@article{pmid41622438,

title = {Thalamic reticular nucleus in the pathophysiology of schizophrenia},

author = {Gonzalo Flores and David J Apam-Castillejos and Hannaford Edwards and Victor M Magdaleno-Madrigal and Juan Nacher and Hiram Tendilla-Beltrán and Lalit K Srivastava},

doi = {10.4103/NRR.NRR-D-25-00928},

issn = {1673-5374},

year  = {2026},

date = {2026-09-01},

journal = {Neural Regen Res},

volume = {21},

number = {9},

pages = {4045--4050},

abstract = {Mechanistic analyses on schizophrenia have traditionally focused on corticolimbic structures such as the prefrontal cortex, hippocampus, and amygdala, given their established roles in cognition. However, the thalamus, a critical hub that interconnects these regions, has garnered comparatively less attention. Of particular interest is the thalamic reticular nucleus, which plays a crucial role in cognition and sensory processing through its connections with the dorsomedial thalamic nucleus and the prefrontal cortex. A potential role of the thalamic reticular nucleus in schizophrenia has been suggested in a few reports; however, recent analyses have identified a specific link between the thalamic reticular nucleus and layer 5 neurons of the prefrontal cortex, a relationship highlighted by our group's earlier findings from 2012, which demonstrated that bilateral thalamic reticular nucleus lesions in adult rats caused neuronal atrophy in these cortical neurons. Building on this foundation, this manuscript explores the role of the thalamic reticular nucleus in schizophrenia neurobiology by reviewing its functional neuroanatomy, its integration within the corticolimbic system, and mechanisms of its potential involvement in the disease. This hypothesis is further developed by describing our novel findings from rats with neonatal ventral hippocampus lesion, widely considered a developmental model for schizophrenia. For the first time, we report dendritic spine pathology in thalamic reticular nucleus neurons, characterized by reduced spine density and a lower proportion of mushroom spines. Furthermore, we demonstrate a decrease in the density of parvalbumin-positive cells within the thalamic reticular nucleus in the neonatal ventral hippocampus lesion model. Together, these findings suggest significant alterations in the corticolimbic network and position the thalamic reticular nucleus as a complex yet promising mechanistic contributor to the neurobiology of schizophrenia.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid41391739,

title = {Characterization of the expression and function of schizophrenia risk gene Dtnbp1 in the suprachiasmatic nucleus},

author = {Genavieve Elizabeth Maloney and Marie-Ève Cloutier and Micah Joseph Provost and Lalit K Srivastava and Nicolas Cermakian},

doi = {10.1016/j.neuroscience.2025.12.029},

issn = {1873-7544},

year  = {2026},

date = {2026-02-01},

journal = {Neuroscience},

volume = {595},

pages = {250--261},

abstract = {Schizophrenia (SZ) is a debilitating neurodevelopmental disorder with environmental and genetic origins. Circadian rhythm disruption is observed in a large proportion of patients with SZ. We previously found that Sandy (Sdy) mice, which carry a mutation in the SZ-associated gene dystrobrevin binding protein 1 (Dtnbp1, also called Dysbindin-1), show altered rhythms of locomotor activity. To address the possible mechanisms underlying the circadian phenotype of these mice, we set out to address the expression and function of Dtnbp1 in the suprachiasmatic nucleus (SCN), the location of the central circadian clock in mammals. Immunohistochemistry revealed that DTNBP1 protein was expressed throughout the SCN, with stronger expression in the dorsal part. DTNBP1 immunoreactive signal colocalized with neurons expressing either arginine vasopressin peptide (AVP) or vasoactive intestinal peptide (VIP). Fluorescent in situ hybridization showed a time-dependent variation of expression of Dtnbp1 transcript, and confirmed its location in cell bodies of AVP- and VIP-expressing cells. Since DTNBP1 is known to be implicated in synaptic transmission, we studied the effect of Dtnbp1 gene mutation on SCN neuropeptide expression and neuroanatomy in Sdy mice. There was no significant effect of the Dtnbp1 mutation on AVP and VIP expression in the SCN. We then used transmission electron microscopy to study synaptic morphology and secretory vesicles. There was no effect of the Dtnbp1 mutation on these neuroanatomical features. Our data show that Dtnbp1 is expressed with a daily rhythm across the SCN, but that a loss-of-function mutation did not impair AVP or VIP neuropeptide expression nor general synaptic architecture.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid40118225,

title = {Large-scale effects of prenatal inflammation and early life circadian disruption in mice: Implications for neurodevelopmental disorders},

