Introduction: Post-stroke epilepsy (PSE) is an important complication of stroke. We aimed to identify genomic associations and build a protein-protein interaction (PPI) network linking stroke- and epilepsy-related genes, using open-source databases for potential clinical insights. Methods: We searched and retrieved genomic data from the National Human Genome Research Institute-European Bioinformatics Institute Catalog, Ensembl Variant Effect Predictor, ClinVar, and Open Targets databases. We conducted PPI network analysis of proteins commonly identified between stroke and epilepsy using STRING 12 and Cytoscape 3.10.0. Network hub proteins were identified through four topological analyses using CytoHubba and functional clusters were determined using Molecular Complex Detection (MCODE). Functional enrichment analysis was performed with the Ingenuity Pathway Analysis tool. Enriched pathways were identified with a false discovery rate (FDR)-corrected p-value < 0.05, and pathways were ranked according to their FDR-corrected p-values. We used GEO RNA-seq expression datasets to validate the findings from GWAS and other databases. Results: The database search identified 3618 unique gene associations (930 for stroke, 2688 for epilepsy, and 115 common between stroke and epilepsy). The resulting PPI network of 115 common proteins contained 108 nodes (proteins) and 145 edges (interactions). The overlapping hub proteins in the PPI network included TK2, MT-ND1, MT-ND2, MT-ND4, MT-ND5, MT-ND6, MT-CO1, MT-CO2, MT-CYB, and POLG. We identified 5 functional clusters in our PPI network (Figure 1), mainly associated with neuroinflammation, oxidative phosphorylation, blood vessel development, mitochondrial matrix, and neuronal migration. Common proteins were enriched in pathways including brain development, neuroinflammation, mitochondrial complex, and oxidative phosphorylation. Of 115 common proteins, we validated 20 common proteins in RNA-seq expression datasets of patients with stroke and epilepsy. We validated 20 proteins associated with cerebrovascular dysfunction in patients with stroke and epilepsy (Figure 2) , and will report protein pathways associated with PSE. Conclusions: This comprehensive analysis identifies key hub proteins and indicates neuroinflammation’s role at the intersection of stroke and epilepsy. Our findings highlight potential biomarkers or therapeutic targets of PSE that warrant further investigation.

BACKGROUND:Women are disproportionately affected by neuropsychiatric symptoms following recovery from acute COVID-19. However, whether there are central nervous system-specific changes in gene expression in women with neuropsychiatric Long COVID (NP-Long COVID) remains unknown. METHODS:Twenty-two women with and 10 women without NP-Long COVID were enrolled from New Haven, Connecticut, and the surrounding region and consented to a blood draw and large volume lumbar puncture. Total RNA was extracted from cerebrospinal fluid (CSF) cells and peripheral blood mononuclear cells (PBMC). Polyadenylated RNA was sequenced, and differential expression analyses were performed. RESULTS:Both CSF and PBMC samples showed differential gene expression associated with Long COVID status. There were CSF-specific differentially expressed genes in people with Long COVID, including in genes related to oxidative stress, reactive oxygen species, and P53 response, indicating compartment-specific immune responses. Some pathways were dysregulated in both the CSF and PBMC of Long COVID compared with controls, including those related to androgen response, MTORC1 signaling, and lipid metabolism. CONCLUSIONS:Women with NP-long COVID show compartment-specific, transcriptional profiles in the CSF with evidence of enrichment in cellular stress pathways. These results underscore the importance of examining CSF-specific molecular profiles to better understand post-viral neurological syndromes.

