Pub Date : 2025-01-29DOI: 10.1038/s41380-025-02909-1
Silas A. Buck, Samuel J. Mabry, Jill R. Glausier, Tabitha Banks-Tibbs, Caroline Ward, Jenesis Kozel, Chen Fu, Kenneth N. Fish, David A. Lewis, Ryan W. Logan, Zachary Freyberg
Age-related dopamine (DA) neuron loss is a primary feature of Parkinson’s disease. However, whether similar biological processes occur during healthy aging, but to a lesser degree, remains unclear. We therefore determined whether midbrain DA neurons degenerate during aging in mice and humans. In mice, we identified no difference in midbrain neuron numbers throughout aging. Despite this, we found age-related decreases in midbrain mRNA expression of tyrosine hydroxylase (Th), the rate limiting enzyme of DA synthesis. Among midbrain glutamatergic cells, we similarly identified age-related declines in vesicular glutamate transporter 2 (Vglut2) mRNA expression. In co-transmitting Th+/Vglut2+ neurons, Th and Vglut2 transcripts decreased with aging. However, Th and Vglut2 protein levels in striatal synaptic release sites (e.g., terminals and axonal projections) did not differ throughout aging. Similar to the mouse, an initial study of human brain showed no effect of aging on midbrain neuron number with a concomitant decrease in TH and VGLUT2 mRNA expression. Unlike in mice, the density of striatal TH+ dopaminergic terminals was lower in aged human subjects. However, TH and VGLUT2 protein levels were unaffected in the remaining striatal boutons. Finally, in contrast to Th and Vglut2 mRNA, expression of most ribosomal genes in Th+ neurons was either maintained or even upregulated during aging. This suggests a homeostatic mechanism where age-related declines in transcriptional efficiency are overcome by ongoing ribosomal translation. Overall, we demonstrate species-conserved transcriptional effects of aging in midbrain dopaminergic and glutamatergic neurons that are not accompanied by marked cell death or lower striatal protein expression. This opens the door to novel therapeutic approaches to maintain neurotransmission and bolster neuronal resilience.
{"title":"Aging disrupts the coordination between mRNA and protein expression in mouse and human midbrain","authors":"Silas A. Buck, Samuel J. Mabry, Jill R. Glausier, Tabitha Banks-Tibbs, Caroline Ward, Jenesis Kozel, Chen Fu, Kenneth N. Fish, David A. Lewis, Ryan W. Logan, Zachary Freyberg","doi":"10.1038/s41380-025-02909-1","DOIUrl":"https://doi.org/10.1038/s41380-025-02909-1","url":null,"abstract":"<p>Age-related dopamine (DA) neuron loss is a primary feature of Parkinson’s disease. However, whether similar biological processes occur during healthy aging, but to a lesser degree, remains unclear. We therefore determined whether midbrain DA neurons degenerate during aging in mice and humans. In mice, we identified no difference in midbrain neuron numbers throughout aging. Despite this, we found age-related decreases in midbrain mRNA expression of tyrosine hydroxylase (<i>Th</i>), the rate limiting enzyme of DA synthesis. Among midbrain glutamatergic cells, we similarly identified age-related declines in vesicular glutamate transporter 2 (<i>Vglut2</i>) mRNA expression. In co-transmitting <i>Th</i><sup>+</sup>/<i>Vglut2</i><sup>+</sup> neurons, <i>Th</i> and <i>Vglut2</i> transcripts decreased with aging. However, Th and Vglut2 protein levels in striatal synaptic release sites (<i>e.g</i>., terminals and axonal projections) did not differ throughout aging. Similar to the mouse, an initial study of human brain showed no effect of aging on midbrain neuron number with a concomitant decrease in <i>TH</i> and <i>VGLUT2</i> mRNA expression. Unlike in mice, the density of striatal TH<sup>+</sup> dopaminergic terminals was lower in aged human subjects. However, TH and VGLUT2 protein levels were unaffected in the remaining striatal boutons. Finally, in contrast to <i>Th</i> and <i>Vglut2</i> mRNA, expression of most ribosomal genes in <i>Th</i><sup>+</sup> neurons was either maintained or even upregulated during aging. This suggests a homeostatic mechanism where age-related declines in transcriptional efficiency are overcome by ongoing ribosomal translation. Overall, we demonstrate species-conserved transcriptional effects of aging in midbrain dopaminergic and glutamatergic neurons that are not accompanied by marked cell death or lower striatal protein expression. This opens the door to novel therapeutic approaches to maintain neurotransmission and bolster neuronal resilience.