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Mari, Frank
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Digital Document
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 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.
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.
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