PINK1 heterozygous mutations induce subtle alterations in dopamine-dependent synaptic plasticity
Identifieur interne : 000B43 ( Main/Exploration ); précédent : 000B42; suivant : 000B44PINK1 heterozygous mutations induce subtle alterations in dopamine-dependent synaptic plasticity
Auteurs : G. Madeo [Italie] ; T. Schirinzi [Italie] ; G. Martella [Italie] ; E. C. Latagliata [Italie] ; F. Puglisi [Italie] ; J. Shen [États-Unis] ; E. M. Valente [Italie] ; M. Federici [Italie] ; N. B. Mercuri [Italie] ; S. Puglisi-Allegra [Italie] ; P. Bonsi [Italie] ; A. Pisani [Italie]Source :
- Movement disorders : official journal of the Movement Disorder Society [ 0885-3185 ] ; 2013.
English descriptors
- KwdEn :
- Animals, Cerebral Cortex (metabolism), Corpus Striatum (metabolism), Dopamine (metabolism), Mice, Mice, Knockout, Motor Activity (genetics), Neuronal Plasticity (genetics), Protein Kinases (genetics), Protein Kinases (metabolism), Receptors, Dopamine (metabolism), Rotarod Performance Test, Substantia Nigra (metabolism), Synapses (genetics).
- MESH :
- chemical , genetics : Protein Kinases.
- chemical , metabolism : Dopamine, Protein Kinases, Receptors, Dopamine.
- genetics : Motor Activity, Neuronal Plasticity, Synapses.
- metabolism : Cerebral Cortex, Corpus Striatum, Substantia Nigra.
- Animals, Mice, Mice, Knockout, Rotarod Performance Test.
Abstract
Homozygous or compound heterozygous mutations in the
In the present study, we performed a functional analysis of corticostriatal synaptic plasticity in heterozygous PINK1 knock-out (PINK1+/−) mice by a multidisciplinary approach.
We found that, despite a normal motor behavior, repetitive activation of cortical inputs to striatal neurons failed to induce long-term potentiation (LTP), whereas long-term depression (LTD) was normal. Although nigral dopaminergic neurons exhibited normal morphological and electrophysiological properties with normal responses to dopamine receptor activation, we measured a significantly lower dopamine release in the striatum of PINK1+/−, compared to control mice, suggesting that a decrease in stimulus-evoked dopamine overflow acts as a major determinant for the LTP deficit. Accordingly, pharmacological agents capable of increasing the availability of dopamine in the synaptic cleft restored a normal LTP in heterozygous mice. Moreover, MAO-B inhibitors rescued a physiological LTP and a normal dopamine release.
Our results provide novel evidence for striatal plasticity abnormalities even in the heterozygous disease state. These alterations might be considered an endophenotype to this monogenic form of PD, and a valid tool to characterize early disease stage and design possible disease-modifying therapies.
Url:
DOI: 10.1002/mds.25724
PubMed: 24167038
PubMed Central: 4022284
Affiliations:
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Le document en format XML
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heterozygous mutations induce subtle alterations in dopamine-dependent synaptic plasticity</title>
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heterozygous mutations induce subtle alterations in dopamine-dependent synaptic plasticity</title>
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<author><name sortKey="Shen, J" sort="Shen, J" uniqKey="Shen J" first="J." last="Shen">J. Shen</name>
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<author><name sortKey="Valente, E M" sort="Valente, E M" uniqKey="Valente E" first="E. M." last="Valente">E. M. Valente</name>
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<author><name sortKey="Puglisi Allegra, S" sort="Puglisi Allegra, S" uniqKey="Puglisi Allegra S" first="S." last="Puglisi-Allegra">S. Puglisi-Allegra</name>
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<series><title level="j">Movement disorders : official journal of the Movement Disorder Society</title>
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<term>Cerebral Cortex (metabolism)</term>
<term>Corpus Striatum (metabolism)</term>
<term>Dopamine (metabolism)</term>
<term>Mice</term>
<term>Mice, Knockout</term>
<term>Motor Activity (genetics)</term>
<term>Neuronal Plasticity (genetics)</term>
<term>Protein Kinases (genetics)</term>
<term>Protein Kinases (metabolism)</term>
<term>Receptors, Dopamine (metabolism)</term>
<term>Rotarod Performance Test</term>
<term>Substantia Nigra (metabolism)</term>
<term>Synapses (genetics)</term>
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<keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Protein Kinases</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Dopamine</term>
<term>Protein Kinases</term>
<term>Receptors, Dopamine</term>
</keywords>
<keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Motor Activity</term>
<term>Neuronal Plasticity</term>
<term>Synapses</term>
