Early-life blockade of NMDA receptors induces epigenetic abnormalities in the adult medial prefrontal cortex: possible involvement in memory impairment in trace fear conditioning

Abstract

Rationale Several findings indicate that early-life dysfunction of N-methyl-D-aspartate (NMDA) receptors might cause schizophrenia-like abnormalities in adulthood that might be induced by impairments in epigenetic regulation. Objectives In the present study, we investigated whether postnatal blockade of NMDA receptors (within the first 3 weeks of life) by the competitive antagonist CGP 37849 (CGP) might affect some epigenetic markers in the adult medial prefrontal cortex (mPFC). Methods Histone H3 phosphorylation at serine 10 (H3S10ph), histone H3 acetylation at lysine 9 or 14 (H3K9ac or H3K14ac, respectively), or expression of histone deacetylase (HDAC) 2, HDAC5, myocyte enhancer factor (MEF) 2D and activity-regulated cytoskeleton-associated protein (Arc) were analysed. Moreover, we also evaluated whether the deacetylase inhibitor sodium butyrate (SB; 1.2 mg/kg, ip) could prevent behavioural and neurochemical changes in the mPFC induced by CGP during memory retrieval in the trace fear conditioning paradigm. Results The results showed that CGP administration increased the number of H3S10ph nuclei but did not affect H3K9ac and H3K14ac or HDAC2 protein levels. However, CGP administration altered the HDAC5 mRNA and protein levels and increased the mRNA and protein levels of MEF2D. CGP also increased Arc mRNA, which was correlated with an increase in the amount of Arc DNA bound to MEF2D. SB given 2 h after training prevented impairment of the freezing response and disruption of epigenetic markers (H3S10ph, HDAC5, MEF2D) and Arc expression during memory retrieval induced by CGP administration. Conclusions The early-life blockade of NMDA receptors impairs some epigenetic regulatory processes in the mPFC that are involved in fear memory formation.

Effect of Psilocybin and Ketamine on Brain Neurotransmitters, Glutamate Receptors, DNA and Rat Behavior

“…The frontal cortex was dissected and rapidly frozen in liquid nitrogen and stored at −20 °C. The Western blot procedure was performed as previously described in Maćkowiak et al [ 70 ], 2019 and Latusz and Maćkowiak, 2020 [ 71 ]. The tissue was homogenized (TissueLyser, Retsch, Munich, Germany) in lysis buffer (PathScan ® Sandwich ELISA Lysis Buffer, Cell Signaling, Denver, CO, USA).…”

Behavioral Deficits in Adolescent Mice after Sub-Chronic Administration of NMDA during Early Stage of Postnatal Development

“…Three-chamber sociability test was conducted to determine if sub-chronic NMDA injection during early life can affect the social behavior in later life ( Castillo-Gomez et al ., 2017 ; Latusz and Mackowiak, 2020 ; Golitabari et al ., 2021 ). The social interaction behavior was measured and analyzed using the EthoVision behavioral assessment system (Noldus).…”

Epigenetic Targets in Schizophrenia Development and Therapy

“…The early-life or adolescent blockade of NMDA receptors induced the schizophrenia-like behavioural response in adult animals [ 102 ]. Biochemical studies have shown that behavioural changes are related to the alterations in histone acetylation (H3K9ac) [ 103 ] or in HDAC5 levels in the adult PFC of animals with postnatal blockade of NMDA receptors [ 103 , 104 ].…”

“…In clinical practice, VPA treatment showed beneficial effects in schizophrenia patients [ 116 ], and VPA is used in augmentation therapy for treatment-resistant schizophrenia [ 117 ]. Other HDACs of class I and II inhibitors (MS-275, vorinostat, sodium butyrate) also showed potential beneficial effects on schizophrenia-like impairments in animal studies [ 104 , 118 , 119 , 120 ]. There are also some suggestions that HDAC10 might be, among others, a potential target for schizophrenia [ 121 ] because of a single nucleotide polymorphism (SNP) (rs 7634112) located in the HDAC10 gene associated with schizophrenia [ 122 ].…”