Amelia Gallitano

Interests

Research

Neuro-degenerative, developmental and psychiatric disease; Developmental, cell and molecular biology; Gene environment interactions and epigenetics; Signaling and steroid biology

Courses

Scholarly Contributions

Journals/Publications

• Gallitano-Mendel, A. L. (2023). Serial Electroconvulsive Seizure Alters Dendritic Complexity and Promotes Cellular Proliferation in the Mouse Dentate Gyrus; A Role for EGR3. Brain Stimulation, 16(3), 889-900. doi:doi: 10.1016/j.brs.2023.04.022
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  Journal Impact Factor 9.2
• Gallitano-Mendel, A. L. (2022). Identification of activity-induced Egr3-dependent genes reveals genes associated with DNA damage response and schizophrenia.. Transl Psychiatry, 12(1), 320. doi:doi: 10.1038/s41398-022-02069-8
• Gallitano-Mendel, A. L., Marballi, K. K., Alganem, K., Brunwasser, S. J., Barkatullah, A., Meyers, K. T., Campbell, J. M., & Mccullumsmith, R. (2020). Identification of activity-dependent EGR3 target genes reveals genes associated with DNA damage response and schizophrenia. bioRxiv. doi:https://doi.org/10.1101/2020.09.01.276626
• Zhao, X., Ozols, A. B., Meyers, K. T., Campbell, J., McBride, A., Marballi, K. K., Maple, A. M., Raskin, C., Mishra, A., Noss, S. M., Beck, K. L., Khoshaba, R., Bhaskara, A., Godbole, M. N., Lish, J. R., Kang, P., Hu, C., Palner, M., Overgaard, A., , Knudsen, G. M., et al. (2022). Acute sleep deprivation upregulates serotonin 2A receptors in the frontal cortex of mice via the immediate early gene Egr3. Molecular psychiatry.
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  Serotonin 2A receptors (5-HTRs) mediate the hallucinogenic effects of psychedelic drugs and are a key target of the leading class of medications used to treat psychotic disorders. These findings suggest that dysfunction of 5-HTRs may contribute to the symptoms of schizophrenia, a mental illness characterized by perceptual and cognitive disturbances. Indeed, numerous studies have found that 5-HTRs are reduced in the brains of individuals with schizophrenia. However, the mechanisms that regulate 5-HTR expression remain poorly understood. Here, we show that a physiologic environmental stimulus, sleep deprivation, significantly upregulates 5-HTR levels in the mouse frontal cortex in as little as 6-8 h (for mRNA and protein, respectively). This induction requires the activity-dependent immediate early gene transcription factor early growth response 3 (Egr3) as it does not occur in Egr3 deficient (-/-) mice. Using chromatin immunoprecipitation, we show that EGR3 protein binds to the promoter of Htr2a, the gene that encodes the 5-HTR, in the frontal cortex in vivo, and drives expression of in vitro reporter constructs via two EGR3 binding sites in the Htr2a promoter. These results suggest that EGR3 directly regulates Htr2a expression, and 5-HTR levels, in the frontal cortex in response to physiologic stimuli. Analysis of publicly available post-mortem gene expression data revealed that both EGR3 and HTR2A mRNA are reduced in the prefrontal cortex of schizophrenia patients compared to controls. Together these findings suggest a mechanism by which environmental stimuli alter levels of a brain receptor that may mediate the symptoms, and treatment, of mental illness.
• Hartmark-Hill, J. R., Hale, T., & Gallitano-Mendel, A. L. (2021). Letter to the Editor: “Women Physicians & Promotion in Academic Medicine.”. New England Journal of Medicine, 384. doi:10.1056/NEJMc2035793
• Hartmark-Hill, J., Hale, T., & Gallitano, A. (2021). Women Physicians and Promotion in Academic Medicine. The New England Journal of Medicine, 384(7), 680.
• Meyers, K., Marballi, K. K., Brunwasser, S. J., Renda, B., Charbel, M., Marrone, D. F., & Gallitano, A. L. (2018). The immediate early gene Egr3 is required for activity-dependent induction of hippocampal Bdnf. Front. Behav. Neurosci..
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  Myers K, Marballi K, Brunwasser SJ, Renda B, Charbel M. Marrone DF, Gallitano AL:
• Xia, B., Wei, J., Ma, X., Nehme, A., Liong, K., Cui, Y., Chen, C., Gallitano, A., Ferguson, D., & Qiu, S. (2021). Conditional knockout of MET receptor tyrosine kinase in cortical excitatory neurons leads to enhanced learning and memory in young adult mice but early cognitive decline in older adult mice. Neurobiology of learning and memory, 179, 107397.
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  Human genetic studies established MET gene as a risk factor for autism spectrum disorders. We have previously shown that signaling mediated by MET receptor tyrosine kinase, expressed in early postnatal developing forebrain circuits, controls glutamatergic neuron morphological development, synapse maturation, and cortical critical period plasticity. Here we investigated how MET signaling affects synaptic plasticity, learning and memory behavior, and whether these effects are age-dependent. We found that in young adult (postnatal 2-3 months) Met conditional knockout (Met:emx1, cKO) mice, the hippocampus exhibits elevated plasticity, measured by increased magnitude of long-term potentiation (LTP) and depression (LTD) in hippocampal slices. Surprisingly, in older adult cKO mice (10-12 months), LTP and LTD magnitudes were diminished. We further conducted a battery of behavioral tests to assess learning and memory function in cKO mice and littermate controls. Consistent with age-dependent LTP/LTD findings, we observed enhanced spatial memory learning in 2-3 months old young adult mice, assessed by hippocampus-dependent Morris water maze test, but impaired spatial learning in 10-12 months mice. Contextual and cued learning were further assessed using a Pavlovian fear conditioning test, which also revealed enhanced associative fear acquisition and extinction in young adult mice, but impaired fear learning in older adult mice. Lastly, young cKO mice also exhibited enhanced motor learning. Our results suggest that a shift in the window of synaptic plasticity and an age-dependent early cognitive decline may be novel circuit pathophysiology for a well-established autism genetic risk factor.
• Gallitano, A. L. (2020). Editorial: The Role of Immediate Early Genes in Neuropsychiatric Illness. Frontiers in behavioral neuroscience, 14, 16.
• Pine, J. G., Moe, A. M., Maple, A. M., Gallitano, A. L., & Breitborde, N. J. (2020). Activity-regulated cytoskeleton-associated protein predicts symptom response to cognitive behavioral therapy among individuals with first-episode psychosis. Asian journal of psychiatry, 50, 101974.
• Gallitano, A. L., & Marballi, K. K. (2018). Immediate early genes anchor a biological pathway of proteins required for memory formation, long-term depression, and risk for schizophrenia. Front. Behav. Neurosci..
• Maple, A. M., Rowe, R. K., Lifshitz, J., Fernandez, F., & Gallitano, A. L. (2018). Influence of Schizophrenia-Associated Gene Egr3 on Sleep Behavior and Circadian Rhythms in Mice. Journal of biological rhythms, 33(6), 662-670.