author = {Tara C Delorme and Danusa M Arcego and Danae Penichet and Nicholas O'Toole and Nikki Huebener and Patrícia P Silveira and Lalit K Srivastava and Nicolas Cermakian},

doi = {10.1016/j.bbi.2025.03.023},

issn = {1090-2139},

year  = {2025},

date = {2025-07-01},

journal = {Brain Behav Immun},

volume = {127},

pages = {409--422},

abstract = {Around 80 % of individuals with neurodevelopmental disorders such as schizophrenia and autism spectrum disorders experience disruptions in sleep/circadian rhythms. We explored whether environmental circadian disruption interacts with prenatal infection, a risk factor for neurodevelopmental disorders, to induce sex-specific deficits in mice. A maternal immune activation (MIA) protocol was used by injecting pregnant mice with viral mimic poly IC or saline at E9.5. Juvenile/adolescent male and female offspring (3-7 weeks old) were then subjected to a standard light:dark cycle (12:12LD) or to constant light (LL). Significant interactions between treatment (MIA, control) and lighting (12:12LD, LL) were evident in behaviors related to cognition, anxiety, and sociability. This pattern persisted in our RNA sequencing analysis of the dorsal hippocampus, where poly IC exposure resulted in numerous differentially expressed genes (DEGs) in males, while exposure to both poly IC and LL led to a marked reduction in DEGs. Through WGCNA analysis, many significant gene modules were found to be positively associated with poly IC (vs. saline) and LL (vs. LD) in males (fewer in females). Many of the identified hub-bottleneck genes were homologous to human genes associated with sleep/circadian rhythms and neurodevelopmental disorders as revealed by GWA studies. The MIA- and LL-associated modules were enriched in microglia gene signatures, which was paralleled by trends of effects of each of the factors on microglia morphology. In conclusion, in a mouse model of prenatal infection, circadian disruption induced by LL during adolescence acts as a modulator of the effects of MIA at behavioral, cellular, and molecular levels.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid40356274,

title = {Early-Life Ventral Hippocampal Lesion and Circadian Disruption Result in Altered Behavior in Adult Mice in a Sex-Dependent Manner},

author = {Ahmed A Bouteldja and Lianne A Marceau and Lalit K Srivastava and Nicolas Cermakian},

doi = {10.1111/ejn.70134},

issn = {1460-9568},

year  = {2025},

date = {2025-05-01},

journal = {Eur J Neurosci},

volume = {61},

number = {9},

pages = {e70134},

abstract = {Schizophrenia is believed to arise because of the interaction of early abnormal neurodevelopment with environmental insults during key developmental stages later in life. Furthermore, disrupted circadian rhythms are reported in patients, and circadian disruption is associated with increased symptom severity, hinting at its role as a risk factor. Using the neonatal ventral hippocampal lesion mouse model, we aimed to assess the interaction between disrupted ventral hippocampal development with circadian disruption during adolescence in affecting behavior in male and female C57BL/6N mice. After conducting a series of behavioral tests, we found that the neonatal ventral hippocampal lesion and chronic jet lag during adolescence synergistically led to increased anxiety-like behavior in males. In females, the lesion prevented increased social preference caused by chronic jet lag and led to increased anxiety-like behavior. Mice were then moved to running wheel cages to measure their locomotor activity rhythms. We found that the lesioned male mice exposed to chronic jet lag exhibited fragmented rhythms under constant darkness. Moreover, lesioned male and female mice, especially those exposed to chronic jet lag, had reduced activity counts under constant light. These findings highlight that the interaction of abnormal neurodevelopment in areas relevant to schizophrenia with circadian disruption during adolescence results in lasting behavioral changes in a sex-dependent manner in mice.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38956130,

title = {Loss of dysbindin-1 in excitatory neurons in mice impacts NMDAR-dependent behaviors, neuronal morphology and synaptic transmission in the ventral hippocampus},

author = {Sanjeev K Bhardwaj and Moushumi Nath and Tak Pan Wong and Lalit K Srivastava},

doi = {10.1038/s41598-024-65566-4},

issn = {2045-2322},

year  = {2024},

date = {2024-07-01},

journal = {Sci Rep},

volume = {14},

number = {1},

pages = {15239},

abstract = {Dysbindin-1, a protein encoded by the schizophrenia susceptibility gene DTNBP1, is reduced in the hippocampus of schizophrenia patients. It is expressed in various cellular populations of the brain and implicated in dopaminergic and glutamatergic transmission. To investigate the impact of reduced dysbindin-1 in excitatory cells on hippocampal-associated behaviors and synaptic transmission, we developed a conditional knockout mouse model with deletion of dysbindin-1 gene in CaMKIIα expressing cells. We found that dysbindin-1 reduction in CaMKII expressing cells resulted in impaired spatial and social memories, and attenuation of the effects of glutamate N-methyl-d-asparate receptor (NMDAR) antagonist MK801 on locomotor activity and prepulse inhibition of startle (PPI). Dysbindin-1 deficiency in CaMKII expressing cells also resulted in reduced protein levels of NMDAR subunit GluN1 and GluN2B. These changes were associated with increased expression of immature dendritic spines in basiliar dendrites and abnormalities in excitatory synaptic transmission in the ventral hippocampus. These results highlight the functional relevance of dysbindin-1 in excitatory cells and its implication in schizophrenia-related pathologies.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38816965,

