A substrate trapping mutant form of striatal-enriched protein tyrosine phosphatase prevents amphetamine-induced stereotypies and long-term potentiation in the striatum.
BACKGROUND
Chronic, intermittent exposure to psychostimulant drugs results in striatal neuroadaptations leading to an increase in an array of behavioral responses on subsequent challenge days. A brain-specific striatal-enriched tyrosine phosphatase (STEP) regulates synaptic strengthening by dephosphorylating and inactivating several key synaptic proteins. This study tests the hypothesis that a substrate-trapping form of STEP will prevent the development of amphetamine-induced stereotypies.


METHODS
A substrate-trapping STEP protein, TAT-STEP (C-S), was infused into the ventrolateral striatum on each of 5 consecutive exposure days and 1 hour before amphetamine injection. Animals were challenged to see whether sensitization to the stereotypy-producing effects of amphetamine developed. The same TAT-STEP (C-S) protein was used on acute striatal slices to determine the impact on long-term potentiation and depression.


RESULTS
Infusion of TAT-STEP (C-S) blocks the increase of amphetamine-induced stereotypies when given during the 5-day period of sensitization. The TAT-STEP (C-S) has no effect if only infused on the challenge day. Treatment of acute striatal slices with TAT-STEP (C-S) blocks the induction of long-term potentiation and potentates long-term depression.


CONCLUSIONS
A substrate trapping form of STEP blocks the induction of amphetamine-induced neuroplasticity within the ventrolateral striatum and supports the hypothesis that STEP functions as a tonic break on synaptic strengthening.
Tashev
Roman
R
Child Study Center, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Moura
Paula J
PJ
Venkitaramani
Deepa V
DV
Prosperetti
Chiara
C
Centonze
Diego
D
Paul
Surojit
S
Lombroso
Paul J
PJ
D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D017774:Long-Term Potentiation / Q000187:drug effects*; D036881:Long-Term Synaptic Depression / Q000187:drug effects*; D008297:Male; D009473:Neuronal Plasticity / Q000187:drug effects; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000037:antagonists & inhibitors / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013239:Stereotyped Behavior / Q000187:drug effects*
D000697:Central Nervous System Stimulants; D007527:Isoenzymes; D000661:Amphetamine; D054558:Protein Tyrosine Phosphatases, Non-Receptor; C489931:Ptpn5 protein, rat