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  Up to 80% of people meeting DSM-IV definitions for schizophrenia will exhibit difficulties with sleep, along with a breakdown in circadian entrainment and rhythmicity. The changes to the sleep and circadian systems in this population are thought to be interdependent, as evidenced by the frequent use of the combined term "sleep and circadian rhythm disruption" or "SCRD" to describe their occurrence. To understand links between sleep and circadian problems in the schizophrenia population, we analyzed the duration and rhythmicity of sleep behavior in mice lacking function of the immediate early gene early growth response 3 ( Egr3). EGR3 has been associated with schizophrenia risk in humans, and Egr3-deficient (-/-) mice display various features of schizophrenia that are responsive to antipsychotic treatment. While Egr3-/- mice slept less than their wildtype (WT) littermates, they showed no evidence of circadian disorganization; in fact, circadian rhythms of activity were more robust in these mice compared with WT, as measured by time series analysis and the relative amplitude index of Van Someren's suite of non-parametric circadian rhythm analyses. Differences in circadian robustness were maintained when the animals were transferred to several weeks of housing under constant darkness or constant light. Together, our results suggest that Egr3-/- mice retain control over the circadian timekeeping of sleep and wake, while showing impaired sleep. The findings are compatible with those from a surprising array of mouse models of schizophrenia and raise the possibility that SCRD may be 2 separate disorders in the schizophrenia population requiring different treatment strategies.
• Pfaffenseller, B., Kapczinsk, F., Gallitano, A. L., & Klamt, F. (2018). EGR3 immediate early gene and the brain-derived neurotrophic factor in bipolar disorder. Front. Behav. Neurosci..
• Breitborde, N. J., Maple, A. M., Bell, E. K., Dawson, S. C., Woolverton, C., Harrison-Monroe, P., & Gallitano, A. L. (2017). Activity-regulated cytoskeleton-associated protein predicts response to cognitive remediation among individuals with first-episode psychosis. Schizophrenia research, 184, 147-14. doi:10.1016
• Gallitano-Mendel, A. L., Rausch, M. P., Nguyen, J., Kamel, C. M., Levine, S., Muppana, L., Elizalde, D., & Hastings, K. T. (2017). Nab2 maintains thymus cellularity in aging and stress. Molecular Immunology, 85, 185-195.
• Maple, A., Lackie, R. E., Elizalde, D. I., Grella, S. L., Damphousse, C. C., Xa, C., Gallitano, A. L., & Marrone, D. F. (2017). Attenuated Late-Phase Arc Transcription in the Dentate Gyrus of Mice Lacking Egr3. Neural plasticity, 2017, 6063048.
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  The dentate gyrus (DG) engages in sustained Arc transcription for at least 8 hours following behavioral induction, and this time course may be functionally coupled to the unique role of the DG in hippocampus-dependent learning and memory. The factors that regulate long-term DG Arc expression, however, remain poorly understood. Animals lacking Egr3 show less Arc expression following convulsive stimulation, but the effect of Egr3 ablation on behaviorally induced Arc remains unknown. To address this, Egr3-/- and wild-type (WT) mice explored novel spatial environments and were sacrificed either immediately or after 5, 60, 240, or 480 minutes, and Arc expression was quantified by fluorescence in situ hybridization. Although short-term (i.e., within 60 min) Arc expression was equivalent across genotypes, DG Arc expression was selectively reduced at 240 and 480 minutes in mice lacking Egr3. These data demonstrate the involvement of Egr3 in regulating the late protein-dependent phase of Arc expression in the DG.
• Gallitano, A. L., Satvat, E., Gil, M., & Marrone, D. F. (2016). Distinct dendritic morphology across the blades of the rodent dentate gyrus. Synapse (New York, N.Y.), 70(7), 277-82.
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  The dentate gyrus (DG) is a hippocampal region that has long been characterized as a critical mediator of enduring memory formation and retrieval. As such, there is a wealth of studies investigating this area. Most of these studies have either treated the DG as a homogeneous structure, or examined differences in neurons along the septal-temporal axis. Recent data, however, have indicated that a functional distinction exists between the suprapyramidal and infrapyramidal blades of the DG, with the former showing more robust responses during spatial tasks. To date, few anatomical studies have addressed this functional gradient in rats, and no study has done so in the mouse. To address this, we investigated dendritic morphology and spine density in hippocampal granule cells of rats and mice using the Golgi-Cox technique. We find that granule cells from the suprapyramidal blade of the DG contain greater dendritic material in the region receiving spatial information from the medial perforant path. This provides a potential anatomical substrate for the asymmetric response of the DG to spatial input. Synapse 70:277-282, 2016. © 2016 Wiley Periodicals, Inc.
• Grønli, J., Clegern, W. C., Schmidt, M. A., Nemri, R. S., Rempe, M. J., Gallitano, A. L., & Wisor, J. P. (2016). Sleep Homeostatic and Waking Behavioral Phenotypes in Egr3-Deficient Mice Associated with Serotonin Receptor 5-HT2 Deficits. Sleep, 39(12), 2189-2199.
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  The expression of the immediate early gene early growth response 3 (Egr3) is a functional marker of brain activity including responses to novelty, sustained wakefulness, and sleep. We examined the role of this gene in regulating wakefulness and sleep.
• Pfaffenseller, B., da Silva Magalhães, P. V., De Bastiani, M. A., Castro, M. A., Gallitano, A. L., Kapczinski, F., & Klamt, F. (2016). Differential expression of transcriptional regulatory units in the prefrontal cortex of patients with bipolar disorder: potential role of early growth response gene 3. Translational psychiatry, 6, e805.