title = {The circadian system: A neglected player in neurodevelopmental disorders},

author = {Ahmed A Bouteldja and Danae Penichet and Lalit K Srivastava and Nicolas Cermakian},

doi = {10.1111/ejn.16423},

issn = {1460-9568},

year  = {2024},

date = {2024-07-01},

journal = {Eur J Neurosci},

volume = {60},

number = {2},

pages = {3858--3890},

abstract = {Patients with neurodevelopmental disorders, such as autism spectrum disorder, often display abnormal circadian rhythms. The role of the circadian system in these disorders has gained considerable attention over the last decades. Yet, it remains largely unknown how these disruptions occur and to what extent they contribute to the disorders' development. In this review, we examine circadian system dysregulation as observed in patients and animal models of neurodevelopmental disorders. Second, we explore whether circadian rhythm disruptions constitute a risk factor for neurodevelopmental disorders from studies in humans and model organisms. Lastly, we focus on the impact of psychiatric medications on circadian rhythms and the potential benefits of chronotherapy. The literature reveals that patients with neurodevelopmental disorders display altered sleep-wake cycles and melatonin rhythms/levels in a heterogeneous manner, and model organisms used to study these disorders appear to support that circadian dysfunction may be an inherent characteristic of neurodevelopmental disorders. Furthermore, the pre-clinical and clinical evidence indicates that circadian disruption at the environmental and genetic levels may contribute to the behavioural changes observed in these disorders. Finally, studies suggest that psychiatric medications, particularly those prescribed for attention-deficit/hyperactivity disorder and schizophrenia, can have direct effects on the circadian system and that chronotherapy may be leveraged to offset some of these side effects. This review highlights that circadian system dysfunction is likely a core pathological feature of neurodevelopmental disorders and that further research is required to elucidate this relationship.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37179433,

title = {Behavioral and cellular responses to circadian disruption and prenatal immune activation in mice},

author = {Tara C Delorme and William Ozell-Landry and Nicolas Cermakian and Lalit K Srivastava},

doi = {10.1038/s41598-023-34363-w},

issn = {2045-2322},

year  = {2023},

date = {2023-05-01},

journal = {Sci Rep},

volume = {13},

number = {1},

pages = {7791},

abstract = {Most individuals with neurodevelopmental disorders (NDDs), including schizophrenia and autism spectrum disorders, experience disruptions in sleep and circadian rhythms. Epidemiological studies indicate that exposure to prenatal infection increases the risk of developing NDDs. We studied how environmental circadian disruption contributes to NDDs using maternal immune activation (MIA) in mice, which models prenatal infection. Pregnant dams were injected with viral mimetic poly IC (or saline) at E9.5. Adult poly IC- and saline-exposed offspring were subjected to 4 weeks of each of the following: standard lighting (LD1), constant light (LL) and standard lighting again (LD2). Behavioral tests were conducted in the last 12 days of each condition. Poly IC exposure led to significant behavioral differences, including reduced sociability (males only) and deficits in prepulse inhibition. Interestingly, poly IC exposure led to reduced sociability specifically when males were tested after LL exposure. Mice were exposed again to either LD or LL for 4 weeks and microglia were characterized. Notably, poly IC exposure led to increased microglial morphology index and density in dentate gyrus, an effect attenuated by LL exposure. Our findings highlight interactions between circadian disruption and prenatal infection, which has implications in informing the development of circadian-based therapies for individuals with NDDs.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35297476,

title = {Altered excitatory and decreased inhibitory transmission in the prefrontal cortex of male mice with early developmental disruption to the ventral hippocampus},

author = {Moushumi Nath and Sanjeev K Bhardwaj and Lalit K Srivastava and Tak Pan Wong},

