Abstract:
Previous studies in the laboratory have shown that expression of pathogenic
human Huntingtin (HTT-Q128) in circadian pacemaker neurons (ventro lateral
neurons, LNv) of Drosophila, leads to immediate behavioural arrhythmicity in
constant darkness and loss of neuropeptide Pigment Dispersing Factor (PDF)
specifically from a subset of LNv - the small LNv (sLNv), while the large LNv
(lLNv) are intact. In the present study, we have attempted to examine effects of
temporally restricting HTT expression in LNv on neuronal function and behaviour
using an inducible Gene Switch system that enables HTT induction only in the
presence of a progesterone analogue RU. We used this system to ask whether
larval versus adult specific HTT induction alters the selective vulnerability of
sLNv and circadian behavioural dysfunction (arrhythmic locomotor activity) under
constant darkness. It was seen that either adult-restricted or larval-restricted HTT
induction were each sufficient to render flies arrhythmic, albeit to different
magnitudes. Moreover, the onset of arrhythmicity was delayed compared to flies
expressing HTT throughout. Both these treatments were also sufficient to cause
loss of PDF in sLNv; but at a slower rate compared to flies expressing HTT
throughout. Therefore, the selective susceptibility of sLNv does not seem to
depend on the life-stage at which HTT is expressed, but the rate of loss seems to
be affected by the duration of HTT expression.