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  Bipolar disorder (BD) is a severe mental illness with a strong genetic component. Despite its high degree of heritability, current genetic studies have failed to reveal individual loci of large effect size. In lieu of focusing on individual genes, we investigated regulatory units (regulons) in BD to identify candidate transcription factors (TFs) that regulate large groups of differentially expressed genes. Network-based approaches should elucidate the molecular pathways governing the pathophysiology of BD and reveal targets for potential therapeutic intervention. The data from a large-scale microarray study was used to reconstruct the transcriptional associations in the human prefrontal cortex, and results from two independent microarray data sets to obtain BD gene signatures. The regulatory network was derived by mapping the significant interactions between known TFs and all potential targets. Five regulons were identified in both transcriptional network models: early growth response 3 (EGR3), TSC22 domain family, member 4 (TSC22D4), interleukin enhancer-binding factor 2 (ILF2), Y-box binding protein 1 (YBX1) and MAP-kinase-activating death domain (MADD). With a high stringency threshold, the consensus across tests was achieved only for the EGR3 regulon. We identified EGR3 in the prefrontal cortex as a potential key target, robustly repressed in both BD signatures. Considering that EGR3 translates environmental stimuli into long-term changes in the brain, disruption in biological pathways involving EGR3 may induce an impaired response to stress and influence on risk for psychiatric disorders, particularly BD.
• Huentelman, M. J., Muppana, L., Corneveaux, J. J., Dinu, V., Pruzin, J. J., Reiman, R., Borish, C. N., De Both, M., Ahmed, A., Todorov, A., Cloninger, C. R., Zhang, R., Ma, J., & Gallitano, A. L. (2015). Association of SNPs in EGR3 and ARC with Schizophrenia Supports a Biological Pathway for Schizophrenia Risk. PloS one, 10(10), e0135076.
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  We have previously hypothesized a biological pathway of activity-dependent synaptic plasticity proteins that addresses the dual genetic and environmental contributions to schizophrenia. Accordingly, variations in the immediate early gene EGR3, and its target ARC, should influence schizophrenia susceptibility. We used a pooled Next-Generation Sequencing approach to identify variants across these genes in U.S. populations of European (EU) and African (AA) descent. Three EGR3 and one ARC SNP were selected and genotyped for validation, and three SNPs were tested for association in a replication cohort. In the EU group of 386 schizophrenia cases and 150 controls EGR3 SNP rs1877670 and ARC SNP rs35900184 showed significant associations (p = 0.0078 and p = 0.0275, respectively). In the AA group of 185 cases and 50 controls, only the ARC SNP revealed significant association (p = 0.0448). The ARC SNP did not show association in the Han Chinese (CH) population. However, combining the EU, AA, and CH groups revealed a highly significant association of ARC SNP rs35900184 (p = 2.353 x 10(-7); OR [95% CI] = 1.54 [1.310-1.820]). These findings support previously reported associations between EGR3 and schizophrenia. Moreover, this is the first report associating an ARC SNP with schizophrenia and supports recent large-scale GWAS findings implicating the ARC complex in schizophrenia risk. These results support the need for further investigation of the proposed pathway of environmentally responsive, synaptic plasticity-related, schizophrenia genes.
• Maple, A. M., Zhao, X., Elizalde, D. I., McBride, A. K., & Gallitano, A. L. (2015). Htr2a Expression Responds Rapidly to Environmental Stimuli in an Egr3-Dependent Manner. ACS chemical neuroscience, 6(7), 1137-42.
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  Pharmacologic and genetic findings have implicated the serotonin 2A receptor (5-HT2AR) in the etiology of schizophrenia. Recent studies have shown reduced 5-HT2AR levels in schizophrenia patients, yet the cause of this difference is unknown. Environmental factors, such as stress, also influence schizophrenia risk, yet little is known about how environment may affect this receptor. To determine if acute stress alters 5-HT2AR expression, we examined the effect of sleep deprivation on cortical Htr2a mRNA in mice. We found that 6 h of sleep deprivation induces a twofold increase in Htr2a mRNA, a more rapid effect than has been previously reported. This effect requires the immediate early gene early growth response 3 (Egr3), as sleep deprivation failed to induce Htr2a expression in Egr3-/- mice. These findings provide a functional link between two schizophrenia candidate genes and an explanation of how environment may influence a genetic predisposition for schizophrenia.
• Nie, F., Wang, X., Zhao, P., Yang, H., Zhu, W., Zhao, Y., Chen, B., Valenzuela, R. K., Zhang, R., Gallitano, A. L., & Ma, J. (2015). Genetic analysis of SNPs in CACNA1C and ANK3 gene with schizophrenia: A comprehensive meta-analysis. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics, 168(8), 637-48.
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  Recently, genome-wide association studies (GWAS), meta-analyses, and replication studies focusing on bipolar disorder (BD) have implicated the α-1C subunit of the L-type voltage-dependent calcium channel (CACNA1C) and ankyrin 3 (ANK3) genes in BD. Based on the hypothesis that both schizophrenia (SZ) and BD may share some common genetic risk factors, we investigated the association of CACNA1C and ANK3 with SZ using meta-analytic techniques, combining all published data up to April 2015. Nine teams, including four European decent samples and five Asian samples, contributed 14,141 cases and 30,679 controls for the analysis of CACNA1C rs1006737 and SZ. A significant difference was identified between patients and controls for the A-allele of rs1006737 in combined studies (Z = 6.02, P = 1.74E-09), in European studies (Z = 4.08, P = 4.50E-05), and in Asian studies (Z = 4.60, P = 4.22E-06). Meanwhile, for the T-allele of ANK3 rs10761482 (1,794 cases versus 1,395 controls), a significant association was observed in combined samples (Z = 2.06, P = 0.04) and in Asian samples (Z = 3.10, P = 0.002). In summary, our study provides further evidence for the positive association of CACNA1C and ANK3 with SZ. These results support the hypothesis that both SZ and BD share common genetic risk factors. Further research is needed to examine the functions of CACNA1C and ANK3, and their interacting partners in the molecular, developmental, and pathophysiological processes in SZ. © 2015 Wiley Periodicals, Inc.
• Gallitano, A. L., Tillman, R., Dinu, V., & Geller, B. (2012). Family-based association study of early growth response gene 3 with child bipolar I disorder. Journal of affective disorders, 138(3).
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  The risk for relapse of child bipolar I disorder (BP-I) is highly correlated with environmental factors. Immediate early genes of the early growth response (EGR) gene family are activated at high levels in the brain in response to environmental events, including stress, and mediate numerous neurobiological processes that have been associated with mental illness risk. The objective of this study is to evaluate whether single nucleotide polymorphisms (SNPs) in EGR genes are associated with the risk to develop child bipolar I disorder.
• Kurita, M., Holloway, T., García-Bea, A., Kozlenkov, A., Friedman, A. K., Moreno, J. L., Heshmati, M., Golden, S. A., Kennedy, P. J., Takahashi, N., Dietz, D. M., Mocci, G., Gabilondo, A. M., Hanks, J., Umali, A., Callado, L. F., Gallitano, A. L., Neve, R. L., Shen, L., , Buxbaum, J. D., et al. (2012). HDAC2 regulates atypical antipsychotic responses through the modulation of mGlu2 promoter activity. Nature neuroscience, 15(9).