doi = {10.1093/cercor/bhac107},

issn = {1460-2199},

year  = {2023},

date = {2023-01-01},

journal = {Cereb Cortex},

volume = {33},

number = {3},

pages = {865--880},

abstract = {Ventral hippocampal (vHPC)-prefrontal cortical (PFC) pathway dysfunction is a core neuroimaging feature of schizophrenia. However, mechanisms underlying impaired connectivity within this pathway remain poorly understood. The vHPC has direct projections to the PFC that help shape its maturation. Here, we wanted to investigate the effects of early developmental vHPC perturbations on long-term functional PFC organization. Using whole-cell recordings to assess PFC cellular activity in transgenic male mouse lines, we show early developmental disconnection of vHPC inputs, by excitotoxic lesion or cell-specific ablations, impairs pyramidal cell firing output and produces a persistent increase in excitatory and decrease in inhibitory synaptic inputs onto pyramidal cells. We show this effect is specific to excitatory vHPC projection cell ablation. We further identify PV-interneurons as a source of deficit in inhibitory transmission. We find PV-interneurons are reduced in density, show a reduced ability to sustain high-frequency firing, and show deficits in excitatory inputs that emerge over time. We additionally show differences in vulnerabilities to early developmental vHPC disconnection, wherein PFC PV-interneurons but not pyramidal cells show deficits in NMDA receptor-mediated current. Our results highlight mechanisms by which the PFC adapts to early developmental vHPC perturbations, providing insights into schizophrenia circuit pathology.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36168739,

title = {Exposure to Circadian Disruption During Adolescence Interacts With a Genetic Risk Factor to Modify Schizophrenia-relevant Behaviors in a Sex-dependent Manner},

author = {Marie-Ève Cloutier and Lalit K Srivastava and Nicolas Cermakian},

doi = {10.1177/07487304221125363},

issn = {1552-4531},

year  = {2022},

date = {2022-12-01},

journal = {J Biol Rhythms},

volume = {37},

number = {6},

pages = {655--672},

abstract = { is a gene associated with schizophrenia. Postmortem studies found a reduced expression of  in regions associated with schizophrenia in patients' brains. Sandy (Sdy) mice have a loss-of-function mutation in  gene, resulting in behavioral deficits and brain changes similar to those seen in patients with schizophrenia. We previously showed that exposing adult Sdy mice to circadian disruption led to an exacerbation of schizophrenia-relevant behaviors. Here we asked whether the interaction between this genetic risk factor and circadian disruption occurs during adolescence, a period when environmental insults can promote schizophrenia symptoms, and whether sex affects this interaction. Starting at postnatal day 21, wild-type (WT) and Sdy males and females were housed for 4 weeks either in a 12 h light:12 h dark (LD 12:12) cycle or under chronic jetlag (CJL). Then, after 2 weeks in LD 12:12, behavioral assessments were conducted, including elevated plus maze (EPM), novel object recognition (NOR), social interaction, and prepulse inhibition (PPI) of acoustic startle. NOR and social novelty tests showed that, surprisingly, CJL during adolescence had opposite effects on WT and Sdy males, that is, behavioral deficits in WT males while rescuing preexisting deficits in Sdy mice. CJL led to decreased sociability in WT and Sdy mice while decreasing PPI only in females. Sdy mice showed decreased anxiety-like behavior compared with wild-type (WT), which was further accentuated by CJL in males. Thus, circadian disruption during adolescence, on its own or in association with  mutation, can influence cognition, sociability, sensorimotor gating, and anxiety-like behaviors in a sex-dependent manner.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36620856,

title = {Alterations in prefrontal cortical neuregulin-1 levels in post-pubertal rats with neonatal ventral hippocampal lesions},

author = {Kenya Watanabe and Osamu Nakagawasai and Syu-Ichi Kanno and Satoru Mitazaki and Hiroshi Onogi and Kohei Takahashi and Kei-Ichiro Watanabe and Koichi Tan-No and Masaaki Ishikawa and Lalit K Srivastava and Remi Quirion and Takeshi Tadano},

