Correction: Chronic clozapine treatment restrains via HDAC2 the performance of mGlu2 receptor agonism in a rodent model of antipsychotic activity.

Following the publication of this article Figs. 3b, c were published incorrectly. Also in sub-panel c of Fig. 4, 'Chronic cloza ine' should read 'Chronic clozapine'.

Chronic clozapine treatment restrains via HDAC2 the performance of mGlu2 receptor agonism in a rodent model of antipsychotic activity.

Preclinical findings in rodent models pointed toward activation of metabotropic glutamate 2/3 (mGlu2/3) receptors as a new pharmacological approach to treat psychosis. However, more recent studies failed to show clinical efficacy of mGlu2/3 receptor agonism in schizophrenia patients. We previously proposed that long-term antipsychotic medication restricted the therapeutic effects of these glutamatergic agents. However, little is known about the molecular mechanism underlying the potential repercussion of previous antipsychotic exposure on the therapeutic performance of mGlu2/3 receptor agonists. Here we show that this maladaptive effect of antipsychotic treatment is mediated mostly via histone deacetylase 2 (HDAC2). Chronic treatment with the antipsychotic clozapine led to a decrease in mouse frontal cortex mGlu2 mRNA, an effect that required expression of both HDAC2 and the serotonin 5-HT2A receptor. This transcriptional alteration occurred in association with HDAC2-dependent repressive histone modifications at the mGlu2 promoter. We found that chronic clozapine treatment decreased via HDAC2 the capabilities of the mGlu2/3 receptor agonist LY379268 to activate G-proteins in the frontal cortex of mice. Chronic clozapine treatment blunted the antipsychotic-related behavioral effects of LY379268, an effect that was not observed in HDAC2 knockout mice. More importantly, co-administration of the class I and II HDAC inhibitor SAHA (vorinostat) preserved the antipsychotic profile of LY379268 and frontal cortex mGlu2/3 receptor density in wild-type mice. These findings raise concerns on the design of previous clinical studies with mGlu2/3 agonists, providing the rationale for the development of HDAC2 inhibitors as a new epigenetic-based approach to improve the currently limited response to treatment with glutamatergic antipsychotics.

HDAC2-dependent Antipsychotic-like Effects of Chronic Treatment with the HDAC Inhibitor SAHA in Mice.

Antipsychotic drugs, including both typical such as haloperidol and atypical such as clozapine, remain the current standard for schizophrenia treatment. These agents are relatively effective in treating hallucinations and delusions. However, cognitive deficits are at present essentially either persistent or exacerbated following chronic antipsychotic drug exposure. This underlines the need of new therapeutic approaches to improve cognition in treated schizophrenia patients. Our previous findings suggested that upregulation of histone deacetylase 2 (HDAC2) expression upon chronic antipsychotic treatment may lead to negative effects on cognition and cortical synaptic structure. Here we tested different phenotypes of psychosis, synaptic plasticity, cognition and antipsychotic drug action in HDAC2 conditional knockout (HDAC2-cKO) mice and controls. Conditional depletion of HDAC2 function in glutamatergic pyramidal neurons led to a protective phenotype against behavior models induced by psychedelic and dissociative drugs, such as DOI and MK801, respectively. Immunoreactivity toward synaptophysin, which labels presynaptic terminals of functional synapses, was decreased in the frontal cortex of control mice chronically treated with clozapine - an opposite effect occurred in HDAC2-cKO mice. Chronic treatment with the class I and class II HDAC inhibitor SAHA prevented via HDAC2 the disruptive effects of MK801 on recognition memory. Additionally, chronic SAHA treatment affected transcription of numerous plasticity-related genes in the frontal cortex of control mice, an effect that was not observed in HDAC2-cKO animals. Together, these findings suggest that HDAC2 may represent a novel target to improve synaptic plasticity and cognition in treated schizophrenia patients.

Antipsychotic-induced Hdac2 transcription via NF-κB leads to synaptic and cognitive side effects.

Antipsychotic drugs remain the standard for schizophrenia treatment. Despite their effectiveness in treating hallucinations and delusions, prolonged exposure to antipsychotic medications leads to cognitive deficits in both schizophrenia patients and animal models. The molecular mechanisms underlying these negative effects on cognition remain to be elucidated. Here we demonstrate that chronic antipsychotic drug exposure increases nuclear translocation of NF-κB in both mouse and human frontal cortex, a trafficking event triggered via 5-HT2A-receptor-dependent downregulation of the NF-κB repressor IκBα. This upregulation of NF-κB activity led to its increased binding at the Hdac2 promoter, thereby augmenting Hdac2 transcription. Deletion of HDAC2 in forebrain pyramidal neurons prevented the negative effects of antipsychotic treatment on synaptic remodeling and cognition. Conversely, virally mediated activation of NF-κB signaling decreased cortical synaptic plasticity via HDAC2. Together, these observations may aid in developing therapeutic strategies to improve the outcome of schizophrenia treatment.