Nigral injection of antisense oligonucleotides to synaptotagmin I using HVJ-liposome vectors causes disruption of dopamine release in the striatum and impaired skill learning.
To produce an animal model of a dopa-responsive motor disorder with depletion of dopamine (DA) release in the striatum by dysfunction of the transmitter release machinery of the nigrostriatal DA system, we performed an intra-nigral injection of an HVJ-liposome gene transfer vector containing antisense oligodeoxynucleotides (ODNs) against synaptotagmin I (SytI), a key regulator of Ca(2+)-dependent exocytosis and endocytosis in adult rats. A unilateral intra-nigral injection of HVJ-liposome vectors containing antisense ODNs against SytI (syt-AS) caused a moderate disruption of methamphetamine-induced release of DA in the treated side of the striatum, while the syt-AS treatment did not affect physiological release of DA in the treated striatum. A bilateral intra-nigral injection of HVJ-liposome vectors containing syt-AS induced an impairment of the striatal DA-mediated acquisition of skilled behavior in a rotarod task without any deficits in general motor functions, such as spontaneous locomotor activity, motor adjusting steps, equilibrium function, or muscle strength. These findings suggest that an intra-nigral treatment with HVJ-liposome vectors containing syt-AS may cause a long-lasting nigral knockdown of SytI which, in turn, leads to a moderate dysfunction of the DA release machinery in the terminals of the nigrostriatal DA system and a subsequent mild depletion of DA release in the striatum.
Akita
Hisanao
H
Department of Physiology, School of Allied Health Sciences, Kitasato University, Sagamihara 228-8555, Japan.
Ogata
Masanori
M
Jitsuki
Susumu
S
Ogura
Taichi
T
Oh-Nishi
Arata
A
Hoka
Sumio
S
Saji
Makoto
M
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D003342:Corpus Striatum / Q000378:metabolism* / Q000821:virology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D018014:Gene Transfer Techniques; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D008694:Methamphetamine / Q000633:toxicity; D017551:Microdialysis / Q000379:methods; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology*; D009048:Motor Skills / Q000187:drug effects / Q000502:physiology; D019957:Motor Skills Disorders / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology*; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage* / Q000235:genetics; D016627:Oxidopamine / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time / Q000187:drug effects / Q000502:physiology; D045442:Rotarod Performance Test / Q000379:methods; D013378:Substantia Nigra / Q000187:drug effects* / Q000293:injuries / Q000821:virology; D050863:Synaptotagmin I / Q000172:deficiency
D016376:Oligonucleotides, Antisense; D050863:Synaptotagmin I; D008694:Methamphetamine; D016627:Oxidopamine; D004298:Dopamine