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  Histone deacetylases (HDACs) compact chromatin structure and repress gene transcription. In schizophrenia, clinical studies demonstrate that HDAC inhibitors are efficacious when given in combination with atypical antipsychotics. However, the molecular mechanism that integrates a better response to antipsychotics with changes in chromatin structure remains unknown. Here we found that chronic atypical antipsychotics downregulated the transcription of metabotropic glutamate 2 receptor (mGlu2, also known as Grm2), an effect that was associated with decreased histone acetylation at its promoter in mouse and human frontal cortex. This epigenetic change occurred in concert with a serotonin 5-HT(2A) receptor-dependent upregulation and increased binding of HDAC2 to the mGlu2 promoter. Virally mediated overexpression of HDAC2 in frontal cortex decreased mGlu2 transcription and its electrophysiological properties, thereby increasing psychosis-like behavior. Conversely, HDAC inhibitors prevented the repressive histone modifications induced at the mGlu2 promoter by atypical antipsychotics, and augmented their therapeutic-like effects. These observations support the view of HDAC2 as a promising new target for schizophrenia treatment.
• Williams, A. A., Ingram, W. M., Levine, S., Resnik, J., Kamel, C. M., Lish, J. R., Elizalde, D. I., Janowski, S. A., Shoker, J., Kozlenkov, A., González-Maeso, J., & Gallitano, A. L. (2012). Reduced levels of serotonin 2A receptors underlie resistance of Egr3-deficient mice to locomotor suppression by clozapine. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 37(10).
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  The immediate-early gene early growth response 3 (Egr3) is associated with schizophrenia and expressed at reduced levels in postmortem patients' brains. We have previously reported that Egr3-deficient (Egr3(-/-)) mice display reduced sensitivity to the sedating effects of clozapine compared with wild-type (WT) littermates, paralleling the heightened tolerance of schizophrenia patients to antipsychotic side effects. In this study, we have used a pharmacological dissection approach to identify a neurotransmitter receptor defect in Egr3(-/-) mice that may mediate their resistance to the locomotor suppressive effects of clozapine. We report that this response is specific to second-generation antipsychotic agents (SGAs), as first-generation medications suppress the locomotor activity of Egr3(-/-) and WT mice to a similar degree. Further, in contrast to the leading theory that sedation by clozapine results from anti-histaminergic effects, we show that H1 histamine receptors are not responsible for this effect in C57BL/6 mice. Instead, selective serotonin 2A receptor (5HT(2A)R) antagonists ketanserin and MDL-11939 replicate the effect of SGAs, repressing the activity in WT mice at a dosage that fails to suppress the activity of Egr3(-/-) mice. Radioligand binding revealed nearly 70% reduction in 5HT(2A)R expression in the prefrontal cortex of Egr3(-/-) mice compared with controls. Egr3(-/-) mice also exhibit a decreased head-twitch response to 5HT(2A)R agonist 1-(2,5-dimethoxy 4-iodophenyl)-2-amino propane (DOI). These findings provide a mechanism to explain the reduced sensitivity of Egr3(-/-) mice to the locomotor suppressive effects of SGAs, and suggest that 5HT(2A)Rs may also contribute to the sedating properties of these medications in humans. Moreover, as the deficit in cortical 5HT(2A)R in Egr3(-/-) mice aligns with numerous studies reporting decreased 5HT(2A)R levels in the brains of schizophrenia patients, and the gene encoding the 5HT(2A)R is itself a leading schizophrenia candidate gene, these findings suggest a potential mechanism by which putative dysfunction in EGR3 in humans may influence risk for schizophrenia.
• Williams, A., Ingram, W. M., Levine, S., Resnik, J., Janowski, S., Kamel, C., Lish, J., Elizalde, D., Kozlenkov, A., González-Maeso, J., & Gallitano-Mendel, A. L. (2011). Resistance of Egr3-deficient mice to sedation by clozapine is mediated by the 5HT2A receptor.. Neurospychopharmacology, S183-184.
• Gallitano-Mendel, A., Wozniak, D. F., Pehek, E. A., & Milbrandt, J. (2008). Mice lacking the immediate early gene Egr3 respond to the anti-aggressive effects of clozapine yet are relatively resistant to its sedating effects. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 33(6).
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  Immediate early genes (IEGs) of the early growth response gene (Egr) family are activated in the brain in response to stress, social stimuli, and administration of psycho-active medications. However, little is known about the role of these genes in the biological or behavioral response to these stimuli. Here we show that mice lacking the IEG transcription factor Egr3 (Egr3-/- mice) display increased aggression, and a decreased latency to attack, in response to the stressful social stimulus of a foreign intruder. Together with our findings of persistent and intrusive olfactory-mediated social investigation of conspecifics, these results suggest increased impulsivity in Egr3-/- mice. We also show that the aggression of Egr3-/- mice is significantly inhibited with chronic administration of the antipsychotic medication clozapine. Despite their sensitivity to this therapeutic effect of clozapine, Egr3-/- mice display a marked resistance to the sedating effects of acute clozapine compared with WT littermate controls. This indicates that the therapeutic, anti-aggressive action of clozapine is separable from its sedating activity, and that the biological abnormality resulting from loss of Egr3 distinguishes these different mechanisms. Thus Egr3-/- mice may provide an important tool for elucidating the mechanism of action of clozapine, as well as for understanding the biology underlying aggressive behavior. Notably, schizophrenia patients display a similar decreased susceptibility to the side effects of antipsychotic medications compared to non-psychiatric controls, despite the medications producing a therapeutic response. This suggests the possibility that Egr3-/- mice may provide insight into the neurobiological abnormalities underlying schizophrenia.
• Gallitano-Mendel, A., Izumi, Y., Tokuda, K., Zorumski, C. F., Howell, M. P., Muglia, L. J., Wozniak, D. F., & Milbrandt, J. (2007). The immediate early gene early growth response gene 3 mediates adaptation to stress and novelty. Neuroscience, 148(3).