Stressful events are a leading factor in the development of depression. The medial prefrontal cortex (mPFC) is strongly associated with depression etiology and exposure to uncontrollable stressors results in synaptic dysfunction and loss. Learned helplessness is a behavioral paradigm that measures effects of repeated exposure to uncontrollable, inescapable stress on later responses to escapable stress. We therefore performed a proteomic analysis of mPFC synaptosomes in a mouse learned helplessness model to identify molecular changes that could contribute to functional consequences of inescapable stress. Male and female mice were evaluated at baseline and following exposure to escapable or inescapable stress followed by an active avoidance test. Label-free mass spectrometry followed by pathway and protein-protein interaction network analyses identified alterations in signaling pathways involved in energy metabolism, neurotransmitter signaling, and protein shuttling. Furthermore, phosphoproteomics revealed alterations related to synaptic function, neurotransmitter signaling and protein internalization, as well as changes in activity of kinases previously identified as mediators of antidepressant efficacy (GSK3B) and receptor internalization (ADRBK1). We more deeply examined alterations in the acetylcholine receptor signaling pathway and identified muscarinic receptor proteins (Chrm1, Chrm2, Chrm4) and key proteins involved in their translocation to and from the membrane. These results identify substantial changes in the mPFC proteome following exposure to inescapable stressors. In addition, mPFC muscarinic cholinergic signaling is well placed to mediate responses to an inescapable stressor. This proteomic study will be useful in guiding studies of human mPFC relevant to depression. Data are available via ProteomeXchange with identifier PXD073765.

BackgroundNeurosyphilis is increasing in prevalence but its pathophysiology remains incompletely understood. This study assessed for CNS-specific immune responses during neurosyphilis compared to syphilis without neurosyphilis and compared these immune profiles to those observed in other neuroinflammatory diseases.MethodsParticipants with syphilis were categorized as having neurosyphilis if their cerebrospinal fluid (CSF)-venereal disease research laboratory (VDRL) test was reactive and as having syphilis without neurosyphilis if they had a non-reactive CSF-VDRL test and a white blood cell count <5/μL. Neurosyphilis and syphilis without neurosyphilis participants were matched by rapid plasma reagin titer and HIV status. CSF and plasma were assayed for markers of neuronal injury and glial and immune cell activation. Bulk RNA sequencing was performed on CSF cells, with results stratified by the presence of neurological symptoms.FindingsCSF neopterin and five CSF chemokines had levels significantly higher in individuals with neurosyphilis compared to those with syphilis without neurosyphilis, but no markers of neuronal injury or astrocyte activation were significantly elevated. The CSF transcriptome in neurosyphilis was characterized by genes involved in microglial activation and lipid metabolism and did not differ in asymptomatic versus symptomatic neurosyphilis cases.ConclusionsThe CNS immune response observed in neurosyphilis was comparable to other neuroinflammatory diseases and was present in individuals with neurosyphilis regardless of neurological symptoms, yet there was minimal evidence for neuronal or astrocyte injury. These findings support the need for larger studies of the CSF inflammatory response in asymptomatic neurosyphilis.FundingThis work was funded by the National Institutes of Health, grants K23MH118999 (S.F.F.) and R01NS082120 (C.M.M.).

