Synaptic Dysfunction in Parkinson’s Disease
- 27 January 2012
- book chapter
- review article
- Published by Springer Science and Business Media LLC in Advances in experimental medicine and biology
- Vol. 970, 553-572
- https://doi.org/10.1007/978-3-7091-0932-8_24
Abstract
Activity-dependent modifications in synaptic efficacy, such as long-term depression (LTD) and long-term potentiation (LTP), represent key cellular substrates for adaptive motor control and procedural memory. The impairment of these two forms of synaptic plasticity in the nucleus striatum could account for the onset and the progression of motor and cognitive symptoms of Parkinson’s disease (PD), characterized by the massive degeneration of dopaminergic neurons. In fact, both LTD and LTP are peculiarly controlled and modulated by dopaminergic transmission coming from nigrostriatal terminals. Changes in corticostriatal and nigrostriatal neuronal excitability may influence profoundly the threshold for the induction of synaptic plasticity, and changes in striatal synaptic transmission efficacy are supposed to play a role in the occurrence of PD symptoms. Understanding of these maladaptive forms of synaptic plasticity has mostly come from the analysis of experimental animal models of PD. A series of cellular and synaptic alterations occur in the striatum of experimental parkinsonism in response to the massive dopaminergic loss. In particular, dysfunctions in trafficking and subunit composition of glutamatergic NMDA receptors on striatal efferent neurons contribute to the clinical features of the experimental parkinsonism. Interestingly, it has become increasingly evident that in striatal spiny neurons, the correct assembly of NMDA receptor complex at the postsynaptic site is a major player in early phases of PD, and it is sensitive to distinct degrees of DA denervation. The molecular defects at the basis of PD progression may be not confined just at the postsynaptic neuron: accumulating evidences have recently shown that the genes linked to PD play a critical role at the presynaptic site. DA release into the synaptic cleft relies on a proper presynaptic vesicular transport; impairment of SV trafficking, modification of DA flow, and altered presynaptic plasticity have been described in several PD animal models. Furthermore, an impaired DA turnover has been described in presymptomatic PD patients. Thus, given the pathological events occurring precociously at the synapses of PD patients, post- and presynaptic sites may represent an adequate target for early therapeutic intervention.Keywords
This publication has 132 references indexed in Scilit:
- The synaptic pathology of α-synuclein aggregation in dementia with Lewy bodies, Parkinson’s disease and Parkinson’s disease dementiaActa Neuropathologica, 2010
- Leucine-rich repeat kinase 2 induces α-synuclein expression via the extracellular signal-regulated kinase pathwayCellular Signalling, 2010
- Increased Expression of α-Synuclein Reduces Neurotransmitter Release by Inhibiting Synaptic Vesicle Reclustering after EndocytosisNeuron, 2010
- Leucine-Rich Repeat Kinase 2 Regulates the Progression of Neuropathology Induced by Parkinson's-Disease-Related Mutant α-synucleinNeuron, 2009
- Genome-wide association study reveals genetic risk underlying Parkinson's diseaseNature Genetics, 2009
- Mutant LRRK2R1441G BAC transgenic mice recapitulate cardinal features of Parkinson's diseaseNature Neuroscience, 2009
- Phosphorylation of 4E-BP by LRRK2 affects the maintenance of dopaminergic neurons in DrosophilaThe EMBO Journal, 2008
- Synaptic vesicle fusionNature Structural & Molecular Biology, 2008
- SCRAPPER-Dependent Ubiquitination of Active Zone Protein RIM1 Regulates Synaptic Vesicle ReleaseCell, 2007
- Mice Lacking α-Synuclein Display Functional Deficits in the Nigrostriatal Dopamine SystemNeuron, 2000