TY - JOUR
T1 - HDAC2-dependent Antipsychotic-like Effects of Chronic Treatment with the HDAC Inhibitor SAHA in Mice
AU - de la Fuente Revenga, Mario
AU - Ibi, Daisuke
AU - Saunders, Justin M.
AU - Cuddy, Travis
AU - Ijaz, Maryum K.
AU - Toneatti, Rudy
AU - Kurita, Mitsumasa
AU - Holloway, Terrell
AU - Shen, Li
AU - Seto, Jeremy
AU - Dozmorov, Mikhail G.
AU - González-Maeso, Javier
N1 - Funding Information:
The authors would like to thank Hirofumi Morishita for the donation of CaMKIIα-Cre mice; and Eric Olson, Rhonda Bassel-Duby and Eric Nestler for their gift of floxed HDAC2 mice. NIH R01 MH084894 (J.G.M.), MH111940 (J.G.M.), and the Japan Society for the Promotion of Science (JSPS) 15H06719 and 16K19786 (D.I.) participated in the funding of this study. R.T. was recipient of undergraduate fellowship from Pierre et Marie Curie University. D.I. was recipient of postdoctoral fellowships from JSPS (Young Scientists JSPS 23-3454) and the Uehara Memorial Foundation.
Publisher Copyright:
© 2018
PY - 2018/9/15
Y1 - 2018/9/15
N2 - 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.
AB - 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.
KW - HDAC2
KW - antipsychotics
KW - clozapine
KW - histone deacetylase (HDAC)
KW - schizophrenia
KW - vorinostat (SAHA)
UR - http://www.scopus.com/inward/record.url?scp=85050494418&partnerID=8YFLogxK
U2 - 10.1016/j.neuroscience.2018.07.010
DO - 10.1016/j.neuroscience.2018.07.010
M3 - Article
C2 - 30025863
AN - SCOPUS:85050494418
SN - 0306-4522
VL - 388
SP - 102
EP - 117
JO - Neuroscience
JF - Neuroscience
ER -