Potential New Drug Target for Schizophrenia Identified
According to a new study, people with schizophrenia have elevated levels of an enzyme called striatal-enriched tyrosine phosphatase (STEP). The study found antipsychotic medications commonly prescribed for schizophrenia reduce STEP levels in mice. The findings were presented at Neuroscience 2011, the annual meeting of the Society for Neuroscience and the world’s largest source of emerging news about brain science and health.
Schizophrenia alters important molecules called N-methyl-D-aspartate receptors (NMDAR), which are necessary for communication between neurons. Previous studies showed that elevated levels of STEP equate to lower levels of NMDAR, which are required for many aspects of cognition.
To test whether antipsychotics improve cognition by reducing STEP in the brain, researchers led by Nikisha Carty, PhD, at Yale University, bred mice that do not have STEP, and gave them a drug that causes schizophrenia-like symptoms. After exposure to the drug, mice without STEP did not develop schizophrenia-like behaviors and showed increased amounts of NMDAR.
Antipsychotic medications, while effective, often cause adverse side effects and do not improve cognition. Moreover, many people show drug resistance. “Ultimately, these promising new results indicate that developing drugs that lower STEP levels may prove to be a more effective therapeutic strategy in the treatment of schizophrenia,” Carty said.
The word “schizophrenia” is less than 100 years old. However the disease was first identified as a discrete mental illness by Dr. Emile Kraepelin in the 1887 and the illness itself is generally believed to have accompanied mankind through its history.
Written documents that identify Schizophrenia can be traced to the old Pharaonic Egypt, as far back as the second millennium before Christ. Depression, dementia, as well as thought disturbances that are typical in schizophrenia are described in detail in the Book of Hearts. The Heart and the mind seem to have been synonymous in ancient Egypt. The physical illnesses were regarded as symptoms of the heart and the uterus and originating from the blood vessels or from purulence, fecal matter, a poison or demons.
A recent study into the ancient Greek and Roman literature showed that although the general population probably had an awareness of psychotic disorders, there was no condition that would meet the modern diagnostic criteria for schizophrenia in these societies.
The research was supported by the National Institute of Mental Health.
Scientific Presentation: Sunday, Nov. 13, 3–4 p.m., Halls A–C
The evidence that schizophrenia is a biologically-based disease of the brain has accumulated rapidly during the past two decades. Recently this evidence has been also been supported with dynamic brain imaging systems that show very precisely the wave of tissue distruction that takes place in the brain that is suffering from schizophrenia.
With the rapid advances in the genetics of human desease now taking place, the future looks bright that greatly more effective therapies and eventually cures - will be identified.
TECHNICAL ABSTRACT: Glutamatergic receptor function is critical in mediating synaptic plasticity, and disruptions in glutamatergic signaling are proposed to give rise to behavioral abnormalities and cognitive deficits. The more recent glutamate hypothesis of schizophrenia (SZ) posits a hypoglutamatergic state in the disease, possibly through changes in GluN2B containing NMDA receptor trafficking. Aberrant NMDAR trafficking results in loss of NMDARs on neuronal membranes, thus, affecting synaptic plasticity and is proposed to contribute to cognitive dysfunction. STEP61 is a brain-specific tyrosine phosphatase that dephosphorylates a regulatory Tyr1472 on the NR2B subunit, leading to the internalization of NMDA (NR1/NR2B) receptors. Here we find a significant increase in active STEP61 in human cingulate cortex of SZ patients, establishing an important link between elevated STEP levels and aberrant glutamate receptor signaling involved in SZ. One possible underlying mechanism mediating STEP accumulation involves the ubiquitin-proteasome system (UPS) which mediates protein degradation. In the present study we establish that acute blockade of the NMDAR with MK801 lead to a significant increase in STEP61 protein levels as well as a significant decrease in the phosphorylation levels STEP61 and of the several STEP substrates including pERK, pPYK2 a nd pNR2B. Thus, blockade of the NMDAR results in aberrant accumulation of STEP61 via decreased Ca++ mediated activation of the UPS degratory pathway. While typical and atypical antipsychotic medications are most effective in the treatment of positive symptoms of SZ, the underlying cellular mechanisms responsible for these beneficial effects remains unclear. Here we propose the novel hypothesis that STEP mediates the beneficial effects of antipsychotic medications. Furthermore, we demonstrate that dopamine D2R blockade leads to the phosphorylation and inactivation of STEP61 and restore NMDA receptors to neuronal surfaces in vitro. We also show that the antipsychotic drugs haloperidol, clozapine and risperidone lead to a DR2/PKA-mediated phosphorylation and inactivation of STEP61. Inactivation of STEP61 leads to increased trafficking of glutamate receptors to neuronal surfaces. We also show that STEP knockout mice show an attenuated response to the psychotomimetic effects of acute and chronic administration of phencyclidine in both locomotor activity and learning and memory tasks. The present findings connect the dopamine D2 receptor signaling pathway with the restoration of surface NR1/NR2B receptors. Ultimately, these results indicate that STEP inhibitors may prove therapeutic in the treatment of SZ.
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Nikisha Carty, PhD
Yale University
New Haven, Conn.