doi = {10.3389/fnbeh.2022.1008623},

issn = {1662-5153},

year  = {2022},

date = {2022-01-01},

journal = {Front Behav Neurosci},

volume = {16},

pages = {1008623},

abstract = {Genetic studies in humans have implicated the gene encoding neuregulin-1 (NRG-1) as a candidate susceptibility gene for schizophrenia. Furthermore, it has been suggested that NRG-1 is involved in regulating the expression and function of the -methyl-D-aspartate receptor and the GABA receptor in several brain areas, including the prefrontal cortex (PFC), the hippocampus, and the cerebellum. Neonatal ventral hippocampal lesioned (NVHL) rats have been considered as a putative model for schizophrenia with characteristic post-pubertal alteration in response to stress and neuroleptics. In this study, we examined NRG-1, erb-b2 receptor tyrosine kinase 4 (erbB4), and phospho-erbB4 (p-erbB4) levels in the PFC and the distribution of NRG-1 in the NVHL rats by using immunoblotting and immunohistochemical analyses. Neonatal lesions were induced by bilateral injection of ibotenic acid in the ventral hippocampus of postnatal day 7 Sprague-Dawley (SD)-rats. NVHL rats showed significantly decreased levels of NRG-1 and p-erbB4 in the PFC compared to sham controls at post-pubertal period, while the level of erbB4 did not differ between sham and NVHL rats. Moreover, microinjection of NRG-1 into the mPFC improved NVHL-induced prepulse inhibition deficits. Our study suggests PFC NRG-1 alteration as a potential mechanism in schizophrenia-like behaviors in the NVHL model.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid33412254,

title = {Altered circadian rhythms in a mouse model of neurodevelopmental disorders based on prenatal maternal immune activation},

author = {Tara C Delorme and Lalit K Srivastava and Nicolas Cermakian},

doi = {10.1016/j.bbi.2020.12.030},

issn = {1090-2139},

year  = {2021},

date = {2021-03-01},

journal = {Brain Behav Immun},

volume = {93},

pages = {119--131},

abstract = {Individuals with neurodevelopmental disorders, such as schizophrenia and autism spectrum disorder, exhibit various sleep and circadian rhythm disturbances that often persist and worsen throughout the lifespan. To study the interaction between circadian rhythm disruption and neurodevelopmental disorders, we utilized a mouse model based on prenatal maternal immune activation (MIA). We hypothesized that MIA exposure would lead to impaired circadian locomotor activity rhythms in adult mouse offspring. We induced MIA by injecting pregnant dams with polyinosinic:polycytidylic acid (poly IC) at embryonic day 9.5, then aged resulting offspring to adulthood. We first confirmed that poly IC injection in pregnant dams elevated plasma levels of pro- and anti-inflammatory cytokines and chemokines. We then placed adult offspring in running wheels and subjected them to various lighting conditions. Overall, poly IC-exposed male offspring exhibited altered locomotor activity rhythms, reminiscent of individuals with neurodevelopmental disorders. In particular, we report increased (subjective) day activity across 3 different lighting conditions: 12 h of light, 12 h of dark (12:12LD), constant darkness (DD) and constant light. Further data analysis indicated that this was driven by increased activity in the beginning of the (subjective) day in 12:12LD and DD, and at the end of the day in 12:12LD. This effect was sex-dependent, as in utero poly IC exposure led overall to much milder alterations in locomotor activity rhythms in female offspring than in male offspring. We also confirmed that the observed behavioral impairments in adult poly IC-exposed offspring were not due to differences in maternal behavior. These data further our understanding of the link between circadian rhythm disruption and neurodevelopmental disorders and may have implications for mitigating risk to the disorders and/or informing the development of circadian-based therapies.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid33340529,

title = {Mice with dopaminergic neuron-specific deletion of DTNBP-1 gene show blunted nucleus accumbens dopamine release and associated behaviors},

author = {Sanjeev K Bhardwaj and Qiming Cui and Luc Moquin and Alain Gratton and Bruno Giros and Lalit K Srivastava},

doi = {10.1016/j.neuropharm.2020.108440},

issn = {1873-7064},

year  = {2021},

date = {2021-02-01},

journal = {Neuropharmacology},

volume = {184},

pages = {108440},

abstract = {Reduced expression of a schizophrenia-associated gene Dystrobrevin Binding Protein 1 (DTNBP1) and its protein product dysbindin-1, has been reported in the brains of schizophrenia patients. DTNBP1-null mutant Sdy (Sandy) mice exhibit several behavioral features relevant to schizophrenia. Changes in dopaminergic as well as glutamatergic and GABAergic neurotransmission in cortico-limbic regions have been reported in Sdy mice. Since dysbindin-1 is expressed in multiple brain regions, it is not known whether dopamine (DA) changes observed in Sdy null mutants are due to dysbindin-1 deficiency in DAergic neurons specifically. Here, using a mouse line with conditional knockout (cKO) of DTNBP1 in DA neurons, we studied the effects of dysbindin-1 deficiency on DA release and DA-dependent behaviors. Spontaneous locomotor activity of cKO mice in novel environment was significantly reduced initially but was comparable at later time points with littermate controls. However, the locomotion-enhancing effect of a low dose of d-amphetamine (d-AMPH; 2.5 mg/kg, ip) was significantly attenuated in the cKO mice suggesting a dampened mesolimbic DA transmission. Similarly, the prepulse inhibition disrupting effect of d-AMPH was found to be significantly reduced in the mutant mice. No significant differences between the cKO and control mice were observed in tests of anxiety, spatial learning and memory and social interaction. In- vivo microdialysis in the nucleus accumbens (NAc) showed a decrease in d-AMPH-induced extracellular DA release in the cKO mice. No significant alterations in protein levels of DA transporter, phosphorylated CaM kinase-II or Akt308 in the NAc were observed in the cKO mice. Taken together, our data suggest an important role of dysbindin-1 in maintaining mesolimbic DA tone and call for further investigations identifying mechanisms linking dysbindin-1, DA and schizophrenia.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32721441,

