Prepulse Inhibition Deficits Research Articles

PDE4B Missense Variant Increases Susceptibility to Post-traumatic Stress Disorder-Relevant Phenotypes in Mice.

Large-scale genome-wide association studies (GWASs) have associated intronic variants in PDE4B, encoding cAMP-specific phosphodiesterase-4B (PDE4B), with increased risk for post-traumatic stress disorder (PTSD), as well as schizophrenia and substance use disorders that are often comorbid with it. However, the pathophysiological mechanisms of genetic risk involving PDE4B are poorly understood. To examine the effects of PDE4B variation on phenotypes with translational relevance to psychiatric disorders, we focused on PDE4B missense variant M220T, which is present in the human genome as rare coding variant rs775201287. When expressed in HEK-293 cells, PDE4B1-M220T exhibited an attenuated response to a forskolin-elicited increase in the intracellular cAMP concentration. In behavioral tests, homozygous Pde4b M220T male mice with a C57BL/6JJcl background exhibited increased reactivity to novel environments, startle hyperreactivity, prepulse inhibition deficits, altered cued fear conditioning, and enhanced spatial memory, accompanied by an increase in cAMP signaling pathway-regulated expression of BDNF in the hippocampus. In response to a traumatic event (10 tone-shock pairings), neuronal activity was decreased in the cortex but enhanced in the amygdala and hippocampus of Pde4b M220T mice. At 24 h post-trauma, Pde4b M220T mice exhibited increased startle hyperreactivity and decreased plasma corticosterone levels, similar to phenotypes exhibited by PTSD patients. Trauma-exposed Pde4b M220T mice also exhibited a slower decay in freezing at 15 and 30 d post-trauma, demonstrating enhanced persistence of traumatic memories, similar to that exhibited by PTSD patients. These findings provide substantive mouse model evidence linking PDE4B variation to PTSD-relevant phenotypes and thus highlight how genetic variation of PDE4B may contribute to PTSD risk.

Not a Deficit, Just Different: Prepulse Inhibition Disruptions in Autism Depend on Startle Stimulus Intensities.

Sensory processing disruptions are a core symptom of autism spectrum disorder (ASD) and other neurological disorders. The acoustic startle response and prepulse inhibition (PPI) are common metrics used to assess disruptions in sensory processing and sensorimotor gating in clinical studies and animal models. However, often there are inconsistent findings on ASD-related PPI deficits across different studies. Here, we used a novel method for assessing changes in startle and PPI in rodents, using the Cntnap2 knock-out (KO) rat model for neurodevelopmental disorder/ASD that has consistently shown PPI disruptions in past studies. We discovered that not only sex and prepulse intensity but also the intensity of the startle stimulus profoundly impacts whether PPI deficits are evident in the Cntnap2 KO rat or not. We show that rats do not universally exhibit a PPI deficit; instead, impaired PPI is contingent on specific testing conditions. Notably, at lower startle stimulus intensities, Cntnap2 KO rats not only demonstrated intact PPI but also exhibited evidence of enhanced PPI compared with their wild-type counterparts. This finding emphasizes the importance of considering specific testing conditions when evaluating startle and PPI in the context of ASD and other neuropsychiatric conditions and might explain some of the inconsistencies between different studies.

Brain region-specific alterations in gene expression trajectories in the offspring born from influenza A virus infected mice

Influenza A virus (IAV) infection during pregnancy can increase the risk for neurodevelopmental disorders in the offspring, however, the underlying neurobiological mechanisms are largely unknown. To recapitulate viral infection, preclinical studies have traditionally focused on using synthetic viral mimetics, rather than live IAV, to examine consequences of maternal immune activation (MIA)-dependent processes on offspring. In contrast, few studies have used live IAV to assess effects on global gene expression, and none to date have addressed whether moderate IAV, mimicking seasonal influenza disease, alters normal gene expression trajectories in different brain regions across different stages of development. Herein, we show that moderate IAV infection during pregnancy, which causes mild maternal disease and no overt foetal complications in utero, induces lasting effects on the offspring into adulthood. We observed behavioural changes in adult offspring, including disrupted prepulse inhibition, dopaminergic hyper-responsiveness, and spatial recognition memory deficits. Gene profiling in the offspring brain from neonate to adolescence revealed persistent alterations to normal gene expression trajectories in the prefronal cortex, hippocampus, hypothalamus and cerebellum. Alterations were found in genes involved in inflammation and neurogenesis, which were predominately dysregulated in neonatal and early adolescent offspring. Notably, late adolescent offspring born from IAV infected mice displayed altered microglial morphology in the hippocampus. In conclusion, we show that moderate IAV during pregnancy perturbs neurodevelopmental trajectories in the offspring, including alterations in the neuroinflammatory gene expression profile and microglial number and morphology in the hippocampus, resulting in behavioural changes in adult offspring. Such early perturbations may underlie the vulnerability in human offspring for the later development of neurodevelopmental disorders, including schizophrenia. Our work highlights the importance of using live IAV in developing novel preclinical models that better recapitulate the real-world impact of inflammatory insults during pregnancy on offspring neurodevelopmental trajectories and disease susceptibility later in life.

