# Preclinical role of HDAC2 in mGlu2-dependent schizophrenia treatment

> **NIH NIH R01** · VIRGINIA COMMONWEALTH UNIVERSITY · 2021 · $310,002

## Abstract

Project Summary
About 74% of schizophrenia patients discontinue use within 18 months of therapy due to either poor tolerability
of incomplete efficacy. This underscores the need for novel and more effective therapeutic targets for
schizophrenia treatment. Recent clinical studies suggested that the metabotropic glutamate 2/3 receptor
(mGlu2/3) agonist LY2140023 had antipsychotic properties, providing a new alternative for the treatment of
schizophrenia. Unfortunately, follow-up studies with LY2140023 showed either inconclusive results, or clinical
outcomes that were not different from placebo. Our published data demonstrated that chronic treatment with
atypical antipsychotics, such as with clozapine or risperidone, but not with typical antipsychotics, such as
haloperidol, induces repressive histone modifications at the mGlu2 (Grm2) promoter in mouse and human
frontal cortex. Remarkably, the translational significance of our preclinical findings has been validated by a
recent post-hoc analysis: patients previously treated with typical antipsychotics responded to LY2140023,
whereas the effects of LY2140023 in patients previously exposed to atypical antipsychotics did not differ from
placebo. Our published and preliminary data also suggest that these repressive epigenetic modifications
occurred through a signaling mechanism that requires a serotonin 5-HT2A receptor (5HT2A)-dependent
enhancement of NF-B transcriptional function via IB, which is followed by NF-B-dependent up-regulation
and increased binding of histone deacetylase 2 (HDAC2) to the mGlu2 promoter. We have focused our
investigation on the potential role of HDAC2 as the basic molecular mechanism underlying down-regulation of
mGlu2 expression after chronic antipsychotic drug treatment. Our results are expected to provide a route to the
identification of new and more effective epigenetic drugs to improve the currently limited response to treatment
with glutamate antipsychotics.

## Key facts

- **NIH application ID:** 10071883
- **Project number:** 5R01MH111940-05
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** Javier Gonzalez-Maeso
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $310,002
- **Award type:** 5
- **Project period:** 2017-01-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10071883

## Citation

> US National Institutes of Health, RePORTER application 10071883, Preclinical role of HDAC2 in mGlu2-dependent schizophrenia treatment (5R01MH111940-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10071883. Licensed CC0.

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