• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of pnasPNASInfo for AuthorsSubscriptionsAboutThis Article
Proc Natl Acad Sci U S A. Jun 1, 1993; 90(11): 5194–5198.
PMCID: PMC46682

Association of m1 and m2 muscarinic receptor proteins with asymmetric synapses in the primate cerebral cortex: morphological evidence for cholinergic modulation of excitatory neurotransmission.

Abstract

Muscarinic m1 receptors traditionally are considered to be postsynaptic to cholinergic fibers, while m2 receptors are largely presynaptic receptors associated with axons. We have examined the distribution of these receptor proteins in the monkey cerebral cortex and obtained results that are at odds with this expectation. Using immunohistochemistry with specific antibodies to recombinant m1 and m2 muscarinic receptor proteins, we have demonstrated that both m1 and m2 receptors are prominently associated with noncholinergic asymmetric synapses as well as with the symmetric synapses that characterize the cholinergic pathways in the neocortex. At asymmetric synapses, both m1 and m2 receptor immunoreactivity is observed postsynaptically within spines and dendrites; the m2 receptor is also found in presynaptic axon terminals which, in the visual cortex, resemble the parvicellular geniculocortical pathway. In addition, m2 labeling was also found in a subset of nonpyramidal neurons. These findings establish that the m2 receptor is located postsynaptically as well as presynaptically. The association of m1 and m2 receptors with asymmetric synapses in central pathways, which use excitatory amino acids as neurotransmitters, provides a morphological basis for cholinergic modulation of excitatory neurotransmission.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (2.4M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Images in this article

