Biology Reference
In-Depth Information
Other CNS disorders characterized by altered neuronal spine plasticity
Parkinson's disease
Parkinson's disease (PD) is a common neurodegenerative disorder that leads to difficulty
in effectively translating thought into action [Savitt
et al.,
2006]. PD symptoms are caused by
the loss of nigral dopaminergic neurons that innervate the striatum [Albin
et al.,
1989].
Nigrostriatal dopamine axons synapse onto striatal medium spiny neurons (MSNs) which
comprise ~90% of all striatal neurons. These MSNs have radially projecting dendrites that are
densely studded with spines [Wilson and Groves, 1980]. Postmortem studies of PD reveal a
marked decrease in MSN spine density and dendritic length [McNeill
et al.,
1988; Zaja-
Milatovic
et al.,
2005]. Similar morphological changes in MSNs are seen in animal models of
parkinsonism [Arbuthnott
et al.,
2000; Day
et al.,
2006; Neely
et al.,
2007; Solis
et al.,
2007].
These changes in dendritic structure are enduring and do not appear to be reversed by
levedopa [Zaja-Milatovic
et al.,
2005].
Mechanisms underlying spine loss and the biochemical and functional consequences are
poorly understood. Dopamine depletion increases serine/threonine phosphorylation of
multiple synaptic proteins [Brown
et al.,
2005]; increases in protein phosphorylation are
accompanied by a decrease in protein phosphatase 1 (PP1) activity, more specifically
decreased activity of the PP1γ
1
isoform. PP1γ
1
is targeted to synapses by interacting with
spinophilin, an F-actin-targeting subunit. Total levels of spinophilin or PP1γ
1
were unaffected
by striatal dopamine depletion in the 6-hydroxydopamine lesioned rat model of parkinsonism,
while association of PP1γ
1
with spinophilin increased [Baucum
et al.,
2007]. These authors
are currently using proteomics to identify novel spinophilin interacting partners that are
modulated by striatal dopamine depletion.
The prevailing model of PD asserts that dopamine depletion elevates the activity of
striatopallidal neurons and lowers the activity of striatonigral neurons, which leads to an
imbalance in the control of basal ganglia outflow to the thalamus and an inability to move
effectively in response to higher motor commands [Savitt
et al.,
2006]. How striatopallidal
neurons are changing in ways that are critical to the emergence of PD motor symptoms has
remained unknown. A new study now shows that dopamine depletion leads to a rapid and
profound loss of spines and glutamatergic synapses on striatopallidal MSNs but not on
neighboring striatonigral MSNs [Day
et al.,
2006]. Moreover, this loss of connectivity was
triggered by a novel mechanism⎯dysregulation of intraspine Cav1.3 L-type Ca
2+
channels.
The disconnection of striatopallidal neurons from motor command structures is likely to be a
key step in the emergence of pathological activity that is responsible for symptoms in PD
[Day
et al.,
2006].
Fragile X Syndrome
Fragile X syndrome (FXS), a common form of inherited mental retardation, is caused by
amplification of CGG-repeats in the gene [fragile X mental retardation 1 (
Fmr1
)] that
encodes fragile X mental retardation protein (FMRP); this leads to gene silencing and an
absence of FMRP. The fragile X protein associates with polyribosomes and functions as a
negative regulator of protein synthesis [Todd and Malter, 2002], including that occurring in
the vicinity of dendritic spines [Zalfa
et al.,
2003; Weiler
et al.,
2004; Muddashetty
et al.,
2007]. A prominent anatomical feature of FXS is increased frequency of elongated apical