title = {Neurodevelopmental insights into circuit dysconnectivity in schizophrenia},

author = {Moushumi Nath and Tak Pan Wong and Lalit K Srivastava},

doi = {10.1016/j.pnpbp.2020.110047},

issn = {1878-4216},

year  = {2021},

date = {2021-01-01},

journal = {Prog Neuropsychopharmacol Biol Psychiatry},

volume = {104},

pages = {110047},

abstract = {Schizophrenia is increasingly being recognized as a disorder of brain circuits of developmental origin. Animal models, however, have been technically limited in exploring the effects of early developmental circuit abnormalities on the maturation of the brain and associated behavioural outputs. This review discusses evidence of the developmental emergence of circuit abnormalities in schizophrenia, followed by a critical assessment on how animal models need to be adapted through optimized tools in order to spatially and temporally manipulate early developmental events, thereby providing insight into the causal contribution of developmental perturbations to schizophrenia.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32498652,

title = {Are Circadian Disturbances a Core Pathophysiological Component of Schizophrenia?},

author = {Tara C Delorme and Lalit K Srivastava and Nicolas Cermakian},

doi = {10.1177/0748730420929448},

issn = {1552-4531},

year  = {2020},

date = {2020-08-01},

journal = {J Biol Rhythms},

volume = {35},

number = {4},

pages = {325--339},

abstract = {Schizophrenia is a multifactorial disorder caused by a combination of genetic variations and exposure to environmental insults. Sleep and circadian rhythm disturbances are a prominent and ubiquitous feature of many psychiatric disorders, including schizophrenia. There is growing interest in uncovering the mechanistic link between schizophrenia and circadian rhythms, which may directly affect disorder outcomes. In this review, we explore the interaction between schizophrenia and circadian rhythms from 2 complementary angles. First, we review evidence that sleep and circadian rhythm disturbances constitute a fundamental component of schizophrenia, as supported by both human studies and animal models with genetic mutations related to schizophrenia. Second, we discuss the idea that circadian rhythm disruption interacts with existing risk factors for schizophrenia to promote schizophrenia-relevant behavioral and neurobiological abnormalities. Understanding the mechanistic link between schizophrenia and circadian rhythms will have implications for mitigating risk to the disorder and informing the development of circadian-based therapies.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid31521737,

title = {Role of prefrontal cortical 5-HT receptors and serotonin transporter in the behavioral deficits in post-pubertal rats following neonatal lesion of the ventral hippocampus},

author = {Satoru Mitazaki and Osamu Nakagawasai and Hiroshi Onogi and Kenya Watanabe and Kohei Takahashi and Koichi Tan-No and Rémi Quirion and Lalit K Srivastava and Takeshi Tadano},

doi = {10.1016/j.bbr.2019.112226},

issn = {1872-7549},

year  = {2020},

date = {2020-01-01},

journal = {Behav Brain Res},

volume = {377},

pages = {112226},

abstract = {Neonatal ventral hippocampal-lesioned (NVHL) rats have been shown to display neurochemical and behavioral abnormalities at adulthood, analogous to some of those seen in schizophrenia. Serotonergic neurotransmission is implicated the pathophysiology and treatment of schizophrenia. In this study, we evaluated possible role of serotonergic transmission is the behaviors of NVHL-lesioned rats. Bilateral lesions to the ventral hippocampus (VH) in rat pups were made using the excitotoxin ibotenic acid. We investigated 5-HT-receptor and SERT binding sites in cortical and subcortical areas in post-pubertal NVHL and sham-lesioned rats, using quantitative receptor autoradiography. We compared a 5-HT-dependent behavior in NVHL and sham animals, the wet-dog shake response (WDSr) to a 5-HT receptor agonist DOI. In addition, we studied prepulse inhibition (PPI) of startle responses in NVHL and Sham-lesioned animals treated with antipsychotic drugs haloperidol, risperidone and clozapine and 5-HT antagonists ketanserin or MDL100907. The WDSr elicited by DOI was enhanced in post-pubertal NVHL rats compared to sham-lesioned controls. Moreover, post-pubertal NVHL rats exhibited PPI deficits which was reversed by atypical antipsychotics, ketanserin and MDL100907. A significant increase in 5-HT-like receptor binding was observed in the medial prefrontal cortex (mPFC) in post-pubertal NVHL rats without any significant change in the striatum and ventral pallidum. A significant increase in SERT-like binding was also observed in the mPFC and striatum of NVHL rats at pre-pubertal period; however, at post-pubertal age, the binding remained elevated in mPFC only. These data suggest that increased prefrontal cortical 5-HT transmission may play a role in the behavioral deficits observed in this neurodevelopmental model of schizophrenia.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid30831160,

