Herpes Simplex Virus 1 (HSV-1)-Based Vectors - Viral Vector Approaches in Neurobiology and Brain Diseases - page 71

oxygen species (ROS) molecules [ 125 ]. Recently, Decker and
colleagues have demonstrated that blockade of NR1 expression
through the infection of primary cultures of neurons with ampli-
con vectors encoding an anti-NR1 antisense RNA [ 140 ], inhibited
ADDLs binding to synapses [ 139 ]. In the same study, they showed
that there was a great reduction in ADDL-instigated ROS forma-
tion in neurons in which the expression of NR1 had been knocked
down [ 139 ]. Moreover, it has recently been reported that different
NR2 subunits would also be involved in the binding of ADDLs to
synaptic sites [ 141 , 142 ]. Liu and colleagues have suggested that
increasing activity of NR2A and/or reducing that of NR2B may
alter or reduce the expression of cytotoxic effects mediated by
ADDLs in neuronal cultures [ 141 ]. On the other hand, Balducci
and colleagues showed that there is an alteration in the traffi cking
of NR2A and NR2B subunits in mutant mice expressing an amy-
loidogenic human form of APP [ 142 ]. However, in the absence of
more precise studies supporting a specifi c interaction between the
different subunits of the NMDAR and the A peptide, neither in

normal nor in pathological conditions, we cannot conclude which
could be the specifi c site for ADDLs binding. It should be taken into
account that the decrease in NR1, which is essential for assembly
and for the membrane allocation of the receptor, produces a decrease
of all the NMDAR subunits at the postsynaptic site [ 138 ].
Several studies have used amplicons in experimental settings of
PD. A typical feature of PD is the progressive loss of dopaminergic
neurons in the substantia nigra (SN). During et al. [ 143 ] were the
fi rst to report the use of amplicons to deliver human tyrosine
hydroxylase (TH) into the partially denervated striatum of
6-hydrodopamine-lesioned rats, used as model of PD. Effi cient
behavioral and biochemical recovery was maintained for 1 year after
gene transfer. Further studies then achieved striatal dopamine level
restoration by using complex amplicons expressing TH in combina-
tion with aromatic amino acid decarboxylase (AADC) [ 144 ] or TH
in combination with AADC, GTP cyclohydrolase, I (GTP CHI),
and vesicular monoamine transporter 2 (VMAT-2) [ 145 ]. In a
series of elegant studies, this group further compared the activities
of tissue-specifi c promoters to drive gene expression, particularly
the TH, the neurofi lament, and the vesicular glutamate transport 1
(VGLUT1) promoters [ 146 - 150 ].
The effect of amplicon-mediated transduction of the dominant-
negative fi broblast growth factor (FGF) receptor 1 mutant protein
(FGFR1(TK-)) into the rat SN was evaluated in vivo as a possible
strategy to model the reduced FGF signaling already documented
to occur in PD. Following intranigral delivery of the FGFR1(TK-)
expressing amplicon, the number of SN neurons expressing TH
was signifi cantly reduced, leading to the conclusion that reduced
FGF signaling in the SN of Parkinsonian patients could play a role
in the impaired dopaminergic transmission associated with PD

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