Acute nicotine vapor normalizes sensorimotor gating and reduces locomotor activity deficits in HIV-1 transgenic rats.

Despite improved life expectancy of people with HIV (PWH), HIV-associated neurocognitive impairment (NCI) persists, alongside deficits in sensorimotor gating and neuroinflammation. PWH exhibit high smoking rates, possibly due to neuroprotective, anti-inflammatory, and cognitive-enhancing effects of nicotine, suggesting potential self-medication. Here, we tested the effects of acute nicotine vapor exposure on translatable measures of sensorimotor gating and exploratory behavior in the HIV-1 transgenic (HIV-1Tg) rat model of HIV. Male and female HIV-1Tg and F344 control rats (n=57) were exposed to acute nicotine or vehicle vapor. Sensorimotor gating was assessed using prepulse inhibition (PPI) of the acoustic startle response, and exploratory behavior was evaluated using the behavioral pattern monitor (BPM). Vehicle-treated HIV-1Tg rats exhibited PPI deficits at low prepulse intensities compared to F344 controls, as seen previously. No PPI deficits were observed in nicotine-treated HIV1-Tg rats, however. HIV-1Tg rats were hypoactive in the BPM relative to controls, whilst nicotine vapor increased activity and exploratory behavior across genotypes. Cotinine analyses confirmed comparable levels of the primary metabolite of nicotine across genotypes. Previous findings of PPI deficits in HIV-1Tg rats were replicated and, importantly, attenuated by acute nicotine vapor. Evidence for similar cotinine levels suggest a nicotine-specific effect in HIV-1Tg rats. HIV-1Tg rats had reduced exploratory behavior compared to controls, attenuated by acute nicotine vapor. Therefore, acute nicotine may be beneficial for remediating sensorimotor and locomotor activity deficits in PWH. Future studies should determine the long-term effects of nicotine vapor on similar HIV/NCI-relevant behaviors.

DSP-6745, a novel 5-hydroxytryptamine modulator with rapid antidepressant, anxiolytic, antipsychotic and procognitive effects.

Current treatment of major depressive disorder is facing challenges, including a low remission rate, late onset of efficacy, and worsening severity due to comorbid symptoms such as psychosis and cognitive dysfunction. Serotonin (5-HT) neurotransmission is involved in a wide variety of psychiatric diseases and its potential as a drug target continues to attract attention. The present study elucidates the effects of a novel 5-HT modulator, DSP-6745, on depression and its comorbid symptoms. In vitro radioligand binding and functional assays showed that DSP-6745 is a potent inhibitor of 5-HT transporter and 5-HT2A, 5-HT2C, and 5-HT7 receptors. In vivo, DSP-6745 (6.4 and 19.1mg/kg as free base, p.o.) increased the release of not only 5-HT, norepinephrine, and dopamine, but also glutamate in the medial prefrontal cortex. The results of in vivo mouse phenotypic screening by SmartCube® suggested that DSP-6745 has a behavioral signature combined with antidepressant-, anxiolytic-, and antipsychotic-like signals. A single oral dose of DSP-6745 (6.4 and 19.1mg/kg) showed rapid antidepressant-like efficacy in the rat forced swim test, even at 24h post-dosing, and anxiolytic activity in the rat social interaction test. Moreover, DSP-6745 (12.7mg/kg, p.o.) led to an improvement in the apomorphine-induced prepulse inhibition deficit in rats. In the marmoset object retrieval with detour task, which is used to assess cognitive functions such as attention and behavioral inhibition, DSP-6745 (7.8mg/kg, p.o.) enhanced cognition. These data suggest that DSP-6745 is a multimodal 5-HT receptor antagonist and a 5-HT transporter inhibitor and has the potential to be a rapid acting antidepressant with efficacies in mitigating the comorbid symptoms of depression.