Click on the image to see a larger version.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Drachman DA. Memory and cognitive function in man: does the cholinergic system have a specific role? Neurology. 1977 Aug;27(8):783–790. [PubMed]
  • Bartus RT, Dean RL, Pontecorvo MJ, Flicker C. The cholinergic hypothesis: a historical overview, current perspective, and future directions. Ann N Y Acad Sci. 1985;444:332–358. [PubMed]
  • Gitelman DR, Prohovnik I. Muscarinic and nicotinic contributions to cognitive function and cortical blood flow. Neurobiol Aging. 1992 Mar-Apr;13(2):313–318. [PubMed]
  • Metherate R, Cox CL, Ashe JH. Cellular bases of neocortical activation: modulation of neural oscillations by the nucleus basalis and endogenous acetylcholine. J Neurosci. 1992 Dec;12(12):4701–4711. [PubMed]
  • Mash DC, Flynn DD, Potter LT. Loss of M2 muscarine receptors in the cerebral cortex in Alzheimer's disease and experimental cholinergic denervation. Science. 1985 May 31;228(4703):1115–1117. [PubMed]
  • Dilsaver SC. Cholinergic mechanisms in depression. Brain Res. 1986 Sep;396(3):285–316. [PubMed]
  • Vannucchi MG, Goldman-Rakic PS. Age-dependent decrease in the affinity of muscarinic M1 receptors in neocortex of rhesus monkeys. Proc Natl Acad Sci U S A. 1991 Dec 15;88(24):11475–11479. [PMC free article] [PubMed]
  • Tandon R, Shipley JE, Greden JF, Mann NA, Eisner WH, Goodson JA. Muscarinic cholinergic hyperactivity in schizophrenia. Relationship to positive and negative symptoms. Schizophr Res. 1991 Jan-Feb;4(1):23–30. [PubMed]
  • Kubo T, Fukuda K, Mikami A, Maeda A, Takahashi H, Mishina M, Haga T, Haga K, Ichiyama A, Kangawa K, et al. Cloning, sequencing and expression of complementary DNA encoding the muscarinic acetylcholine receptor. Nature. 1986 Oct 2;323(6087):411–416. [PubMed]
  • Bonner TI, Buckley NJ, Young AC, Brann MR. Identification of a family of muscarinic acetylcholine receptor genes. Science. 1987 Jul 31;237(4814):527–532. [PubMed]
  • Levey AI, Stormann TM, Brann MR. Bacterial expression of human muscarinic receptor fusion proteins and generation of subtype-specific antisera. FEBS Lett. 1990 Nov 26;275(1-2):65–69. [PubMed]
  • Levey AI, Kitt CA, Simonds WF, Price DL, Brann MR. Identification and localization of muscarinic acetylcholine receptor proteins in brain with subtype-specific antibodies. J Neurosci. 1991 Oct;11(10):3218–3226. [PubMed]
  • Lidow MS, Gallager DW, Rakic P, Goldman-Rakic PS. Regional differences in the distribution of muscarinic cholinergic receptors in the macaque cerebral cortex. J Comp Neurol. 1989 Nov 8;289(2):247–259. [PubMed]
  • Mash DC, White WF, Mesulam MM. Distribution of muscarinic receptor subtypes within architectonic subregions of the primate cerebral cortex. J Comp Neurol. 1988 Dec 8;278(2):265–274. [PubMed]
  • van der Zee EA, Streefland C, Strosberg AD, Schröder H, Luiten PG. Visualization of cholinoceptive neurons in the rat neocortex: colocalization of muscarinic and nicotinic acetylcholine receptors. Brain Res Mol Brain Res. 1992 Aug;14(4):326–336. [PubMed]
  • Peters A, Sethares C. Layer IVA of rhesus monkey primary visual cortex. Cereb Cortex. 1991 Nov-Dec;1(6):445–462. [PubMed]
  • De Lima AD, Singer W. Cholinergic innervation of the cat striate cortex: a choline acetyltransferase immunocytochemical analysis. J Comp Neurol. 1986 Aug 15;250(3):324–338. [PubMed]
  • Smiley JF, Williams SM, Szigeti K, Goldman-Rakic PS. Light and electron microscopic characterization of dopamine-immunoreactive axons in human cerebral cortex. J Comp Neurol. 1992 Jul 15;321(3):325–335. [PubMed]
  • Sloper JJ, Powell TP. An experimental electron microscopic study of afferent connections to the primate motor and somatic sensory cortices. Philos Trans R Soc Lond B Biol Sci. 1979 Mar 23;285(1006):199–226. [PubMed]
  • Winfield DA, Rivera-Dominguez M, Powell TP. The termination of geniculocortical fibres in area 17 of the visual cortex in the macaque monkey. Brain Res. 1982 Jan 7;231(1):19–32. [PubMed]
  • Wiesel TN, Hubel DH, Lam DM. Autoradiographic demonstration of ocular-dominance columns in the monkey striate cortex by means of transneuronal transport. Brain Res. 1974 Oct 18;79(2):273–279. [PubMed]
  • Hendrickson AE, Wilson JR, Ogren MP. The neuroanatomical organization of pathways between the dorsal lateral geniculate nucleus and visual cortex in Old World and New World primates. J Comp Neurol. 1978 Nov 1;182(1):123–136. [PubMed]
  • Giguere M, Goldman-Rakic PS. Mediodorsal nucleus: areal, laminar, and tangential distribution of afferents and efferents in the frontal lobe of rhesus monkeys. J Comp Neurol. 1988 Nov 8;277(2):195–213. [PubMed]
  • Goldman-Rakic PS, Schwartz ML. Interdigitation of contralateral and ipsilateral columnar projections to frontal association cortex in primates. Science. 1982 May 14;216(4547):755–757. [PubMed]
  • Kennedy H, Dehay C, Bullier J. Organization of the callosal connections of visual areas V1 and V2 in the macaque monkey. J Comp Neurol. 1986 May 15;247(3):398–415. [PubMed]
  • de Lima AD, Bloom FE, Morrison JH. Synaptic organization of serotonin-immunoreactive fibers in primary visual cortex of the macaque monkey. J Comp Neurol. 1988 Aug 8;274(2):280–294. [PubMed]
  • Livingstone M, Hubel D. Segregation of form, color, movement, and depth: anatomy, physiology, and perception. Science. 1988 May 6;240(4853):740–749. [PubMed]
  • Freund TF, Martin KA, Soltesz I, Somogyi P, Whitteridge D. Arborisation pattern and postsynaptic targets of physiologically identified thalamocortical afferents in striate cortex of the macaque monkey. J Comp Neurol. 1989 Nov 8;289(2):315–336. [PubMed]
  • Vogt BA, Crino PB, Jensen EL. Multiple heteroreceptors on limbic thalamic axons: M2 acetylcholine, serotonin1B, beta 2-adrenoceptors, mu-opioid, and neurotensin. Synapse. 1992 Jan;10(1):44–53. [PubMed]
  • Vogt BA, Burns DL. Experimental localization of muscarinic receptor subtypes to cingulate cortical afferents and neurons. J Neurosci. 1988 Feb;8(2):643–652. [PubMed]
  • Buckley NJ, Bonner TI, Brann MR. Localization of a family of muscarinic receptor mRNAs in rat brain. J Neurosci. 1988 Dec;8(12):4646–4652. [PubMed]
  • Conti F, Fabri M, Manzoni T. Glutamate-positive corticocortical neurons in the somatic sensory areas I and II of cats. J Neurosci. 1988 Aug;8(8):2948–2960. [PubMed]
  • Conti F, DeFelipe J, Farinas I, Manzoni T. Glutamate-positive neurons and axon terminals in cat sensory cortex: a correlative light and electron microscopic study. J Comp Neurol. 1989 Dec 1;290(1):141–153. [PubMed]
  • Dori I, Dinopoulos A, Cavanagh ME, Parnavelas JG. Proportion of glutamate- and aspartate-immunoreactive neurons in the efferent pathways of the rat visual cortex varies according to the target. J Comp Neurol. 1992 May 8;319(2):191–204. [PubMed]
  • Smiley JF, Yazulla S. Glycinergic contacts in the outer plexiform layer of the Xenopus laevis retina characterized by antibodies to glycine, GABA and glycine receptors. J Comp Neurol. 1990 Sep 15;299(3):375–388. [PubMed]
  • Marchi M, Raiteri M. Interaction acetylcholine-glutamate in rat hippocampus: involvement of two subtypes of M-2 muscarinic receptors. J Pharmacol Exp Ther. 1989 Mar;248(3):1255–1260. [PubMed]
  • Raiteri M, Marchi M, Costi A, Volpe G. Endogenous aspartate release in the rat hippocampus is inhibited by M2 'cardiac' muscarinic receptors. Eur J Pharmacol. 1990 Feb 27;177(3):181–187. [PubMed]
  • Mrzljak L, Goldman-Rakic PS. Low-affinity nerve growth factor receptor (p75NGFR)- and choline acetyltransferase (ChAT)-immunoreactive axons in the cerebral cortex and hippocampus of adult macaque monkeys and humans. Cereb Cortex. 1993 Mar-Apr;3(2):133–147. [PubMed]
  • Markram H, Segal M. Long-lasting facilitation of excitatory postsynaptic potentials in the rat hippocampus by acetylcholine. J Physiol. 1990 Aug;427:381–393. [PMC free article] [PubMed]
  • McCormick DA, Prince DA. Two types of muscarinic response to acetylcholine in mammalian cortical neurons. Proc Natl Acad Sci U S A. 1985 Sep;82(18):6344–6348. [PMC free article] [PubMed]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

  • Compound
    Compound
    PubChem Compound links
  • PubMed
    PubMed
    PubMed citations for these articles
  • Substance
    Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...