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Cited by 44Schizophrenia research and treatmentNeurotransmitter Receptor Influence on BehaviorNeuroscience and Neuropharmacology Research

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Immediate-Early Genes Modulation by Antipsychotics: Translational Implications for a Putative Gateway to Drug-Induced Long-Term Brain Changes

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de Bartolomeis, Andrea, Buonaguro, Elisabetta F., Latte, Gianmarco, Rossi, Rodolfo, Marmo, Federica, Iasevoli, Felice, Tomasetti, Carmine·2017·Frontiers in Behavioral Neuroscience
DOI 10.3389/fnbeh.2017.00240PMC PMC5732183
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Abstract

An increasing amount of research aims at recognizing the molecular mechanisms involved in long-lasting brain architectural changes induced by antipsychotic treatments. Although both structural and functional modifications have been identified following acute antipsychotic administration in humans, currently there is scarce knowledge on the enduring consequences of these acute changes. New insights in immediate-early genes (IEGs) modulation following acute or chronic antipsychotic administration may help to fill the gap between primary molecular response and putative long-term changes. Moreover, a critical appraisal of the spatial and temporal patterns of IEGs expression may shed light on the functional "signature" of antipsychotics, such as the propensity to induce motor side effects, the potential neurobiological mechanisms underlying the differences between antipsychotics beyond D2 dopamine receptor affinity, as well as the relevant effects of brain region-specificity in their mechanisms of action. The interest for brain IEGs modulation after antipsychotic treatments has been revitalized by breakthrough findings such as the role of early genes in schizophrenia pathophysiology, the involvement of IEGs in epigenetic mechanisms relevant for cognition, and in neuronal mapping by means of IEGs expression profiling. Here we critically review the evidence on the differential modulation of IEGs by antipsychotics, highlighting the association between IEGs expression and neuroplasticity changes in brain regions impacted by antipsychotics, trying to elucidate the molecular mechanisms underpinning the effects of this class of drugs on psychotic, cognitive and behavioral symptoms.