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"9 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143054766","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-28DOI: 10.1038/s41380-025-02914-4
Na Cai, Brad Verhulst, Ole A Andreassen, Jan Buitelaar, Howard J Edenberg, John M Hettema, Michael Gandal, Andrew Grotzinger, Katherine Jonas, Phil Lee, Travis T Mallard, Manuel Mattheisen, Michael C Neale, John I Nurnberger, Wouter J Peyrot, Elliot M Tucker-Drob, Jordan W Smoller, Kenneth S Kendler
{"title":"Correction: Assessment and ascertainment in psychiatric molecular genetics: challenges and opportunities for cross-disorder research.","authors":"Na Cai, Brad Verhulst, Ole A Andreassen, Jan Buitelaar, Howard J Edenberg, John M Hettema, Michael Gandal, Andrew Grotzinger, Katherine Jonas, Phil Lee, Travis T Mallard, Manuel Mattheisen, Michael C Neale, John I Nurnberger, Wouter J Peyrot, Elliot M Tucker-Drob, Jordan W Smoller, Kenneth S Kendler","doi":"10.1038/s41380-025-02914-4","DOIUrl":"https://doi.org/10.1038/s41380-025-02914-4","url":null,"abstract":"","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143059832","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-26DOI: 10.1038/s41380-025-02904-6
Maria De Risi, Lorenzo Cusimano, Xabier Bujanda Cundin, Mariateresa Pizzo, Ylenia Gigante, Mariagrazia Monaco, Chiara Di Eugenio, Elvira De Leonibus
Lysosomal storage disorders characterized by defective heparan sulfate (HS) degradation, such as Mucopolysaccharidosis type IIIA-D (MPS-IIIA-D), result in neurodegeneration and dementia in children. However, dementia is preceded by severe autistic-like behaviours (ALBs), presenting as hyperactivity, stereotypies, social interaction deficits, and sleep disturbances. The absence of experimental studies on ALBs’ mechanisms in MPS-III has led clinicians to adopt symptomatic treatments, such as antipsychotics, which are used for non-genetic neuropsychiatric disorders. However, they have limited efficacy in MPS-III and lead to higher extrapyramidal effects, leaving ALBs in MPS-IIIA as an unmet medical need with a significant burden on patients and their families. Using mouse and cellular models of MPS-IIIA, we have previously shown that ALBs result from increased proliferation of mesencephalic dopamine neurons during embryogenesis. In adulthood, MPS-IIIA mice exhibit an imbalance of dopaminergic receptor subtypes, resulting in striatal overstimulation of the D1 dopamine receptor (D1R)-direct pathway, contrasting with a downregulation of the D2 dopamine receptor (D2R)-indirect pathway. In this study, we aimed to provide an evidence-based pharmacological approach for managing ALBs in MPS-IIIA. We hypothesized that rebalancing dopaminergic receptor signalling with a D1R antagonist, rather than a D2 antagonist, would lead to safe and effective treatment. Neither risperidone nor methylphenidate improves ALBs in the MPS-IIIA mouse model, with the former showing increased cataleptic (extrapyramidal-like) side effects compared to littermate wild-type animals. Methylphenidate, however, showed some beneficial effects on neuroinflammation and later manifesting dementia-like behaviours. In contrast, ecopipam, a D1 antagonist already used in the clinic for other neuropsychiatric disorders, rescues ALBs, cognition, D1 hyperactivity, and does not worsen neurodegenerative signs. These results align with recent evidence highlighting the clinical relevance of D1 antagonists for neuropsychiatric disorders and pave the way for their use in managing psychotic symptoms in neurodegenerative disorders such as dementia with Lewy bodies.