Abstract The immune milieu within tumors, consisting of diverse cell types including adaptive immune cells as well as macrophages, dendritic cells, natural killer and other innate immune cells, is critical to determining cancer outcome. However, the immune tumor microenvironment (TME) has been challenging to model, owing to inherent inter-species differences. While humanized mice can support human immune cells, the hematopoietic stem and progenitor cells (HSPCs) used for transplantation have been largely limited to fetal or neonatal stem cell sources, necessitating allogeneic experiments with limited applicability. We sought to develop a method to pre-clinically model an individual adult cancer patient, capturing the unique features of an individual such as germline genetic determinants of immune function and somatic tumor heterogeneity, and creating an autologous system. MISTRG6 may be engrafted with low numbers of HSPCs. When engrafted with equivalent numbers of CD34+ cells from human fetal liver (FL), neonatal cord blood (CB), adult mobilized peripheral blood (MPB), or adult bone marrow (BM), MISTRG6 mice harbored greatly increased human hematopoietic cells as a proportion of total hematopoietic cells in peripheral blood compared with NOD-scid-gamma (NSG) and MISTRG mice (p<0.0001). We found that MISTRG6 mice could be engrafted with as few as 1,000 human HSPCs, arguably 100x more efficient than other models, and achieve robust hematopoietic transplantation after 10-12 weeks, indicating the efficiency of this strain in supporting the growth of hematopoietic cells. To better elucidate the mechanism responsible for this enhanced human engraftment, we enumerated human and mouse hematopoietic progenitors in BM of NSG, MISTRG, and MISTRG6 mice. Human progenitors, including CD34+ and CD34+CD38+ cells, were significantly increased in both frequency and absolute numbers in MISTRG and MISTRG6 mice compared with NSG mice (p<0.001), and mouse hematopoietic lin(-)cKit+ (LK) and lin(-)Sca1+cKit+ (LSK) progenitor populations were significantly diminished (p<0.0001), suggesting that the enhanced hematopoietic engraftment observed in MISTRG6 is, in part, a consequence of increased human progenitor frequency and reduced mouse competition. MISTRG6 allows efficient engraftment of patient derived HSPCs. We sought to apply this improved engraftment prospectively to model individual patients’ TME through collection of BM-derived CD34+ cells from patients under active treatment along with tumor tissue from the same patient. At two cancer centers, we enrolled patients with melanoma, NSCLC, PDAC, and HNSCC to provide BM aspirate, peripheral blood, and tumor tissue. CD34+ cells were isolated from BM aspirates and tumor tissue was utilized to generate PDXs. Overall, 71 patients were enrolled, 46 melanoma, 19 NSCLC, 4 PDAC, 2 HNSCC, ages 22-85, 39% females. These yielded autologous, immune-reconstituted MISTRG6 hosts from 14 melanoma, 5 NSCLC, 2 PDAC, and 1 HNSCC patients. Autologously engrafted MISTRG6 mice displayed the gamut of human immune cells of adaptive and innate types in PB at 7 weeks of age. Notably, this included CD33+ myeloid cells such as CD14+CD16− classical, CD14+CD16+ intermediate, and CD14−CD16+ non-classical monocytes. Moreover, human dendritic cells (DCs), key innate immune cells for initiation of anti-tumor responses were readily detected by flow cytometry in spleens of autologously-engrafted mice, including cDC1, cDC2, and pDC cells. MISTRG6 mice bearing a patient’s hematopoietic cells support autologous PDX growth. Having achieved successful engraftment of patient hematopoietic systems in MISTRG6 hosts, we next subcutaneously introduced the patient’s matched PDX tumor tissue to generate autologously engrafted PDX mice. For most patients, tumors grown in autologous HSPC-engrafted hosts were significantly larger than in non-engrafted hosts. Multicolor immunofluorescence staining of PDX tumors demonstrated that human immune cells, including CD3+ T cells, CD14+ and HLA-DR+ myeloid cells, penetrated deeply into the tumor and co-localized with tumor cells as well as with other engrafted immune cells. Indeed, HLA-DR+CD14+macrophages and HLA-DR+CD14(-) dendritic cells were present, and direct physical interaction between T cells and macrophages was evident. Using whole-exome sequencing, we found that 225 somatic changes were shared between patient Mel738’s surgical resection sample, two PDX tumors from non-engrafted mice lacking human immune cells, and two PDX tumors from mice with autologous engraftment. 5 additional changes were shared among the tumor samples and absent from the cell line, with 36 additional mutations being specific to the cell line. These data underscore the capacity of the autologous PDX method to recapitulate the somatic heterogeneity that the patient tumor possesses. Autologous MISTRG6 mice display diverse human immune cell populations and recapitulate an immunosuppressive TME. To fully characterize the autologous MISTRG6 model and investigate mechanisms by which autologous human immune cells enhance tumor growth, we performed single cell transcriptomics on hCD45+-enriched cells from blood and tumor isolated from autologous mice. This revealed 16 distinct cell subtypes, including 3 myeloid, 2 NK cell, 2 CD8 T cell, 3 CD4 T cell, 2 cycling lymphocyte, 1 B cell, and 3 melanoma cell clusters. Subclustering of myeloid cells revealed 9 distinct clusters including 4 monocyte, 4 macrophage, and 1 DC cluster. Comparing CD8 T cells present in blood versus tumor revealed that the most differentially expressed genes (DEGs) found in blood were characteristic of naïve T cells, while genes present in the TME were consistent with activated T cell phenotypes. In addition, sub-clustering revealed 3 distinct CD8 T cell types that included two activated-like populations, with one of these populations also expressing an activated/exhausted program typified by expression of PDCD1, LAG3, and GZMA. Naïve-like T cells were most highly represented in the blood, while activated and activated/exhausted-like genes were more present in the TME. Inhibiting the actions of human VEGF-A blocks the enhanced tumor growth in autologously engrafted mice. Notably, IPA Upstream Regulator Analysis identified VEGFA, a central player in tumor growth and vascularization, as a key upstream inducer of genes in the TME (FDR p= 5.65 × 10−13). Indeed, expression VEGFA itself was nearly absent in blood but induced in the TME, especially in macrophages and VEGFA targets were highly represented among the DEGs between tumor and blood.To test the relevance of VEGF-A in the TME, we selectively blocked human VEGF-A by treating autologous mice humanized from Mel2 with the anti-hVEGF-A antibody bevacizumab that has high affinity for human VEGF-A yet low affinity for mouse VEGF-A. PDXs grown in untreated autologously engrafted MISTRG6 mice grew significantly larger than those in non-engrafted littermate control hosts (p<0.05). When treated with bevacizumab, the enhanced tumor growth was significantly abrogated, with bevacizumab-treated mice bearing significantly smaller tumors compared with controls (p<0.001). Future Directions: Thus, these in silico and in vivo results suggest that human VEGF-A production in the autologous TME enhances tumor growth in MISTRG6 PDX models and underscores the utility of the MISTRG6 system for pre-clinical testing of drugs that act on human immune components of the TME. By engrafting mice with bone marrow derived stem cells followed by implantation of tumor derived from the same donor, we have demonstrated that autologous MISTRG6 models recapitulate important features of the human TME, including sufficient immunosuppression to prevent tumor clearance, presence of activated/exhausted T cells, and innate immune cells including DCs, monocytes, NK cells, and macrophages, the latter especially relevant to the production of VEGF-A. Citation Format: Michael Chiorazzi, Jan Martinek, Bradley Krasnick, Yunjiang Zheng, Keenan Robbins, Rihao Qu, Gabriel Kaufmann, Zachary Skidmore, Laura Henze, Frederic Brösecke, Adam Adonyi, Jun Zhao, Liang Shan, Esen Sefik, Jacqueline Mudd, Ye Bi, S Peter Goedegebuure, Malachi Griffith, Obi Griffith, Abimbola Oyedeji, Sofia Fertuzinhos, Roland Garcia-Milian, Daniel Boffa, Frank Detterbeck, Andrew Dhanasopon, Justin Blasberg, Benjamin Judson, Scott Gettinger, Katerina Politi, Yuval Kluger, A Karolina Palucka, Ryan Fields, Richard A. Flavell. Autologous humanized PDX modeling for immuno-oncology recapitulates the human tumor microenvironment. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr NG11.