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Figure 1 Representative molecular imaging of Homer1a IEG expression by acute antipsychotics administration. Molecular imaging of IEGs expression may represent a tool to investigate topographic distribution of antipsychotic-mediated acute and long-term molecular effects within brain Regions of Interest (ROIs). Here we show a representative depiction of Homer1a IEG expression by different antipsychotics acutely administered in rodents. The autoradiographic film images of Homer1a mRNA detected by means of in situ hybridization histochemistry in coronal brain sections have been extracted from different studies carried on by our laboratory (Polese et al., 2002; Ambesi-Impiombato et al., 2007; Tomasetti et al., 2007, 2011; Iasevoli et al., 2009, 2010a,b, 2011; De Bartolomeis et al., 2015a) and representatively placed side by side in order to outline gene expression topography after treatments with haloperidol (HAL), olanzapine (OLA), sertindole (SERT), amisulpiride (AMS), risperidone (RISP), clozapine (CLO), and different doses of ziprasidone (4 mg/kg, ZIP4; 10 mg/kg, ZIP10), aripriprazole (12 mg/kg, ARI12; 30 mg/kg, ARI30), quetiapine (15 mg/kg, QUE15; 30 mg/kg, QUE30). Homer1a is a postsynaptic effector of plastic synaptic changes mainly mediated by dopamine and glutamate-dependent signaling pathways. Therefore, in this case, IEG molecular imaging may also provide putative information on antipsychotic-triggered changes in synaptic plasticity. ROIs: AC, Anterior Cingulate Cortex; M2, Medial Agranular Cortex; M1, Motor Cortex; SS, Somatosensory Cortex; I, Insular Cortex; dmCP, Dorso Medial Caudate-Putamen; dlCP, Dorso Lateral Caudate-Putamen; vlCP, Ventro Lateral Caudate-Putamen; vmCP, Ventro Medial Caudate-Putamen; Core, Nucleus Accumbens; Core, Shell, Nucleus Accumbens, Shell. Red, significant gene induction as compared to the respective control (p < 0.05); Dark red, significant gene induction as compared to the respective control (p < 0.001).
Figure 1 Representative molecular imaging of Homer1a IEG expression by acute antipsychotics administration. Molecular imaging of IEGs expression may represent a tool to investigate topographic distribution of antipsychotic-mediated acute and long-term molecular effects within brain Regions of Interest (ROIs). Here we show a representative depiction of Homer1a IEG expression by different antipsychotics acutely administered in rodents. The autoradiographic film images of Homer1a mRNA detected by means of in situ hybridization histochemistry in coronal brain sections have been extracted from different studies carried on by our laboratory (Polese et al., 2002; Ambesi-Impiombato et al., 2007; Tomasetti et al., 2007, 2011; Iasevoli et al., 2009, 2010a,b, 2011; De Bartolomeis et al., 2015a) and representatively placed side by side in order to outline gene expression topography after treatments with haloperidol (HAL), olanzapine (OLA), sertindole (SERT), amisulpiride (AMS), risperidone (RISP), clozapine (CLO), and different doses of ziprasidone (4 mg/kg, ZIP4; 10 mg/kg, ZIP10), aripriprazole (12 mg/kg, ARI12; 30 mg/kg, ARI30), quetiapine (15 mg/kg, QUE15; 30 mg/kg, QUE30). Homer1a is a postsynaptic effector of plastic synaptic changes mainly mediated by dopamine and glutamate-dependent signaling pathways. Therefore, in this case, IEG molecular imaging may also provide putative information on antipsychotic-triggered changes in synaptic plasticity. ROIs: AC, Anterior Cingulate Cortex; M2, Medial Agranular Cortex; M1, Motor Cortex; SS, Somatosensory Cortex; I, Insular Cortex; dmCP, Dorso Medial Caudate-Putamen; dlCP, Dorso Lateral Caudate-Putamen; vlCP, Ventro Lateral Caudate-Putamen; vmCP, Ventro Medial Caudate-Putamen; Core, Nucleus Accumbens; Core, Shell, Nucleus Accumbens, Shell. Red, significant gene induction as compared to the respective control (p < 0.05); Dark red, significant gene induction as compared to the respective control (p < 0.001).CC BY · PubMed Central
Figure 2 IEGs modulation by antipsychotic drugs. Membrane receptors activate multiple signal transduction pathways, which interact at several sites through the mediation of a large number of second messengers. A crucial role in the post-membrane interaction is played by the PSD, which serves as a physical connection among ionotropic and metabotropic glutamate receptors, and links them to intracellular calcium stores. All these pathways converge in the end to appropriate nuclear targets (i.e., transcription factors, TFs) via specific effectors, largely kinases (e.g., CAMK, MAPKs, PKA etc.), in order to fine modulate long-term activity dependent neuronal rearrangements through changes in IEGs expression levels. On the left side of the picture, antipsychotic compounds are depicted near to the membrane receptors to which they show maximum affinity. NMDAR, N-methyl-D-aspartate glutamate receptor; mGluR1a/5, metabotropic glutamate receptor type 1a/5; D1, dopamine receptor D1; D2, dopamine receptor D2; DAG, diacylglycerol; IP3, inositol 1,4,5-trisphosphate; Akt1, RAC-alpha serine/threonine-protein kinase; PP2A, protein phosphatase 2A; GSK3b, Glycogen synthase kinase 3 beta; DISC1, Disrupted in schizophrenia 1; CAMK, Ca2+/calmodulin-dependent protein kinase; cAMP, cyclic adenosine monophosphate; PKC, protein kinase C; PKA, protein kinase A; MAPKs, mitogen-activated protein kinases; ERK, extracellular signal-regulated kinase; CREB-P, cAMP response element-binding protein; IEGs, immediate early genes; PSD, post-synaptic density; PAMs, positive allosteric modulators of mGluRs; GlyT, glycine transporter.
Figure 2 IEGs modulation by antipsychotic drugs. Membrane receptors activate multiple signal transduction pathways, which interact at several sites through the mediation of a large number of second messengers. A crucial role in the post-membrane interaction is played by the PSD, which serves as a physical connection among ionotropic and metabotropic glutamate receptors, and links them to intracellular calcium stores. All these pathways converge in the end to appropriate nuclear targets (i.e., transcription factors, TFs) via specific effectors, largely kinases (e.g., CAMK, MAPKs, PKA etc.), in order to fine modulate long-term activity dependent neuronal rearrangements through changes in IEGs expression levels. On the left side of the picture, antipsychotic compounds are depicted near to the membrane receptors to which they show maximum affinity. NMDAR, N-methyl-D-aspartate glutamate receptor; mGluR1a/5, metabotropic glutamate receptor type 1a/5; D1, dopamine receptor D1; D2, dopamine receptor D2; DAG, diacylglycerol; IP3, inositol 1,4,5-trisphosphate; Akt1, RAC-alpha serine/threonine-protein kinase; PP2A, protein phosphatase 2A; GSK3b, Glycogen synthase kinase 3 beta; DISC1, Disrupted in schizophrenia 1; CAMK, Ca2+/calmodulin-dependent protein kinase; cAMP, cyclic adenosine monophosphate; PKC, protein kinase C; PKA, protein kinase A; MAPKs, mitogen-activated protein kinases; ERK, extracellular signal-regulated kinase; CREB-P, cAMP response element-binding protein; IEGs, immediate early genes; PSD, post-synaptic density; PAMs, positive allosteric modulators of mGluRs; GlyT, glycine transporter.CC BY · PubMed Central

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Authors
de Bartolomeis, A., Buonaguro, E. F., Latte, G., Rossi, R., Marmo, F., Iasevoli, F., & Tomasetti, C.
Affiliations
Federico II University Hospital (IT)
ORCID
Venue
Frontiers in Behavioral Neuroscience
Publisher
Frontiers Media SA
Published
2017-12-11
Volume
11
Pages
240-240
ISSN
1662-5153 (ISSN-L)
DOI
10.3389/fnbeh.2017.00240
PMC
PMC5732183
OpenAlex
W2771406275
Cited by
44
References
270
Citations by year
2026: 3 · 2025: 5 · 2024: 3 · 2023: 6 · 2022: 6 · 2021: 5 · 2020: 9 · 2019: 4 · 2018: 3
FWCI
0.67
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Frontiers in Behavioral Neuroscience (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Cineca Institutional Research Information System (Tor Vergata University) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
immediate early genes, antipsychotic drugs, neuroplasticity, schizophrenia, epigenetics, dopamine D2 receptor, motor side effects, brain region specificity, gene expression profiling

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