"RNSP (Rannasangpei)" Rescued MK-801-induced Schizophrenia-like Behaviors in Mice via Oxidative Stress and BDNF-TrkB/Akt Pathway.

Schizophrenia (SCZ) is a complex, severe psychotic disorder that is highly persistent. Patients often cannot control their emotions and have delusions of victimization, world-weariness, and even suicide. Therefore, safer and more effective drugs are urgently needed. Rannasangpei (RNSP) from "the four medicine tantras" was used as a neuroprotective agent. The objective of this study was to investigate the effect and mechanism of RNSP on MK-801-induced SCZ in mice. Fifty C57BL/6J mice were randomly divided into a normal group, a model group, an RNSP group, a crocin (CRO) group, and an olanzapine (OLA) group, except for the normal group. The remaining mice were used to establish the MK-801-induced SCZ model. Changes in positive symptoms and cognitive impairment in mice before and after drug intervention were assessed by using the prepulse inhibition (PPI) test, Y-maze test (YMT), and open-field test (OFT). Intragastric administration of RNSP alleviated the symptoms of SCZ in SCZ mice, as demonstrated by the PPI, YMT, and OFT results. Compared with the model group, the first-line antipsychotic olanzapine reversed the anxiety-like phenotypes, hypermotility, and PPI deficits in the SCZ model mice. Further analysis revealed that RNSP reduced oxidative stress in SCZ model mice, as evidenced by increased superoxide dismutase (SOD) levels and decreased malondialdehyde (MDA) levels in the hippocampus, cortex, and blood of SCZ model mice. In our study, RNSP treatment restored the expression of brain-derived neurotrophic factor (BDNF), dopamine D2 receptor, p-Trkb, Akt/p-Akt, and doublecortin and inhibited the expression of IBA1 and Bax in the hippocampus of SCZ model mice. The polymerase chain reaction data indicated that RNSP treatment increased the expression of Bcl-2 and TGF-β and decreased the expression of Bax, IL-1β, and TNF-α in the brains of the model mice. Our results are the first to show that RNSP reverses SCZ-like behaviors in rodents (both positive symptoms and cognitive deficits) by reducing oxidative stress and activating the BDNF-TrkB/Akt pathway, suggesting that RNSP is a novel approach for treating SCZ.

Differential impact of intermittent versus continuous treatment with clozapine on fatty acid metabolism in the brain of an MK-801-induced mouse model of schizophrenia

Continuous antipsychotic treatment is often recommended to prevent relapse in schizophrenia. However, the efficacy of antipsychotic treatment appears to diminish in patients with relapsed schizophrenia and the underlying mechanisms are still unknown. Moreover, though the findings are inconclusive, several recent studies suggest that intermittent versus continuous treatment may not significantly differ in recurrence risk and therapeutic efficacy but potentially reduce the drug dose and side effects. Notably, disturbances in fatty acid (FA) metabolism are linked to the onset/relapse of schizophrenia, and patients with multi-episode schizophrenia have been reported to have reduced FA biosynthesis. We thus utilized an MK-801-induced animal model of schizophrenia to evaluate whether two treatment strategies of clozapine would affect drug response and FA metabolism differently in the brain. Schizophrenia-related behaviors were assessed through open field test (OFT) and prepulse inhibition (PPI) test, and FA profiles of prefrontal cortex (PFC) and hippocampus were analyzed by gas chromatography–mass spectrometry. Additionally, we measured gene expression levels of enzymes involved in FA synthesis. Both intermittent and continuous clozapine treatment reversed hypermotion and deficits in PPI in mice. Continuous treatment decreased total polyunsaturated fatty acids (PUFAs), saturated fatty acids (SFAs) and FAs in the PFC, whereas the intermittent administration increased n-6 PUFAs, SFAs and FAs compared to continuous administration. Meanwhile, continuous treatment reduced the expression of Fads1 and Elovl2, while intermittent treatment significantly upregulated them. This study discloses the novel findings that there was no significant difference in clozapine efficacy between continuous and intermittent administration, but intermittent treatment showed certain protective effects on phospholipid metabolism in the PFC.