title = {Prenatal treatment with methylazoxymethanol acetate as a neurodevelopmental disruption model of schizophrenia in mice},

author = {Kohei Takahashi and Osamu Nakagawasai and Wakana Sakuma and Wataru Nemoto and Takayo Odaira and Jia-Rong Lin and Hiroshi Onogi and Lalit K Srivastava and Koichi Tan-No},

doi = {10.1016/j.neuropharm.2019.02.034},

issn = {1873-7064},

year  = {2019},

date = {2019-05-01},

journal = {Neuropharmacology},

volume = {150},

pages = {1--14},

abstract = {Methylazoxymethanol (MAM)-treated pregnant rat at gestation day (GD) 17 has been shown to be a valuable developmental animal model for schizophrenia. Yet, this model remains to be established in mice. In the present study, we examined behavioral, cytoarchitectural, and neurochemical changes in the offspring of MAM-treated mice and validated the model's face, construct and predictive validities. We found that in contrast to a single injection of MAM to dams at GD 15, 16 or 17, its daily administration from GD 15 to 17 led to deficits in prepulse inhibition (PPI) of startle in the post-pubertal offspring. In addition, we observed behavioral deficits in working memory and social interactions, as well as an increase in locomotor activity induced by the NMDA antagonist MK-801 in GD15-17 MAM offspring. These animals also showed a reduction in the volume of the prefrontal cortex (PFC) and hippocampus, neuroanatomical changes such as discontinuities and heterotopias in the hippocampus, and an increase of DA level and DOPAC/DA ratio in the medial PFC. Atypical antipsychotic drugs clozapine, risperidone, and aripiprazole, but not the typical drug haloperidol, reversed the deficit in PPI and social withdrawal in the offspring of MAM-treated dams. In contrast, MK-801-induced hyperactivity in MAM mice was reversed by both and typical or atypical antipsychotic drugs. Taken together, the treatment of pregnant mice with MAM during GD 15-17 offers a new approach to study neurobiological mechanisms involved in the pathogenesis of schizophrenia.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid30537477,

title = {Microglia in the developing prefrontal cortex of rats show dynamic changes following neonatal disconnection of the ventral hippocampus},

author = {Chin Wai Hui and Sanjeev K Bhardwaj and Kaushik Sharma and Antoneta T Joseph and Kanchan Bisht and Katherine Picard and Marie-Ève Tremblay and Lalit K Srivastava},

doi = {10.1016/j.neuropharm.2018.12.007},

issn = {1873-7064},

year  = {2019},

date = {2019-03-01},

journal = {Neuropharmacology},

volume = {146},

pages = {264--275},

abstract = {Impaired ventral hippocampal (VH)-prefrontal cortex (PFC) connectivity is implicated in many cognitive and behavioral disorders. Excitotoxic neonatal VH (nVH) lesion in rat pups has been shown to induce synaptic pruning in the PFC as well as behavioral changes of relevance to developmental neuropsychiatric disorders. In the current study, we hypothesized that microglia, immune cells required for proper brain development and plasticity, may play a role in the development of abnormal behaviors in the nVH-lesioned animals. Ibotenic acid-induced nVH lesion was induced in postnatal day (P)7 male rats. Developmental changes in microglial density, morphology, ultrastructure and gene expression were analyzed in the PFC at P20 and P60. Our results revealed increased microglial reactivity and phagocytic activity in the lesioned rats at P20. Increased mRNA levels of C3 and C1q, complement molecules involved in synaptic pruning, were concomitantly observed. Diminished, but maintained, microglial reactivity and reduced antioxidative defenses were identified in lesioned rats at P60. Behavioral deficits were significantly reduced in the post-pubertal rats by suppressing microglial reactivity by a one-week minocycline treatment immediately after the lesion, These results suggest that early-life disconnection of the VH has long-lasting consequences for microglial functions in the connected structures. Alterations in microglia may underlie synaptic reorganization and behavioral deficits observed following neonatal VH disconnection.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid29750935,