{"title":"D1 dopamine receptor antagonists as a new therapeutic strategy to treat autistic-like behaviours in lysosomal storage disorders","authors":"Maria De Risi, Lorenzo Cusimano, Xabier Bujanda Cundin, Mariateresa Pizzo, Ylenia Gigante, Mariagrazia Monaco, Chiara Di Eugenio, Elvira De Leonibus","doi":"10.1038/s41380-025-02904-6","DOIUrl":"https://doi.org/10.1038/s41380-025-02904-6","url":null,"abstract":"<p>Lysosomal storage disorders characterized by defective heparan sulfate (HS) degradation, such as Mucopolysaccharidosis type IIIA-D (MPS-IIIA-D), result in neurodegeneration and dementia in children. However, dementia is preceded by severe autistic-like behaviours (ALBs), presenting as hyperactivity, stereotypies, social interaction deficits, and sleep disturbances. The absence of experimental studies on ALBs’ mechanisms in MPS-III has led clinicians to adopt symptomatic treatments, such as antipsychotics, which are used for non-genetic neuropsychiatric disorders. However, they have limited efficacy in MPS-III and lead to higher extrapyramidal effects, leaving ALBs in MPS-IIIA as an unmet medical need with a significant burden on patients and their families. Using mouse and cellular models of MPS-IIIA, we have previously shown that ALBs result from increased proliferation of mesencephalic dopamine neurons during embryogenesis. In adulthood, MPS-IIIA mice exhibit an imbalance of dopaminergic receptor subtypes, resulting in striatal overstimulation of the D1 dopamine receptor (D1R)-direct pathway, contrasting with a downregulation of the D2 dopamine receptor (D2R)-indirect pathway. In this study, we aimed to provide an evidence-based pharmacological approach for managing ALBs in MPS-IIIA. We hypothesized that rebalancing dopaminergic receptor signalling with a D1R antagonist, rather than a D2 antagonist, would lead to safe and effective treatment. Neither risperidone nor methylphenidate improves ALBs in the MPS-IIIA mouse model, with the former showing increased cataleptic (extrapyramidal-like) side effects compared to littermate wild-type animals. Methylphenidate, however, showed some beneficial effects on neuroinflammation and later manifesting dementia-like behaviours. In contrast, ecopipam, a D1 antagonist already used in the clinic for other neuropsychiatric disorders, rescues ALBs, cognition, D1 hyperactivity, and does not worsen neurodegenerative signs. These results align with recent evidence highlighting the clinical relevance of D1 antagonists for neuropsychiatric disorders and pave the way for their use in managing psychotic symptoms in neurodegenerative disorders such as dementia with Lewy bodies.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"38 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143034996","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-22DOI: 10.1038/s41380-025-02896-3
Maite Arribas, Joseph M. Barnby, Rashmi Patel, Robert A. McCutcheon, Daisy Kornblum, Hitesh Shetty, Kamil Krakowski, Daniel Stahl, Nikolaos Koutsouleris, Philip McGuire, Paolo Fusar-Poli, Dominic Oliver
Modelling the prodrome to severe mental disorders (SMD), including unipolar mood disorders (UMD), bipolar mood disorders (BMD) and psychotic disorders (PSY), should consider both the evolution and interactions of symptoms and substance use (prodromal features) over time. Temporal network analysis can detect causal dependence between and within prodromal features by representing prodromal features as nodes, with their connections (edges) indicating the likelihood of one feature preceding the other. In SMD, node centrality could reveal insights into important prodromal features and potential intervention targets. Community analysis can identify commonly occurring feature groups to define SMD at-risk states. This retrospective (2-year) cohort study aimed to develop a global transdiagnostic SMD network of the temporal relationships between prodromal features and to examine within-group differences with sub-networks specific to UMD, BMD and PSY. Electronic health records (EHRs) from South London and Maudsley (SLaM) NHS Foundation Trust were included from 6462 individuals with SMD diagnoses (UMD:2066; BMD:740; PSY:3656). Validated natural language processing algorithms extracted the occurrence of 61 prodromal features every three months from two years to six months before SMD onset. Temporal networks of prodromal features were constructed using generalised vector autoregression panel analysis, adjusting for covariates. Edge weights (partial directed correlation coefficients, z) were reported in autocorrelative, unidirectional and bidirectional relationships. Centrality was calculated as the sum of (non-autoregressive) connections leaving (out-centrality, cout) or entering (in-centrality, cin) a node. The three sub-networks (UMD, BMD, PSY) were compared using permutation analysis, and community analysis was performed using Spinglass. The SMD network revealed strong autocorrelations (0.04 ≤ z ≤ 0.10), predominantly positive connections, and identified aggression (cout = 0.103) and tearfulness (cin = 0.134) as the most central features. Sub-networks for UMD, BMD, and PSY showed minimal differences, with 3.5% of edges differing between UMD and PSY, 0.8% between UMD and BMD, and 0.4% between BMD and PSY. Community analysis identified one positive psychotic community (delusional thinking-hallucinations-paranoia) and two behavioural communities (aggression-cannabis use-cocaine use-hostility, aggression-agitation-hostility) as the most common. This study represents the most extensive temporal network analysis conducted on the longitudinal interplay of SMD prodromal features. The findings provide further evidence to support transdiagnostic early detection services across SMD, refine assessments to detect individuals at risk and identify central features as potential intervention targets.