BACKGROUND:Interactions between immune and tumor cells are critical to determining cancer progression and response. In addition, preclinical prediction of immune-related drug efficacy is limited by interspecies differences between human and mouse, as well as inter-person germline and somatic variation. To address these gaps, we developed an autologous system that models the tumor microenvironment (TME) from individual patients with solid tumors. METHOD:With patient-derived bone marrow hematopoietic stem and progenitor cells (HSPCs), we engrafted a patient's hematopoietic system in MISTRG6 mice, followed by transfer of patient-derived xenograft (PDX) tissue, providing a fully genetically matched model to recapitulate the individual's TME. We used this system to prospectively study tumor-immune interactions in patients with solid tumor. RESULTS:Autologous PDX mice generated innate and adaptive immune populations; these cells populated the TME; and tumors from autologously engrafted mice grew larger than tumors from non-engrafted littermate controls. Single-cell transcriptomics revealed a prominent vascular endothelial growth factor A (VEGFA) signature in TME myeloid cells, and inhibition of human VEGF-A abrogated enhanced growth. CONCLUSIONS:Humanization of the interleukin 6 locus in MISTRG6 mice enhances HSPC engraftment, making it feasible to model tumor-immune interactions in an autologous manner from a bedside bone marrow aspirate. The TME from these autologous tumors display hallmarks of the human TME including innate and adaptive immune activation and provide a platform for preclinical drug testing.

