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- Title
- Development of a novel assay for in vivo screening of neuromodulatory drugs and targeted disruption of cholinergic synaptic transmission in Drosophila melanogaster.
- Creator
- Mejia, Monica, Charles E. Schmidt College of Science, Department of Biological Sciences
- Abstract/Description
-
Finding novel compounds that affect neuronal or muscular function is of great interest, as they can serve as potential pharmacological agents for a variety of neurological disorders. For instance, conopeptides have been developed into powerful drugs like the painkiller PrialtTM. Most conopeptides, however, have yet to be characterized, revealing the need for a rapid and straightforward screening method. We have designed a novel bioassay, which allows for unbiased screening of biological...
Show moreFinding novel compounds that affect neuronal or muscular function is of great interest, as they can serve as potential pharmacological agents for a variety of neurological disorders. For instance, conopeptides have been developed into powerful drugs like the painkiller PrialtTM. Most conopeptides, however, have yet to be characterized, revealing the need for a rapid and straightforward screening method. We have designed a novel bioassay, which allows for unbiased screening of biological activity of compounds in vivo against numerous molecular targets on a wide variety of neurons and muscles in a rapid and straightforward manner. For this, we paired nanoinjection of compounds with electrophysiological recordings from the Giant Fiber System of Drosophila melanogaster, which mediates the escape response of the fly.
Show less - Date Issued
- 2013
- PURL
- http://purl.flvc.org/fcla/dt/3362560
- Subject Headings
- Drosophila melanogaster, Genetics, Drosophila melanogaster, Life cycles, Insects, Physiology, Developmental neurobiology, Neural transmission, Cholinergic mechanisms
- Format
- Document (PDF)
- Title
- New Tools for Targeted Disruption of Cholinergic Synaptic Transmission in Drosophila melanogaster.
- Creator
- Mejia, Monica, Heghinian, Mari D., Mari, Frank, Godenschwege, Tanja A., McCabe, Brian D.
- Abstract/Description
-
Nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated ion channels. The a7 subtype of nAChRs is involved in neurological pathologies such as Parkinson’s disease, Alzheimer’s disease, addiction, epilepsy and autism spectrum disorders. The Drosophila melanogaster a7 (Da7) has the closest sequence homology to the vertebrate a7 subunit and it can form homopentameric receptors just as the vertebrate counterpart. The Da7 subunits are essential for the function of the Giant Fiber...
Show moreNicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated ion channels. The a7 subtype of nAChRs is involved in neurological pathologies such as Parkinson’s disease, Alzheimer’s disease, addiction, epilepsy and autism spectrum disorders. The Drosophila melanogaster a7 (Da7) has the closest sequence homology to the vertebrate a7 subunit and it can form homopentameric receptors just as the vertebrate counterpart. The Da7 subunits are essential for the function of the Giant Fiber circuit, which mediates the escape response of the fly. To further characterize the receptor function, we generated different missense mutations in the Da7 nAChR’s ligand binding domain. We characterized the effects of targeted expression of two UAS-constructs carrying a single mutation, D197A and Y195T, as well as a UAS-construct carrying a triple D77T, L117Q, I196P mutation in a Da7 null mutant and in a wild type background. Expression of the triple mutation was able to restore the function of the circuit in Da7 null mutants and had no disruptive effects when expressed in wild type. In contrast, both single mutations severely disrupted the synaptic transmission of Da7-dependent but not glutamatergic or gap junction dependent synapses in wild type background, and did not or only partially rescued the synaptic defects of the null mutant. These observations are consistent with the formation of hybrid receptors, consisting of D197A or Y195T subunits and wild type Da7 subunits, in which the binding of acetylcholine or acetylcholine-induced conformational changes of the Da7 receptor are altered and causes inhibition of cholinergic responses. Thus targeted expression of D197A or Y195T can be used to selectively disrupt synaptic transmission of Da7-dependent synapses in neuronal circuits. Hence, these constructs can be used as tools to study learning and memory or addiction associated behaviors by allowing the manipulation of neuronal processing in the circuits without affecting other cellular signaling.
Show less - Date Issued
- 2013-05-30
- PURL
- http://purl.flvc.org/fau/fd/FAUIR000083
- Format
- Citation