{"title":"Longitudinal evolution of the transdiagnostic prodrome to severe mental disorders: a dynamic temporal network analysis informed by natural language processing and electronic health records","authors":"Maite Arribas, Joseph M. Barnby, Rashmi Patel, Robert A. McCutcheon, Daisy Kornblum, Hitesh Shetty, Kamil Krakowski, Daniel Stahl, Nikolaos Koutsouleris, Philip McGuire, Paolo Fusar-Poli, Dominic Oliver","doi":"10.1038/s41380-025-02896-3","DOIUrl":"https://doi.org/10.1038/s41380-025-02896-3","url":null,"abstract":"<p>Modelling the prodrome to severe mental disorders (SMD), including unipolar mood disorders (UMD), bipolar mood disorders (BMD) and psychotic disorders (PSY), should consider both the evolution and interactions of symptoms and substance use (prodromal features) over time. Temporal network analysis can detect causal dependence between and within prodromal features by representing prodromal features as nodes, with their connections (edges) indicating the likelihood of one feature preceding the other. In SMD, node centrality could reveal insights into important prodromal features and potential intervention targets. Community analysis can identify commonly occurring feature groups to define SMD at-risk states. This retrospective (2-year) cohort study aimed to develop a global transdiagnostic SMD network of the temporal relationships between prodromal features and to examine within-group differences with sub-networks specific to UMD, BMD and PSY. Electronic health records (EHRs) from South London and Maudsley (SLaM) NHS Foundation Trust were included from 6462 individuals with SMD diagnoses (UMD:2066; BMD:740; PSY:3656). Validated natural language processing algorithms extracted the occurrence of 61 prodromal features every three months from two years to six months before SMD onset. Temporal networks of prodromal features were constructed using generalised vector autoregression panel analysis, adjusting for covariates. Edge weights (partial directed correlation coefficients, <i>z</i>) were reported in autocorrelative, unidirectional and bidirectional relationships. Centrality was calculated as the sum of (non-autoregressive) connections leaving (out-centrality, <i>c</i><sub><i>out</i></sub>) or entering (in-centrality, <i>c</i><sub><i>in</i></sub>) a node. The three sub-networks (UMD, BMD, PSY) were compared using permutation analysis, and community analysis was performed using Spinglass. The SMD network revealed strong autocorrelations (0.04 ≤ <i>z</i> ≤ 0.10), predominantly positive connections, and identified aggression (<i>c</i><sub><i>out</i></sub> = 0.103) and tearfulness (<i>c</i><sub><i>in</i></sub> = 0.134) as the most central features. Sub-networks for UMD, BMD, and PSY showed minimal differences, with 3.5% of edges differing between UMD and PSY, 0.8% between UMD and BMD, and 0.4% between BMD and PSY. Community analysis identified one positive psychotic community (delusional thinking-hallucinations-paranoia) and two behavioural communities (aggression-cannabis use-cocaine use-hostility, aggression-agitation-hostility) as the most common. This study represents the most extensive temporal network analysis conducted on the longitudinal interplay of SMD prodromal features. The findings provide further evidence to support transdiagnostic early detection services across SMD, refine assessments to detect individuals at risk and identify central features as potential intervention targets.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"136 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143020686","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-22DOI: 10.1038/s41380-025-02887-4
Hyewon Kim, Jin Hyung Jung, Kyungdo Han, Hong Jin Jeon
Mental disorders are associated with an increased risk of premature death, including suicide. This study aimed to examine the risk of suicide and all-cause death in patients with mental disorders after considering demographic, clinical, and lifestyle factors. Data from the National Health Insurance Sharing Service database and linked data from Statistics Korea were used. In total, 3,951,398 people aged ≥20 years were eligible for this study. Among the participants, 14 types of mental disorders were identified, and the subsequent incidences of suicide and all-cause death were monitored. The mean age of those with mental disorders and those without mental disorders was 56.5 (SD, 13.6) years and 46.6 (SD, 13.6) years, respectively. During an average follow-up period of 11.1 years (SD, 1.5), 249,830 participants died, of whom 12,290 died by suicide. Overall, the risk of suicide and all-cause death was higher in people with mental disorders than in controls. The risk of suicide was the highest among those with personality disorders, followed by those with bipolar disorder and schizophrenia spectrum disorder. The risk of all-cause death was the highest among those with intellectual disability, followed by those with schizophrenia spectrum disorder and alcohol use disorder. In conclusion, the risk of suicide and all-cause death increased among those with mental disorders, but there was substantial variation between the types of mental disorders for both suicide and all-cause death.