Mutations in tubulins cause distinct neurodevelopmental and degenerative diseases termed “tubulinopathies”; however, little is known about the functional requirements of tubulins or how mutations cause cell-specific pathologies. Here, we identify a mutation in the gene Tubb4a that causes degeneration of cerebellar granule neurons and myelination defects. We show that the neural phenotypes result from a cell type–specific enrichment of a dominant mutant form of Tubb4a relative to the expression other β-tubulin isotypes. Loss of Tubb4a function does not underlie cellular pathology but is compensated by the transcriptional up-regulation of related tubulin genes in a cell type–specific manner. This work establishes that the expression of a primary tubulin mutation in mature neurons is sufficient to promote cell-autonomous cell death, consistent with a causative association of microtubule dysfunction with neurodegenerative diseases. These studies provide evidence that mutations in tubulins cause specific phenotypes based on expression ratios of tubulin isotype genes.

Abstract Background Neurosyphilis (NS) is increasing in prevalence in the U.S. but remains challenging to diagnose, particularly in asymptomatic cases. Uncovering central nervous system (CNS) specific immune pathways may shed light on disease pathogenesis and potential biomarkers. Methods Paired cerebrospinal fluid and blood were collected from participants with syphilis without neurological symptoms from 2013–2019. Participants were categorized as NS if CSF VDRL was positive and matched by RPR and date of enrollment to participants without neurosyphilis (non-NS), defined by VDRL negative and CSF WBC < 5/uL. Paired CSF and plasma were run on a 71-plex chemokine/cytokine array, high-sensitivity (SIMOA) ELISA for markers of neuronal and astrocyte injury, and ELISA for neopterin, a marker of intrathecal macrophage/microglial activation. Comparisons between NS and non-NS were made using T-tests and Wilcoxon rank-sum tests, with p-values adjusted (FDR) for multiple comparisons. Results 24 participants were enrolled with characteristics as in Table 1. HIV status, age, race/ethnicity, and plasma RPR values did not significantly differ by group. Six cytokines were significantly (p< 0.05, FDR < 0.10) different in the CSF in NS compared to non-NS, including MIG/CXCL9, IP-10/CXCL10, macrophage-derive-chemokine (MDC), IL-8/CXCL8 and BCA-1/CXCL13, which was previously recognized as elevated in NS (Figure 1B). Neopterin, but no neuronal or astrocyte markers, was elevated in the CSF of NS versus non-NS (p < 0.001) (Figure 1A). After adjusting for multiple comparisons, there were no significant differences between markers in plasma of NS vs non-NS. Differences between NS and non-NS groups were not affected by HIV status. Conclusion There is a distinct and compartmentalized CNS immune response occurring in individuals with NS, as indicated by elevated markers of CNS inflammation and of key chemoattractants, the CXC family of proteins. Elevation of neopterin, but not neuronal injury markers suggest asymptomatic disease elicits an immune response without incurring neuronal damage. These immune biomarkers can provide insight into neuroinflammatory processes during asymptomatic NS and should be explored as potential CSF biomarkers of NS. Disclosures Magnus Gisslen, MD, PhD, Amgen: Honoraria|AstraZeneca: Advisor/Consultant|AstraZeneca: DSMB membership|Biogen: Honoraria|Gilead Sciences: Advisor/Consultant|Gilead Sciences: Honoraria|GlaxoSmithKline/ViiV: Advisor/Consultant|GlaxoSmithKline/ViiV: Honoraria|MSD: Advisor/Consultant|MSD: Honoraria|Novo Nordic: Honoraria|Novocure: Honoraria|Pfizer: Advisor/Consultant|Pfizer: Honoraria|Sanofi: Honoraria.

The hallmark of the cerebral neocortex is its organization into six layers, each containing a characteristic set of cell types and synaptic connections. The transcriptional events involved in laminar development and function still remain elusive. Here, we employed deep sequencing of mRNA and small RNA species to gain insights into transcriptional differences among layers and their temporal dynamics during postnatal development of the mouse primary somatosensory neocortex. We identify a number of coding and noncoding transcripts with specific spatiotemporal expression and splicing patterns. We also identify signature trajectories and gene coexpression networks associated with distinct biological processes and transcriptional overlap between these processes. Finally, we provide data that allow the study of potential miRNA and mRNA interactions. Overall, this study provides an integrated view of the laminar and temporal expression dynamics of coding and noncoding transcripts in the mouse neocortex and a resource for studies of neurodevelopment and transcriptome.