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  Stress and exploration of novel environments induce neural expression of immediate early gene transcription factors (IEG-TFs). However, as yet no IEG-TF has been shown to be required for the normal biological or behavioral responses to these stimuli. Here we show that mice deficient for the IEG-TF early growth response gene (Egr) 3, display accentuated behavioral responses to the mild stress of handling paralleled by increased release of the stress hormone corticosterone. Egr3-/- mice also display abnormal responses to novelty, including heightened reactivity to novel environments and failure to habituate to social cues or startling acoustic stimuli. In a Y-maze spontaneous alternation task, they perform fewer sequential arm entries than controls, suggesting defects in immediate memory. Because stress and novelty stimulate hippocampal long-term depression (LTD), and because abnormalities in habituation to novelty and Y-maze performance have been associated with LTD deficits, we examined this form of synaptic plasticity in Egr3-/- mice. We found that Egr3-/- mice fail to establish hippocampal LTD in response to low frequency stimulation and exhibit dysfunction of an ifenprodil-sensitive (NR1/NR2B) N-methyl-d-aspartate receptor subclass. Long term potentiation induction was not altered. The NR2B-dependent dysfunction does not result from transcriptional regulation of this subunit by Egr3, because NR2B mRNA levels did not differ in the hippocampi of Egr3-/- and control mice. These findings are the first demonstration of the requirement for an IEG-TF in mediating the response to stress and novelty, and in the establishment of LTD.
• Ko, S. W., Ao, H. S., Gallitano-Mendel, A. L., Qui, C. S., Wei, F., Milbrandt, J., & Zhou, M. (2005). Transcription factor Egr-1 is required for long-term fear memory and anxiety. Sheng Li Xue Bao, 4(57), 421-432.
• Ko, S. W., Vadakkan, K. I., Ao, H., Gallitano-Mendel, A., Wei, F., Milbrandt, J., & Zhuo, M. (2005). Selective contribution of Egr1 (zif/268) to persistent inflammatory pain. The journal of pain : official journal of the American Pain Society, 6(1).
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  The zinc finger transcription factor Egr1 is critical for coupling extracellular signals to changes in cellular gene expression. Expression of Egr1, as well as other immediate early genes, is up-regulated in response to a number of noxious stimuli. Activity-dependent activation of Egr1 has been reported in forebrain regions, including the anterior cingulate cortex (ACC), after peripheral injury. However, no study has reported a direct contribution of Egr1 to behavioral nociceptive responses. Here, we use Egr1 knockout mice to show that Egr1 is selectively required for behavioral responses to persistent inflammatory pain. Behavioral responses to peripheral inflammation were significantly reduced in Egr1 knockout mice, whereas responses to acute noxious stimuli were normal. In addition, inflammation triggered an up-regulation of Egr1 expression in the ACC of wild-type mice. Last, synaptic potentiation induced by theta (theta) burst stimulation in the ACC was significantly reduced or blocked in Egr1 knockout mice. Our study suggests that the transcription factor Egr1 plays a selective role in nociceptive behavioral responses to persistent inflammatory pain but not to acute noxious stimuli.
• Corcoran, C., Gallitano, A., Leitman, D., & Malaspina, D. (2001). The neurobiology of the stress cascade and its potential relevance for schizophrenia. Journal of psychiatric practice, 7(1).
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  This review explores the neurobiology of stress and its possible role in the etiology of schizophrenia. Major life events may play a role in onset and relapse in schizophrenia. Other data suggest that early stress exposure increases schizophrenia risk, especially in individuals with latent vulnerability. Animal research has led to an elucidation of the mechanisms by which stress and cortisol are toxic to the hippocampus and impair cognition. Associations among these factors have been found in a variety of human conditions, including psychiatric illness and normal aging. These mechanisms are plausible in schizophrenia, which is characterized by a degree of cortisol dysregulation, hippocampal abnormality, and cognitive impairment. Characterization of the role of the stress cascade in schizophrenia has implications for novel pharmacologic and other treatment, especially for cognitive symptoms, which are debilitating and largely refractory to treatment.
• Gallitano-Mendel, A., & Finkelstein, R. (1998). Ectopic orthodenticle expression alters segment polarity gene expression but not head segment identity in the Drosophila embryo. Developmental biology, 199(1).
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  The cephalic gap genes specify anterior head development in the Drosophila embryo. However, the mechanisms of action of these genes remain poorly understood. Here, we focused on the cephalic gap gene orthodenticle (otd), which establishes a specific region of the anterior head. It has been proposed that otd acts in a combinatorial fashion with the cephalic gap genes empty spiracles (ems) and buttonhead (btd) to assign segmental identities in this region. To test this model, we used a heat-inducible transgene to generate pulses of ubiquitous otd expression during embryonic development. Ectopic otd expression caused significant defects in head formation, including the duplication of sensory structures derived from otd-dependent segments. However, these defects do not appear to result from the transformation of head segment identities predicted by the combinatorial model. Instead, they correlate with specific regulatory effects of otd on the expression of the segment polarity genes engrailed (en) and wingless (wg). Ectopic otd expression also caused the loss of head structures derived from the maxillary segment, which lies posterior to the otd domain. We show that this effect is associated with otd repression of the homeotic selector gene Deformed (Dfd).
• Gallitano-Mendel, A., & Finkelstein, R. (1997). Novel segment polarity gene interactions during embryonic head development in Drosophila. Developmental biology, 192(2).
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  In the trunk of the Drosophila embryo, the segment polarity genes are initially activated by the pair-rule genes, and later maintain each other's expression through a complex network of cross-regulatory interactions. These interactions, which are critical to cell fate specification, are similar in each of the trunk segments. To determine whether segment polarity gene expression is established differently outside the trunk, we studied the regulation of the genes hedgehog (hh), wingless (wg), and engrailed (en) in each of the segments of the developing head. We show that the cross-regulatory relationships among these genes, as well as their initial mode of activation, in the anterior head are significantly different from those in the trunk. In addition, each head segment exhibits a unique network of segment polarity gene interactions. We propose that these segment-specific interactions evolved to specify the high degree of structural diversity required for head morphogenesis.