{"title":"Risk of suicide and all-cause death in patients with mental disorders: a nationwide cohort study","authors":"Hyewon Kim, Jin Hyung Jung, Kyungdo Han, Hong Jin Jeon","doi":"10.1038/s41380-025-02887-4","DOIUrl":"https://doi.org/10.1038/s41380-025-02887-4","url":null,"abstract":"<p>Mental disorders are associated with an increased risk of premature death, including suicide. This study aimed to examine the risk of suicide and all-cause death in patients with mental disorders after considering demographic, clinical, and lifestyle factors. Data from the National Health Insurance Sharing Service database and linked data from Statistics Korea were used. In total, 3,951,398 people aged ≥20 years were eligible for this study. Among the participants, 14 types of mental disorders were identified, and the subsequent incidences of suicide and all-cause death were monitored. The mean age of those with mental disorders and those without mental disorders was 56.5 (SD, 13.6) years and 46.6 (SD, 13.6) years, respectively. During an average follow-up period of 11.1 years (SD, 1.5), 249,830 participants died, of whom 12,290 died by suicide. Overall, the risk of suicide and all-cause death was higher in people with mental disorders than in controls. The risk of suicide was the highest among those with personality disorders, followed by those with bipolar disorder and schizophrenia spectrum disorder. The risk of all-cause death was the highest among those with intellectual disability, followed by those with schizophrenia spectrum disorder and alcohol use disorder. In conclusion, the risk of suicide and all-cause death increased among those with mental disorders, but there was substantial variation between the types of mental disorders for both suicide and all-cause death.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"15 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143020687","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Perineuronal nets (PNNs) are a condensed form of extracellular matrix primarily found around parvalbumin-expressing (PV+) interneurons. The postnatal maturation of PV+ neurons is accompanied with the formation of PNNs and reduced plasticity. Alterations in PNN and PV+ neuron function have been described for mental disorders such as schizophrenia and autism. The formation of PNNs is highly dependent on aggrecan, a proteoglycan encoded by the ACAN gene, but it remains unknown if it is produced by the PV+ neurons themselves. Thus, we established a knockout (KO) mouse model (ACANflx/PVcre) and an adeno-associated virus to specifically eliminate aggrecan production from PV+ neurons, in the germline or adult animals, respectively. The germline KO (ACANflx/PVcre) eliminated the expression of PNNs labeled by Wisteria floribunda agglutinin (WFA), the most commonly used PNN marker. Surprisingly, electrophysiological properties of PV+ interneurons and ocular dominance plasticity of adult ACANflx/PVcre mice were similar to controls. In contrast, AAV-mediated ACAN knockout in adult mice increased ocular dominance plasticity. Moreover, in vivo Chondroitinase ABC treatment of KO mice resulted in reduced firing rate of PV+ cells and increased frequency of spontaneous excitatory postsynaptic currents (sEPSC), a phenotype associated with chABC treatment of WT animals. These findings suggest that compensatory mechanisms may be activated during development in response to the germline loss of aggrecan. Indeed, qPCR of bulk tissue indicates that other PNN components, including neurocan and tenascin-R, are expressed at higher levels in the KO animals. Finally, behavioral testing revealed that ACANflx/PVcre mice had similar long-term memory as controls in the Morris water maze. However, they employed bolder search strategies during spatial learning and showed lower level of anxiety-related behavior in an open field and zero maze.