</keywords>
<keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Cerebral Cortex</term>
<term>Corpus Striatum</term>
<term>Substantia Nigra</term>
</keywords>
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<front><div type="abstract" xml:lang="en"><sec id="S1"><title>Background</title>
<p id="P1">Homozygous or compound heterozygous mutations in the <italic>PTEN-induced kinase 1</italic>
(<italic>PINK1</italic>
) gene are causative of autosomal recessive, early onset PD. Single heterozygous mutations have been repeatedly detected in a subset of patients as well as in non-affected subjects, and their significance has long been debated. Several neurophysiological studies from non-manifesting <italic>PINK1</italic>
heterozygotes have shown the existence of neural plasticity abnormalities, indicating the presence of specific endophenotypic traits in the heterozygous state.</p>
</sec>
<sec id="S2"><title>Methods</title>
<p id="P2">In the present study, we performed a functional analysis of corticostriatal synaptic plasticity in heterozygous PINK1 knock-out (PINK1<sup>+/−</sup>
) mice by a multidisciplinary approach.</p>
</sec>
<sec id="S3"><title>Results</title>
<p id="P3">We found that, despite a normal motor behavior, repetitive activation of cortical inputs to striatal neurons failed to induce long-term potentiation (LTP), whereas long-term depression (LTD) was normal. Although nigral dopaminergic neurons exhibited normal morphological and electrophysiological properties with normal responses to dopamine receptor activation, we measured a significantly lower dopamine release in the striatum of PINK1<sup>+/−</sup>
, compared to control mice, suggesting that a decrease in stimulus-evoked dopamine overflow acts as a major determinant for the LTP deficit. Accordingly, pharmacological agents capable of increasing the availability of dopamine in the synaptic cleft restored a normal LTP in heterozygous mice. Moreover, MAO-B inhibitors rescued a physiological LTP and a normal dopamine release.</p>
</sec>
<sec id="S4"><title>Conclusions</title>
<p id="P4">Our results provide novel evidence for striatal plasticity abnormalities even in the heterozygous disease state. These alterations might be considered an endophenotype to this monogenic form of PD, and a valid tool to characterize early disease stage and design possible disease-modifying therapies.</p>
</sec>
</div>
</front>
</TEI>
<affiliations><list><country><li>Italie</li>
<li>États-Unis</li>
</country>
<region><li>Latium</li>
<li>Massachusetts</li>
</region>
<settlement><li>Rome</li>
</settlement>
</list>
<tree><country name="Italie"><region name="Latium"><name sortKey="Madeo, G" sort="Madeo, G" uniqKey="Madeo G" first="G." last="Madeo">G. Madeo</name>
</region>
<name sortKey="Bonsi, P" sort="Bonsi, P" uniqKey="Bonsi P" first="P." last="Bonsi">P. Bonsi</name>
<name sortKey="Federici, M" sort="Federici, M" uniqKey="Federici M" first="M." last="Federici">M. Federici</name>
<name sortKey="Latagliata, E C" sort="Latagliata, E C" uniqKey="Latagliata E" first="E. C." last="Latagliata">E. C. Latagliata</name>
<name sortKey="Latagliata, E C" sort="Latagliata, E C" uniqKey="Latagliata E" first="E. C." last="Latagliata">E. C. Latagliata</name>
<name sortKey="Martella, G" sort="Martella, G" uniqKey="Martella G" first="G." last="Martella">G. Martella</name>
<name sortKey="Mercuri, N B" sort="Mercuri, N B" uniqKey="Mercuri N" first="N. B." last="Mercuri">N. B. Mercuri</name>
<name sortKey="Mercuri, N B" sort="Mercuri, N B" uniqKey="Mercuri N" first="N. B." last="Mercuri">N. B. Mercuri</name>
<name sortKey="Pisani, A" sort="Pisani, A" uniqKey="Pisani A" first="A." last="Pisani">A. Pisani</name>
<name sortKey="Pisani, A" sort="Pisani, A" uniqKey="Pisani A" first="A." last="Pisani">A. Pisani</name>
<name sortKey="Puglisi Allegra, S" sort="Puglisi Allegra, S" uniqKey="Puglisi Allegra S" first="S." last="Puglisi-Allegra">S. Puglisi-Allegra</name>
<name sortKey="Puglisi Allegra, S" sort="Puglisi Allegra, S" uniqKey="Puglisi Allegra S" first="S." last="Puglisi-Allegra">S. Puglisi-Allegra</name>
<name sortKey="Puglisi, F" sort="Puglisi, F" uniqKey="Puglisi F" first="F." last="Puglisi">F. Puglisi</name>
<name sortKey="Schirinzi, T" sort="Schirinzi, T" uniqKey="Schirinzi T" first="T." last="Schirinzi">T. Schirinzi</name>
<name sortKey="Valente, E M" sort="Valente, E M" uniqKey="Valente E" first="E. M." last="Valente">E. M. Valente</name>
<name sortKey="Valente, E M" sort="Valente, E M" uniqKey="Valente E" first="E. M." last="Valente">E. M. Valente</name>
</country>
<country name="États-Unis"><region name="Massachusetts"><name sortKey="Shen, J" sort="Shen, J" uniqKey="Shen J" first="J." last="Shen">J. Shen</name>
</region>
</country>
</tree>
</affiliations>
</record>
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