• Boundy, V. A., Luedtke, R. R., Gallitano, A. L., Smith, J. E., Filtz, T. M., Kallen, R. G., & Molinoff, P. B. (1993). Expression and characterization of the rat D3 dopamine receptor: pharmacologic properties and development of antibodies. The Journal of pharmacology and experimental therapeutics, 264(2).
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  A baculovirus expression system provided an enriched source of biologically and immunologically active D3 dopamine receptors. Receptors expressed in Spodoptera frugiperda insect (Sf9) cells at a density of 5 to 15 pmol/mg of protein displayed high affinity for the antagonists, eticlopride, fluphenazine and spiroperidol, and the agonist, N-propylnorapomorphine. The binding of agonists was not sensitive to GTP. Antisera raised against synthetic peptides in the third intracellular loop of the D3 dopamine receptor immunoprecipitated binding sites for (S)-3-[125I]-iodo-2-hydroxy-5,6-dimethoxy-N-[(1-ethyl-2-pyrrolidinyl)- methyl]-benzamide from solubilized extracts of infected Sf9 cells and detergent extracts of rat caudate. These antisera specifically recognized a single band on immunoblots of Sf9 cells infected with recombinant D3 baculovirus. Both the immunoprecipitation and immunoblot reactions were blocked by preincubation of the antisera with the immunization peptide. These results suggest that the D3 receptor protein is expressed in rat brain.
• Teicher, M. H., Barber, N. I., Gelbard, H. A., Gallitano, A. L., Campbell, A., Marsh, E., & Baldessarini, R. J. (1993). Developmental differences in acute nigrostriatal and mesocorticolimbic system response to haloperidol. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 9(2).
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  Dose-dependent effects of haloperidol (2.66 nmol/kg to 79.8 mmol/kg, IP) on levels of dopamine, homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC) were assessed in the corpus striatum, nucleus accumbens, and medial prefrontal cortex (PFCTX) of 18-, 30-, and 110-day-old rats. Eighteen-day-old rats were 35% and 63% more sensitive than adults to the effects of haloperidol on striatal and accumbens turnover and had steeper dose-response curves. The dose-response function in the PFCTX was similar to striatum at 18 days, but became shallower and nonsigmoidal with age. Maximally effective doses of haloperidol produced, at all ages, a comparable percent rise in DOPAC levels in all regions. With maturation, the percent rise in HVA progressively outstripped DOPAC response in nucleus accumbens and striatum. Overall, prominent developmental differences emerged in these regions in their sensitivity and response to haloperidol, which are consistent with previously reported differences in behavioral sensitivity.
• Andrews, K. M., McGowan, M. K., Gallitano, A., & Grossman, S. P. (1992). Water intake during chronic preoptic infusions of osmotically active or inert solutions. Physiology & behavior, 52(2).
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  To further elucidate the role of the lateral preoptic area (LPO) as an osmoreceptive region, rats received chronic infusions (2 weeks) of low volumes (0.5 microliters/h) solutions of hypertonic sodium chloride (NaCl; 0.16 M), hypertonic potassium chloride (KCl; 0.16 M), hypertonic (0.32 M) or hypotonic (0.16 M) mannitol, isotonic saline, or water delivered bilaterally via subcutaneous osmotic minipumps attached to intracranial cannulae. All cannulae terminated within the anterior hypothalamus-preoptic region. Hypertonic NaCl and KCl increased water intake over preinfusion levels in the majority of animals tested. However, the effects were variable, including some sizable increases as well as decreases. Hypertonic mannitol decreased daily water intake in 15 of 25 rats and produced essentially no change in the average intake of the group. Isotonic NaCl produced smaller increases and decreases, while water produced larger changes in individual rats, but neither solution had a significant effect on the average intake of the group. None of the infusates significantly altered food intake.
• Teicher, M. H., Gallitano, A. L., Gelbard, H. A., Evans, H. K., Marsh, E. R., Booth, R. G., & Baldessarini, R. J. (1991). Dopamine D1 autoreceptor function: possible expression in developing rat prefrontal cortex and striatum. Brain research. Developmental brain research, 63(1-2).
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  Synthesis-modulating dopamine (DA) autoreceptor function was studied in vivo using gamma-butyrolactone (GBL) to block propagation along DA axons. DA synthesis was measured by the accumulation of L-3,4-dihydroxyphenylalanine (L-DOPA) after inhibition of aromatic L-amino acid decarboxylase. GBL treatment markedly increased DOPA accumulation in both the striatum and prefrontal cortex of developing rats. The selective DA partial D1 agonist SKF-38393 inhibited this GBL-induced rise in DA synthesis in both the striatum and prefrontal cortex of 15- and 22-day-old rats, but not in adults. The effects of SKF-38393 in developing rats were mimicked by the non-catechol D1 partial agonist CY-208-243, and were blocked by the D1 antagonist SCH-23390, suggesting receptor mediation. The mixed D2/D3 agonist quinpirole attenuated DA synthesis in striatum of both two-week-old and adult rats, but failed to inhibit the GBL-induced increase in DA synthesis in the developing prefrontal cortex. These findings suggest that synthesis-modulating D1-like receptor function may emerge transiently in the developing mammalian forebrain. In the adult striatum these functions appear to be subsumed by D2-like receptors, whereas all synthesis-modulating DA receptor function in prefrontal cortex appears to be essentially lost with maturation.
• Gelbard, H. A., Teicher, M. H., Baldessarini, R. J., Gallitano, A., Marsh, E. R., Zorc, J., & Faedda, G. (1990). Dopamine D1 receptor development depends on endogenous dopamine. Brain research. Developmental brain research, 56(1).
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  Profound depletion of forebrain dopamine by 6-hydroxydopamine in neonatal rats (day 3) was associated with up to 82% loss of D1 receptor sites labeled with [3H]SCH-23390 at day 21. Administration of the selective D1 agonist SKF-38393 (days 6-18) abolished the correlation between D1 receptor density and DA concentrations, even with greater than 99% depletion of DA. In intact control animals, there was an inverse correlation between spontaneous variation in levels of DA and D1 receptor site density in forebrain tissue (r = -0.79) which also was abolished by treatment with the D1 agonist. Thus, D1 receptor density may be regulated by reciprocal regulatory processes during normal development, but may fail to develop in the absence of an adequate level of stimulation.