{"title":"Differential impacts of germline and adult aggrecan knockout in PV+ neurons on perineuronal nets and PV+ neuronal function","authors":"Sverre Grødem, Elise Holter Thompson, Malin Benum Røe, Guro Helen Vatne, Ingeborg Nymoen Nystuen, Alessio Buccino, Tarjei Otterstad, Torkel Hafting, Marianne Fyhn, Kristian Kinden Lensjø","doi":"10.1038/s41380-025-02894-5","DOIUrl":"https://doi.org/10.1038/s41380-025-02894-5","url":null,"abstract":"<p>Perineuronal nets (PNNs) are a condensed form of extracellular matrix primarily found around parvalbumin-expressing (PV+) interneurons. The postnatal maturation of PV+ neurons is accompanied with the formation of PNNs and reduced plasticity. Alterations in PNN and PV+ neuron function have been described for mental disorders such as schizophrenia and autism. The formation of PNNs is highly dependent on aggrecan, a proteoglycan encoded by the ACAN gene, but it remains unknown if it is produced by the PV+ neurons themselves. Thus, we established a knockout (KO) mouse model (ACANflx/PVcre) and an adeno-associated virus to specifically eliminate aggrecan production from PV+ neurons, in the germline or adult animals, respectively. The germline KO (ACANflx/PVcre) eliminated the expression of PNNs labeled by <i>Wisteria floribunda</i> agglutinin (WFA), the most commonly used PNN marker. Surprisingly, electrophysiological properties of PV+ interneurons and ocular dominance plasticity of adult ACANflx/PVcre mice were similar to controls. In contrast, AAV-mediated ACAN knockout in adult mice increased ocular dominance plasticity. Moreover, in vivo Chondroitinase ABC treatment of KO mice resulted in reduced firing rate of PV+ cells and increased frequency of spontaneous excitatory postsynaptic currents (sEPSC), a phenotype associated with chABC treatment of WT animals. These findings suggest that compensatory mechanisms may be activated during development in response to the germline loss of aggrecan. Indeed, qPCR of bulk tissue indicates that other PNN components, including neurocan and tenascin-R, are expressed at higher levels in the KO animals. Finally, behavioral testing revealed that ACANflx/PVcre mice had similar long-term memory as controls in the Morris water maze. However, they employed bolder search strategies during spatial learning and showed lower level of anxiety-related behavior in an open field and zero maze.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"10 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142992099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-22DOI: 10.1038/s41380-025-02903-7
Yi-Zhi Wang, Jeffrey N. Savas
We would like to express our sincere gratitude to Dr. Ruiying Ma and Dr. Kihoon Han for their thoughtful comments on our recent publication, “Neuron type-specific proteomics reveals distinct Shank3 proteoforms in iSPNs and dSPNs lead to striatal synaptopathy in Shank3B–/–mice“ [1, 2]. We are delighted by their strong interest in our work and found their two publications on Shank3NT both insightful and potentially relevant [3, 4]. Their research highlights the presence of Shank3NT in the Shank3B–/– brain and proposes a potential hypothesis that this may be due to potential off-target effects related to the neomycin resistance cassette in the Shank3 gene of the Shank3B–/– mouse model.
Drs. Ma and Han raised concerns about our decision not to discuss the potential “off-target effects related to the neomycin resistance cassette in the Shank3 gene” in this widely used mouse model of autism spectrum disorder (ASD). They also expressed unease over the wording in our paper’s title, specifically “distinct Shank3 proteoforms in iSPNs and dSPNs in Shank3B−/− mice.”
{"title":"Reply to “Concerns regarding the interpretation of Shank3 protein isoforms expressed in Shank3B−/− mice: potential off-target effects by a neomycin resistance cassette”","authors":"Yi-Zhi Wang, Jeffrey N. Savas","doi":"10.1038/s41380-025-02903-7","DOIUrl":"https://doi.org/10.1038/s41380-025-02903-7","url":null,"abstract":"<p>We would like to express our sincere gratitude to Dr. Ruiying Ma and Dr. Kihoon Han for their thoughtful comments on our recent publication, “<i>Neuron type-specific proteomics reveals distinct Shank3 proteoforms in iSPNs and dSPNs lead to striatal synaptopathy in Shank3B</i><sup><i>–/–</i></sup> <i>mice</i>“ [1, 2]. We are delighted by their strong interest in our work and found their two publications on Shank3NT both insightful and potentially relevant [3, 4]. Their research highlights the presence of Shank3NT in the <i>Shank3B</i><sup><i>–/–</i></sup> brain and proposes a potential hypothesis that this may be due to potential off-target effects related to the neomycin resistance cassette in the <i>Shank3</i> gene of the <i>Shank3B</i><sup><i>–/–</i></sup> mouse model.</p><p>Drs. Ma and Han raised concerns about our decision not to discuss the potential “off-target effects related to the neomycin resistance cassette in the <i>Shank3</i> gene” in this widely used mouse model of autism spectrum disorder (ASD). They also expressed unease over the wording in our paper’s title, specifically “distinct Shank3 proteoforms in iSPNs and dSPNs in <i>Shank3B</i><sup><i>−/−</i></sup> mice.”</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"62 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143020685","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Non-invasive brain stimulation is promising for treating many neuropsychiatric and neurological conditions. It could be optimized by understanding its intracranial responses in different brain regions. We implanted multi-site intracranial electrodes and systematically assessed the acute responses in these regions to transcranial alternating current stimulation (tACS) at different frequencies. We observed robust neural oscillation changes in the hippocampus and amygdala in response to non-invasive tACS procedures, and these effects were frequency-specific and state-dependent. Notably, the hippocampus responded most strongly and stably to 10 Hz stimulation, with pronounced changes across a wide frequency range, suggesting the potential of 10 Hz oscillatory stimulation to modulate a broad range of neural activity related to cognitive functions. Future work with increased sample sizes is required to determine the clinical implications of these findings for therapeutic efficiency.