A dynamic interplay between intrinsic regional molecular cues and extrinsic factors from the thalamus shape multiple features of early cortical development. It remains uncertain and controversial, however, whether the initial formation of cortical columns depends on neuronal activity, and there is little evidence that cortical lamination or neuronal differentiation is influenced by extrinsic activity. We examined the role of thalamic-derived factors in cortical development by selectively eliminating glutamatergic synaptic transmission from thalamocortical neurons in mice and found that eliminating thalamocortical neurotransmission prevented the formation of "barrel" columns in somatosensory cortex. Interestingly, based on cytoarchitectonic criteria and genetic markers, blocking thalamocortical neurotransmission also perturbed the development of superficial cortical lamina and the morphologic development of neurons. These experiments demonstrate that barrels and aspects of the layer-dependent pattern of cortical cytoarchitecture, gene expression, and neuronal differentiation depend on thalamocortical neurotransmission, extending the apparent influence of extrinsic, presumably activity-dependent factors, on cortical development.

Autism spectrum disorder (ASD) is a complex developmental syndrome of unknown etiology. Recent studies employing exome- and genome-wide sequencing have identified nine high-confidence ASD (hcASD) genes. Working from the hypothesis that ASD-associated mutations in these biologically pleiotropic genes will disrupt intersecting developmental processes to contribute to a common phenotype, we have attempted to identify time periods, brain regions, and cell types in which these genes converge. We have constructed coexpression networks based on the hcASD "seed" genes, leveraging a rich expression data set encompassing multiple human brain regions across human development and into adulthood. By assessing enrichment of an independent set of probable ASD (pASD) genes, derived from the same sequencing studies, we demonstrate a key point of convergence in midfetal layer 5/6 cortical projection neurons. This approach informs when, where, and in what cell types mutations in these specific genes may be productively studied to clarify ASD pathophysiology.

Fragile X syndrome (FXS), the leading monogenic cause of intellectual disability and autism, results from loss of function of the RNA-binding protein FMRP. Here, we show that FMRP regulates translation of neuronal nitric oxide synthase 1 (NOS1) in the developing human neocortex. Whereas NOS1 mRNA is widely expressed, NOS1 protein is transiently coexpressed with FMRP during early synaptogenesis in layer-and region-specific pyramidal neurons. These include midfetal layer 5 subcortically projecting neurons arranged into alternating columns in the prospective Broca's area and orofacial motor cortex. Human NOS1 translation is activated by FMRP via interactions with coding region binding motifs absent from mouse Nos1 mRNA, which is expressed in mouse pyramidal neurons, but not efficiently translated. Correspondingly, neocortical NOS1 protein levels are severely reduced in developing human FXS cases, but not FMRP-deficient mice. Thus, alterations in FMRP posttranscriptional regulation of NOS1 in developing neocortical circuits may contribute to cognitive dysfunction in FXS.

Brain development and function depend on the precise regulation of gene expression. However, our understanding of the complexity and dynamics of the transcriptome of the human brain is incomplete. Here we report the generation and analysis of exon-level transcriptome and associated genotyping data, representing males and females of different ethnicities, from multiple brain regions and neocortical areas of developing and adult post-mortem human brains. We found that 86 per cent of the genes analysed were expressed, and that 90 per cent of these were differentially regulated at the whole-transcript or exon level across brain regions and/or time. The majority of these spatio-temporal differences were detected before birth, with subsequent increases in the similarity among regional transcriptomes. The transcriptome is organized into distinct co-expression networks, and shows sex-biased gene expression and exon usage. We also profiled trajectories of genes associated with neurobiological categories and diseases, and identified associations between single nucleotide polymorphisms and gene expression. This study provides a comprehensive data set on the human brain transcriptome and insights into the transcriptional foundations of human neurodevelopment.

