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development of atypical motor patterns leading to dyskinesias (Chase et al., 2000, 2004).
Thus, as the number of activated NMDA channels increases, a higher amount of Ca
2+
will
enter the cell. The resulting rapid increase in Ca
2+
concentration in the neuron induces the
storage of this ion in the mitochondria, which further compromises energy supply. In fact,
Ca
2+
overload of mitochondria inhibits ATP synthesis (Miller et al., 1989). The latter event
irreversibly blocks the respiratory chain leading to activation of phospholipases,
excitotoxicity and neuronal death (Turski and Turski, 1993).
In this way, Neely et al., (2007) demonstrate that removal of the cortex after lesioning the
striatal dopamine innervation completely prevented the spine loss. Their findings are thus
similar to
in vivo
studies where prolonged blockade of excitatory transmission led to
increased spine density (Rocha and Sur, 1995), and to observations made by Kirov et al.
(2004), who found that blocking excitatory transmission in acute slices from adult rats results
in an increase in spine density in CA1 pyramidal neurons. Moreover, preliminary studies in 6-
OHDA lesioned rats show that blockade of the NMDA subset of glutamate receptors
normalize both the D1 system downregulation and the D2 system upregulation (Chase et al.,
1994). In this context, antiglutamatergic drugs may be of interest in PD. Yet, before such
therapy can be envisaged, the exact nature of the receptors for excitatory amino acids
involved in corticostriatal neurotransmission has to be analyzed in order to develop specific
therapeutic agents without adverse side effects.
The perforated synapses are particularly interesting for several reasons. They have large
PSD and thus probably also more receptors (Desmond and Weinberg, 1998). These
morphological changes could be directly related to the increase in synaptic strength, because
the process of membrane expansion that characterizes synapses with segmented PSD includes
an enlargement of the PSD area and thus probably also insertion of new receptors in the
synaptic membrane (Lüscher et al., 2000). Furthermore, the formation of segmented, fully
partitioned PSD may result in the creation of two independent release sites, with their own
release probabilities (Geinisman, 1993; Edwards, 1995). This suggests that perforated
synapses may release more glutamate, which could trigger other biochemical changes that are
important in the induction of excitatory potentials, and possibly excitotoxicity and more cell
damage.
Calabresi et al. (1997b) demonstrated that D2Rs play a key role in mechanisms
underlying the direction of long-term changes in synaptic efficacy in the striatum. These
authors also show that an imbalance between D2R and NMDA receptor activity induces
altered synaptic plasticity at corticostriatal synapses. This abnormal synaptic plasticity might
cause the movement disorders observed in PD. Thus, we consider that the increase in the
number of perforated synapses in the denervated striatum might be a sign of negative synaptic
plasticity, since this type of synapses seems to induce more glutamate release, excitotoxicity
and neuronal death. Cell death results in appearance of focal dendritic and axon terminals
swellings or disappearance of dendritic spines, as we found here. There is also strong
evidence that swelling and spine loss are caused by activation of excitatory amino acid
receptors (Smart and Halpain, 2000). Furthermore, swelling appears to be a potentially very
damaging process, disrupting the membrane continuity. It is very interesting in this respect
that the phenomenon may in fact occur on dendrites, spines, as well as presynaptic terminals,
being therefore not structure specific.
In conclusion, selective synaptic changes in shape and function are possibly signs of
excitotoxic injury, and observed in diverse neurological diseases and neurodegenerative