{"title":"Frequency-specific and state-dependent neural responses to brain stimulation","authors":"Huichun Luo, Xiaolai Ye, Hui-Ting Cai, Mo Wang, Yue Wang, Qiangqiang Liu, Ying Xu, Ziyu Mao, Yanqing Cai, Jing Hong, Chencheng Zhang, Pengfei Wei, Yong Lu, Quanying Liu, Jiwen Xu, Ti-Fei Yuan","doi":"10.1038/s41380-025-02892-7","DOIUrl":"https://doi.org/10.1038/s41380-025-02892-7","url":null,"abstract":"<p>Non-invasive brain stimulation is promising for treating many neuropsychiatric and neurological conditions. It could be optimized by understanding its intracranial responses in different brain regions. We implanted multi-site intracranial electrodes and systematically assessed the acute responses in these regions to transcranial alternating current stimulation (tACS) at different frequencies. We observed robust neural oscillation changes in the hippocampus and amygdala in response to non-invasive tACS procedures, and these effects were frequency-specific and state-dependent. Notably, the hippocampus responded most strongly and stably to 10 Hz stimulation, with pronounced changes across a wide frequency range, suggesting the potential of 10 Hz oscillatory stimulation to modulate a broad range of neural activity related to cognitive functions. Future work with increased sample sizes is required to determine the clinical implications of these findings for therapeutic efficiency.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"74 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142991470","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-18DOI: 10.1038/s41380-025-02899-0
Chiara Fabbri
Treatment-resistant depression (TRD) is associated with chronic depression, suicidal behaviours, and reduced quality of life. TRD has a demonstrated genetic component, estimated around 8% based on common genetic variation in unrelated individuals. However, only six genome-wide association studies of TRD were published, and no replicated signals at locus or gene level have been identified; furthermore, apparently opposite results were reported in terms of genetic overlap between TRD and other traits. Other than limited power, an important issue of previous studies was the scarce consideration of TRD heterogeneity, as TRD likely comprises different groups and talking about TRDs could be more appropriate. This review points out important issues in the definition of TRD and differences across samples included in previous studies, which can be partly responsible for the inconsistency across results. Different definitions of TRD should not be expected to have similar genetic profiles, and the whole TRD group can partitioned into subgroups, based on clinical and biological features, to increase reproducibility, as exemplified by recent findings. This can be a key factor to develop/repurpose targeted treatments, or simply to aid a more personalised prescription of available medications compared to current clinical practice, that is largely concentrated on the prescription of a limited number of antidepressants compared to those available.
