Role of acetylcholinesterase on the structure and function of cholinergic synapses

insights gained from studies on knockout mice.

Michael Adler, Richard E. Sweeney, Tracey A. Hamilton, Oksana Lockridge, Ellen G. Duysen, Angela L. Purcell, Sharad S. Deshpande

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Electrophysiological and ultrastructural studies were performed on phrenic nerve-hemidiaphragm preparations isolated from wild-type and acetylcholinesterase (AChE) knockout (KO) mice to determine the compensatory mechanisms manifested by the neuromuscular junction to excess acetylcholine (ACh). The diaphragm was selected since it is the primary muscle of respiration, and it must adapt to allow for survival of the organism in the absence of AChE. Nerve-elicited muscle contractions, miniature endplate potentials (MEPPs) and evoked endplate potentials (EPPs) were recorded by conventional electrophysiological techniques from phrenic nerve-hemidiaphragm preparations isolated from 1.5- to 2-month-old wild-type (AChE(+/+)) or AChE KO (AChE(-/-)) mice. These recordings were chosen to provide a comprehensive assessment of functional alterations of the diaphragm muscle resulting from the absence of AChE. Tension measurements from AChE(-/-) mice revealed that the amplitude of twitch tensions was potentiated, but tetanic tensions underwent a use-dependent decline at frequencies below 70 Hz and above 100 Hz. MEPPs recorded from hemidiaphragms of AChE(-/-) mice showed a reduction in frequency and a prolongation in decay (37%) but no change in amplitude compared to values observed in age-matched wild-type littermates. In contrast, MEPPs recorded from hemidiaphragms of wild-type mice that were exposed for 30 min to the selective AChE inhibitor 5-bis(4-allyldimethyl-ammoniumphenyl)pentane-3-one (BW284C51) exhibited a pronounced increase in amplitude (42%) and a more marked prolongation in decay (76%). The difference between MEPP amplitudes and decays in AChE(-/-) hemidiaphragms and in wild-type hemidiaphragms treated with BW284C51 represents effective adaptation by the former to a high ACh environment. Electron microscopic examination revealed that diaphragm muscles of AChE(-/-) mice had smaller nerve terminals and diminished pre- and post-synaptic surface contacts relative to neuromuscular junctions of AChE(+/+) mice. The morphological changes are suggested to account, in part, for the ability of muscle from AChE(-/-) mice to function in the complete absence of AChE.

Original languageEnglish (US)
Pages (from-to)909-920
Number of pages12
JournalCellular and Molecular Neurobiology
Volume31
Issue number6
StatePublished - 2011
Externally publishedYes

Fingerprint

Acetylcholinesterase
Knockout Mice
Synapses
Cholinergic Agents
Benzenaminium, 4,4'-(3-oxo-1,5-pentanediyl)bis(N,N-dimethyl-N-2-propenyl-), Dibromide
Diaphragm
Muscles
Phrenic Nerve
Neuromuscular Junction
Acetylcholine
Cholinesterase Inhibitors
Muscle Contraction
Evoked Potentials
Respiration
Electrons

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Cell Biology

Cite this

Adler, M., Sweeney, R. E., Hamilton, T. A., Lockridge, O., Duysen, E. G., Purcell, A. L., & Deshpande, S. S. (2011). Role of acetylcholinesterase on the structure and function of cholinergic synapses: insights gained from studies on knockout mice. Cellular and Molecular Neurobiology, 31(6), 909-920.

Role of acetylcholinesterase on the structure and function of cholinergic synapses : insights gained from studies on knockout mice. / Adler, Michael; Sweeney, Richard E.; Hamilton, Tracey A.; Lockridge, Oksana; Duysen, Ellen G.; Purcell, Angela L.; Deshpande, Sharad S.

In: Cellular and Molecular Neurobiology, Vol. 31, No. 6, 2011, p. 909-920.

Research output: Contribution to journalArticle

Adler, Michael ; Sweeney, Richard E. ; Hamilton, Tracey A. ; Lockridge, Oksana ; Duysen, Ellen G. ; Purcell, Angela L. ; Deshpande, Sharad S. / Role of acetylcholinesterase on the structure and function of cholinergic synapses : insights gained from studies on knockout mice. In: Cellular and Molecular Neurobiology. 2011 ; Vol. 31, No. 6. pp. 909-920.
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