Presentations

• Gallitano-Mendel, A. L. (2019, March). Pilot Proposal to Develop a Rapid and Cost-Effective Diagnostic Test for Schizophrenia.. 4th Annual Arizona Biomedical Research Consortium Conference.
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  Campbell JM, Maple AM, Chung S, Gallitano AL: Pilot Proposal to Develop a Rapid and Cost-Effective Diagnostic Test for Schizophrenia. 4th Annual Arizona Biomedical Research Consortium Conference, Phoenix, AZ, March 2, 2019
• Gallitano-Mendel, A. L., Muppana, L., Corneveaux, J., Monib, A., & Huentelman, M. (2013, November). Case-control and family association study of early growth response gene 3 with schizophrenia.. Society for Neuroscience Annual Meeting.
• Williams, A. A., Ingram, W. M., Levine, S., Resnik, J., Kamel, C. M., Lish, J., Elizalde, D., Janowski, S. A., Kozlenkov, A., González-Maeso, J., & Gallitano-Mendel, A. L. (2012, July). Reduced levels of serotonin 2A receptors underlie resistance of Egr3-deficient mice to locomotor suppression by clozapine.. Serotonin Club 25th Anniversary Meeting. Montpellier, France.
• Gallitano-Mendel, A. L., Todorov, A., Dinu, V., Selvaraj, S., Cloninger, C. R., Todd, R., & Milbrandt, J. (2009, March). Evaluating the influence of EGR3, an environmentally-regulated immediate early gene, on the risk to develop schizophrenia.. Keystone Symposium: The Molecular Basis of Schizophrenia and Bipolar Disorder. Keystone, CO.
• Gallitano-Mendel, A. L. (2008, November). "Integrative approaches to candidate gene models of schizophrenia: exploring the neuregulin/ErbB4 pathway". Annual Society for Neuroscience Meeting. Washington D.C..
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  Talk entitled Dysfunction of the immediate early gene transcription factor Egr3 is implicated in schizophrenia; in the mini-symposium co-chaired by Joshua Gordon, M.D., Ph.D. and Amelia Gallitano, M.D., Ph.D.
• Gallitano-Mendel, A. L., Boundy, V., Leudtke, R., & Molinoff, P. B. (1992, Spring). Properties of the rat dopamine D3 receptor expressed in SF9 cells.. 18th Annual Meeting of the Eastern Student Research Forum. Miami, FL.