{"title":"Treatment-resistant depression: role of genetic factors in the perspective of clinical stratification and treatment personalisation","authors":"Chiara Fabbri","doi":"10.1038/s41380-025-02899-0","DOIUrl":"https://doi.org/10.1038/s41380-025-02899-0","url":null,"abstract":"<p>Treatment-resistant depression (TRD) is associated with chronic depression, suicidal behaviours, and reduced quality of life. TRD has a demonstrated genetic component, estimated around 8% based on common genetic variation in unrelated individuals. However, only six genome-wide association studies of TRD were published, and no replicated signals at locus or gene level have been identified; furthermore, apparently opposite results were reported in terms of genetic overlap between TRD and other traits. Other than limited power, an important issue of previous studies was the scarce consideration of TRD heterogeneity, as TRD likely comprises different groups and talking about TRDs could be more appropriate. This review points out important issues in the definition of TRD and differences across samples included in previous studies, which can be partly responsible for the inconsistency across results. Different definitions of TRD should not be expected to have similar genetic profiles, and the whole TRD group can partitioned into subgroups, based on clinical and biological features, to increase reproducibility, as exemplified by recent findings. This can be a key factor to develop/repurpose targeted treatments, or simply to aid a more personalised prescription of available medications compared to current clinical practice, that is largely concentrated on the prescription of a limited number of antidepressants compared to those available.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"55 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142988544","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-18DOI: 10.1038/s41380-024-02871-4
Heemin Kang, Bernt D. Glaser, Alina I. Sartorius, Kristin Audunsdottir, Emilie Smith-Meyer Kildal, Terje Nærland, Ole A. Andreassen, Lars T. Westlye, Daniel S. Quintana
Background
Oxytocin has received considerable research attention for its role in affiliative behaviors, particularly regarding its pro-social effects. More recent evidence has pointed to a broader role of oxytocin signaling, which includes non-social cognitive processes. However, meta-analytic data on oxytocin’s effects on non-social cognition is currently limited.
Methods
We registered plans for a systematic review and meta-analysis on the effects of oxytocin administration on non-social executive functions prior to data collection via a time-stamped protocol. We performed searches in PubMed, Europe PubMed Central, and the Bielefeld Academic Search Engine. We conducted a meta-analysis of 20 effect estimates from 13 eligible studies. Subgroup meta-analyses and a test for publication bias were also performed.
Results
We found no overall significant effect of oxytocin administration on non-social executive functions (p = 0.30; Hedges’ g = 0.07). However, effect sizes across sub-categories of executive function varied, where the effect of oxytocin administration was the largest for cognitive flexibility (p = 0.02; Hedges’ g = 0.2). Publication bias was assessed using Robust Bayesian Meta-Analysis, which yielded moderate support for the absence of publication bias (BFPB = 0.32).
Conclusion
Our analysis suggests that oxytocin’s effects may extend beyond social cognitive processing as data synthesis provided evidence supporting a role in non-social cognitive flexibility. The data and analysis output from this meta-analysis can be viewed in a point-and-click web application.
{"title":"Effects of oxytocin administration on non-social executive functions in humans: a preregistered systematic review and meta-analysis","authors":"Heemin Kang, Bernt D. Glaser, Alina I. Sartorius, Kristin Audunsdottir, Emilie Smith-Meyer Kildal, Terje Nærland, Ole A. Andreassen, Lars T. Westlye, Daniel S. Quintana","doi":"10.1038/s41380-024-02871-4","DOIUrl":"https://doi.org/10.1038/s41380-024-02871-4","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background</h3><p>Oxytocin has received considerable research attention for its role in affiliative behaviors, particularly regarding its pro-social effects. More recent evidence has pointed to a broader role of oxytocin signaling, which includes non-social cognitive processes. However, meta-analytic data on oxytocin’s effects on non-social cognition is currently limited.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>We registered plans for a systematic review and meta-analysis on the effects of oxytocin administration on non-social executive functions prior to data collection via a time-stamped protocol. We performed searches in PubMed, Europe PubMed Central, and the Bielefeld Academic Search Engine. We conducted a meta-analysis of 20 effect estimates from 13 eligible studies. Subgroup meta-analyses and a test for publication bias were also performed.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>We found no overall significant effect of oxytocin administration on non-social executive functions (<i>p</i> = 0.30; Hedges’ <i>g</i> = 0.07). However, effect sizes across sub-categories of executive function varied, where the effect of oxytocin administration was the largest for cognitive flexibility (<i>p</i> = 0.02; Hedges’ <i>g</i> = 0.2). Publication bias was assessed using Robust Bayesian Meta-Analysis, which yielded moderate support for the absence of publication bias (<i>BF</i><sub><i>PB</i></sub> = 0.32).</p><h3 data-test=\"abstract-sub-heading\">Conclusion</h3><p>Our analysis suggests that oxytocin’s effects may extend beyond social cognitive processing as data synthesis provided evidence supporting a role in non-social cognitive flexibility. The data and analysis output from this meta-analysis can be viewed in a point-and-click web application.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"3 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142988606","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}