Cortical excitatory glutamatergic projection neurons and inhibitory GABAergic interneurons follow substantially different developmental programs. In rodents, projection neurons originate from progenitors within the dorsal forebrain, whereas interneurons arise from progenitors in the ventral forebrain. In contrast, it has been proposed that in humans, the majority of cortical interneurons arise from progenitors within the dorsal forebrain, suggesting that their origin and migration is complex and evolutionarily divergent. However, whether molecularly defined human cortical interneuron subtypes originate from distinct progenitors, including those in the ventral forebrain, remains unknown. Furthermore, abnormalities in cortical interneurons have been linked to human disorders, yet no distinct cell population selective loss has been reported. Here we show that cortical interneurons expressing nitric oxide synthase 1, neuropeptide Y, and somatostatin, are either absent or substantially reduced in fetal and infant cases of human holoprosencephaly (HPE) with severe ventral forebrain hypoplasia. Notably, another interneuron subtype normally abundant from the early fetal period, marked by calretinin expression, and different subtypes of projection neuron were present in the cortex of control and HPE brains. These findings have important implications for the understanding of neuronal pathogenesis underlying the clinical manifestations associated with HPE and the developmental origins of human cortical interneuron diversity.

OBJECTIVE:The serotonin 5-HT(1A) receptor may modulate some of the negative, cognitive, and affective symptoms of schizophrenia and is a potential target of action of some antipsychotic drugs. A functional polymorphism in the promoter region of the 5-HT(1A) receptor gene is associated with depression and suicidal behavior. The authors sought to determine whether this polymorphism influences symptom response to antipsychotic drug treatment.METHOD:Sixty-three drug-naive patients with first-episode psychosis who were genotyped for the -1019C/G polymorphism were recruited for this study and received standard care. The Positive and Negative Syndrome Scale and the Calgary Depression Scale were used to monitor symptom changes over 3 months.RESULTS:The polymorphism was associated with, and accounted for much of the variance in, changes in negative and depressive symptoms but not positive symptoms.CONCLUSIONS:These findings identify an important genetic factor predicting much of the response in negative and depressive symptoms to antipsychotic drug treatment.

Investigators of independent studies reported alterations in cytokine serum levels in patients with different mood disorders. Several polymorphisms associated with neuropsychiatric disorders such as schizophrenia and Alzheimer's disease have been reported at the interleukin-1 (IL-1) panel. Here we report the results of three specific polymorphisms at the IL-1alpha, IL-1beta, and IL-1RA genes, which were analyzed in 128 Brazilian subjects: 59 dysthymic patients and 69 normal controls. We found a statistically significant difference (p = 0.002) in the frequency of haplotypes with alleles 2+ (IL-1RA), T+ (IL-1alpha), and C+ (IL-1beta) in patients as compared to controls. We also observed that haplotype IL-1RA1.2/IL-1alpha CT/IL-1beta CC, present in 6 dysthymic patients (10%) was absent in the normal control group (p = 0.012). These results suggest that these polymorphisms might confer a greater susceptibility to develop dysthymia in Brazilian patients. However, to validate these data it will be of great interest to repeat this study in larger samples and other ethnic groups.

Investigators of independent studies reported alterations in cytokine serum levels in patients with different mood disorders. Several polymorphisms associated with neuropsychiatric disorders such as schizophrenia and Alzheimer’s disease have been reported at the interleukin-1 (IL-1) panel. Here we report the results of three specific polymorphisms at the IL-1α, IL-1β, and IL-1RA genes, which were analyzed in 128 Brazilian subjects: 59 dysthymic patients and 69 normal controls. We found a statistically significant difference (p=0.002) in the frequency of haplotypes with alleles 2+ (IL-1RA), T+ (IL-1α), and C+ (IL-1β) in patients as compared to controls. We also observed that haplotype IL-1RA1.2/IL-1α CT/IL-1β CC, present in 6 dysthymic patients (10%) was absent in the normal control group (p=0.012). These results suggest that these polymorphisms might confer a greater susceptibility to develop dysthymia in Brazilian patients. However, to validate these data it will be of great interest to repeat this study in larger samples and other ethnic groups.