title = {Altered regulation of Nur77 nuclear receptor gene expression in the mesocorticolimbic regions of rat brain by amphetamine sensitization},

author = {Sanjeev K Bhardwaj and Fatéma Dodat and Daniel Lévesque and Lalit K Srivastava},

doi = {10.1016/j.brainres.2018.05.007},

issn = {1872-6240},

year  = {2018},

date = {2018-09-01},

journal = {Brain Res},

volume = {1694},

pages = {46--54},

abstract = {The mechanisms underlying psychostimulant drug-induced sensitization include long-term cellular and molecular adaptations in dopaminergic circuits. Nur77, a member of the Nur family of transcription factors, is expressed in brain regions receiving dopamine inputs and plays a role in activity-induced synaptic modification. Here we evaluated changes in Nur77 mRNA levels in the medial prefrontal cortex (mPFC), dorsal striatum (Str) and nucleus accumbens (NAc) of rats receiving a repeated, sensitizing regimen of amphetamine (AMPH). Results were compared to two groups of controls - animals receiving repeated injections of saline (Rp-SAL) or with no treatment (CON). Two weeks after the last injection, the effect of an acute challenge dose of AMPH on Nur77 expression was evaluated using in-situ hybridization. Repeated AMPH treatment (Rp-AMPH) increased the levels of Nur77 mRNA in the mPFC, NAc core and shell regions. However, the effects of an acute injection of AMPH in each of the three groups of animals was distinct. Whereas an acute AMPH led to a significant increase of Nur77 in all brain regions of the CON animals, it had no significant effect in Rp-SAL animals. Interestingly, in acute AMPH-injected Rp-AMPH animals, Nur77 mRNA levels in the mPFC, Str and NAc regions were significantly lower compared to CON and Rp-SAL animals treated with acute AMPH. There was a positive correlation between AMPH -induced locomotor activity and Nur77 mRNA expression in CON animals; however, this relationship was absent in Rp-SAL and Rp-AMPH animals. The data suggest that Nur77 is a part of neuroadaptive changes caused by either mild stress of repeated injections as well as AMPH-sensitization and may play a role in abnormal behaviors induced by the drug.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid30038210,

title = {Schizophrenia-related dysbindin-1 gene is required for innate immune response and homeostasis in the developing subventricular zone},

author = {Abeer R Al-Shammari and Sanjeev K Bhardwaj and Ksenia Musaelyan and Lalit K Srivastava and Francis G Szele},

doi = {10.1038/s41537-018-0057-5},

issn = {2334-265X},

year  = {2018},

date = {2018-07-01},

journal = {NPJ Schizophr},

volume = {4},

number = {1},

pages = {15},

abstract = {Schizophrenia is a neurodevelopmental disorder likely caused by environmental and genetic risk factors but functional interactions between the risk factors are unclear. We tested the hypothesis that dysbindin-1 (Dtnbp1) gene mutation combined with postnatal exposure to viral mimetic polyI:C results in schizophrenia-related behavioural changes in adulthood, and mediates polyI:C-induced inflammation in the subventricular zone (SVZ). Adult Sandy (Sdy, Dtnbp1 mutant) mice given early postnatal polyI:C injections displayed reduced prepulse inhibition of startle, reduced locomotion and deficits in novel object recognition. PolyI:C induced a canonical immune response in the SVZ; it increased mRNA expression of its toll-like receptor 3 (Tlr3) and downstream transcription factors RelA and Sp1. PolyI:C also increased SVZ Dtnbp1 mRNA expression, suggesting dysbindin-1 regulates immune responses. Dysbindin-1 loss in Sdy mice blocked the polyI:C-induced increases in mRNA expression of Tlr3, RelA and Sp1 in the SVZ. Dtnbp1 overexpression in SVZ-derived Sdy neurospheres rescued Tlr3, RelA and Sp1 mRNA expression supporting a functional interaction between dysbindin-1 and polyI:C-induced inflammation. Immunohistochemistry showed higher Iba1+ immune cell density in the SVZ of Sdy mice than in WT postnatally. PolyI:C did not alter SVZ Iba1+ cell density but increased CD45+/Iba1- cell numbers in the SVZ of Sdy mice. Finally, polyI:C injections in Sdy, but not WT mice reduced postnatal and adult SVZ proliferation. Together, we show novel functional interactions between the schizophrenia-relevant dysbindin-1 gene and the immune response to polyI:C. This work sheds light on the molecular basis for amplified abnormalities due to combined genetic predisposition and exposure to environmental schizophrenia risk factors.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}