Poster Presentations

• Gallitano-Mendel, A. L. (2019, March 6). Egr3-/- mice, a mouse-model of schizophrenia, show decreased levels of Htr2a mRNA in the anterior frontal cortex after sleep deprivation compared to WT mice.. Scholarly Project Symposium. Phoenix, AZ: UACOM-Phoenix.
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  Elizalde DI, Maple AM, Vannan A, Meyers KT, Gallitano AL: Egr3-/- mice, a mouse-model of schizophrenia, show decreased levels of Htr2a mRNA in the anterior frontal cortex after sleep deprivation compared to WT mice. UACOM-Phoenix Scholarly Project Symposium, March 6, 2019
• Gallitano-Mendel, A. L. (2019, May 16). EGR3 is required for activity dependent Bdnf factor exon IV and VI induction in the mouse hippocampus.. Arizona Alzheimer’s Consortium Scientific Conference.
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  Marballi KK, Meyers KT, Zhao X, Campbell JM, Gallitano AL: EGR3 is required for activity dependent Bdnf factor exon IV and VI induction in the mouse hippocampus. Arizona Alzheimer’s Consortium Scientific Conference, May 16, 2019.
• Gallitano-Mendel, A. L. (2019, November). Strategic initiative to create a Women in Medicine and Science (WIMS) program at a recently established and independently accredited College of Medicine.. AAMC Learn, Serve, Lead. Phoenix, AZ: AAMC American Association of Medical Colleges.
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  Currier Thomas T, Gulati M, Hartmark-Hill J, Mallin E, Lucio F, Parrish J, Muhammad S, Nelson L, O’Malley C, Garcia-Filion P, Mahnert N, Federico G, Titelbaum A, Gonzales R, Herbst-Kralovetz M, Hale T, Gallitano A. Strategic initiative to create a Women in Medicine and Science (WIMS) program at a recently established and independently accredited College of Medicine. AAMC-Learn, Serve, Lead. November 2019, Phoenix, AZ.
• Martinez, G. F., Gallitano-Mendel, A. L., Nelson, L. R., Lucio, F., Hartmark-Hill, J. R., Garcia, P. C., Gulati, M., Mallin, E., Thomas, T., & Herbst-Kralovetz, M. (2019, November). Strategic initiative to create a Women in Medicine and Science (WIMS) program at a recently established and independently accredited College of Medicine. AAMC Learn Serve Lead. Phoenix, AZ: AAMC.

Reviews

• Gallitano-Mendel, A. L. (2006. Folie a Une: Personal Accounts of One of the Most Intriguing Phenomena in Psychiatry..
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  [Review of the book Divided Minds: Twin Sisters and Their Journey Through Schizophrenia]PsycCRITIQUES-Contemporary Psychology: APA Review of Books; Published online March 8, 2006

Others

• Williams, A., Ingram, W. M., Kozlenkov, A., González-Maeso, J., & Gallitano-Mendel, A. L. (2011, Spring). Resistance of Egr3-deficient mice to sedation by clozapine is mediated by the 5HT2A receptor.. Soc. for Neuroscience.
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  Program No. 368.15/ll24, 2011 Abstract Viewer/Itinerary Planner. Washington D.C.
• Gallitano-Mendel, A. L., Wozniak, D. F., Boyle, M., Muglia, L., & Milbrandt, J. (2005, Spring). Mice deficient for Egr3 show a heightened response to environmental stressors consistent with a schizophrenia phenotype.. Soc. for Neuroscience.
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  Program No., 2005 Abstract Viewer/Itinerary Planner. Washington, D.C.
• Gallitano-Mendel, A. L., Wozniak, D. F., & Milbrandt, J. (2004, Spring). Mice deficient for the immediate early gene Egr3 show emotional behavior abnormalities consistent with a schizophrenia phenotype.. Soc. for Neuroscience.
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  Program No. 797.14, 2004 Abstract Viewer/Itinerary Planner. San Diego, CA
• Gallitano-Mendel, A. L., & Finkelstein, R. (1996, Spring). Ectopic expression of orthodenticle reveals differential regulation of segment polarity genes in the embryonic head segment primordial.. Annual Drosophila Research Conf..
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  San Diego, CA
• Gallitano-Mendel, A. L., Wang, Y., & Finkelstein, R. (1995, Spring). orthodenticle regulation in embryonic head development. Annual Drosophila Research Conf.
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  Atlanta, GA
• Gelbard, H. A., Teicher, M. H., Gallitano-Mendel, A. L., & Baldessarini, R. J. (1989, Spring). Neonatal Depletion of Dopamine Decreases D1 and Forskolin Binding Sites in Rat Striatum. Society for Neuroscience Abstracts.