Deciphering the role of brainstem glycinergic neurons during startle and prepulse inhibition

Prepulse inhibition (PPI) of the auditory startle response, a key measure of sensorimotor gating, diminishes with age and is impaired in various neurological conditions. While PPI deficits are often associated with cognitive impairments, their reversal is routinely used in experimental systems for antipsychotic drug screening. Yet, the cellular and circuit-level mechanisms of PPI remain unclear, even under non-pathological conditions. We recently showed that brainstem neurons located in the caudal pontine reticular nucleus (PnC) expressing the glycine transporter type 2 (GlyT2±) receive inputs from the central nucleus of the amygdala (CeA) and contribute to PPI but via an uncharted pathway. Here, using tract-tracing, immunohistochemistry and in vitro optogenetic manipulations coupled to field electrophysiological recordings, we reveal the neuroanatomical distribution of GlyT2± PnC neurons and PnC-projecting CeA glutamatergic neurons and we provide mechanistic insights on how these glutamatergic inputs suppress auditory neurotransmission in PnC sections. Additionally, in vivo experiments using GlyT2-Cre mice confirm that optogenetic activation of GlyT2± PnC neurons enhances PPI and is sufficient to induce PPI in young mice, emphasizing their role. However, in older mice, PPI decline is not further influenced by inhibiting GlyT2± neurons. This study highlights the importance of GlyT2± PnC neurons in PPI and underscores their diminished activity in age-related PPI decline.

The Development of a Regulator of Human Serine Racemase for N-Methyl-D-aspartate Function.

It is crucial to regulate N-methyl-D-aspartate (NMDA) function bivalently depending on the central nervous system (CNS) conditions. CNS disorders with NMDA hyperfunction are involved in the pathogenesis of neurotoxic and/or neurodegenerative disorders with elevated D-serine, one of the NMDA receptor co-agonists. On the contrary, NMDA-enhancing agents have been demonstrated to improve psychotic symptoms and cognition in CNS disorders with NMDA hypofunction. Serine racemase (SR), the enzyme regulating both D- and L-serine levels through both racemization (catalysis from L-serine to D-serine) and β-elimination (degradation of both D- and L-serine), emerges as a promising target for bidirectional regulation of NMDA function. In this study, we explored using dimethyl malonate (DMM), a pro-drug of the SR inhibitor malonate, to modulate NMDA activity in C57BL/6J male mice via intravenous administration. Unexpectedly, 400 mg/kg DMM significantly elevated, rather than decreased (as a racemization inhibitor), D-serine levels in the cerebral cortex and plasma. This outcome prompted us to investigate the regulatory effects of dodecagalloyl-α-D-xylose (α12G), a synthesized tannic acid analog, on SR activity. Our findings showed that α12G enhanced the racemization activity of human SR by about 8-fold. The simulated and fluorescent assay of binding affinity suggested a noncooperative binding close to the catalytic residues, Lys56 and Ser84. Moreover, α12G treatment can improve behaviors associated with major CNS disorders with NMDA hypofunction including hyperactivity, prepulse inhibition deficit, and memory impairment in animal models of positive symptoms and cognitive impairment of psychosis. In sum, our findings suggested α12G is a potential therapeutic for treating CNS disorders with NMDA hypofunction.

Influencing Factors of Prepulse Inhibition Deficit in Patients with Schizophrenia and Observations on the Efficacy of Traditional Chinese Medicine

This study aims to analyze the abnormal expression of lncRNAs in peripheral blood mononuclear cells (PBMCs) of patients with schizophrenia, investigate the influencing factors of prepulse inhibition deficit in patients and observe the efficacy of traditional Chinese medicine. A total of 106 patients with schizophrenia who underwent treatment at our hospital from January 2020 to December 2022 were included, along with 45 healthy individuals who received routine check-ups as control subjects. The significantly expressed lncRNAs were validated and analyzed using ROC curve analysis, and logistic regression analysis was used to identify the factors influencing prepulse inhibition deficit. Find 125 lncRNAs were found to be differentially expressed lncRNAs in the PBMCs of patients with schizophrenia, including 62 upregulated and 63 downregulated lncRNAs. And smoking amount, and relapse frequency were influencing factors for prepulse inhibition deficit in patients with schizophrenia. Animal experiments were conducted using hematoxylin eosin staining to observe the number and morphology of neurons in the hippocampal CA3 area and prefrontal cortex of rats, and the effects of natural Chinese medicine Poria cocos on the nervous system were analyzed. Find the acidic polysaccharides from Poria cocos, a natural traditional Chinese medicine, can promote the regeneration of neuronal cells, reduce excessive autophagy of neurons in the CA3 area of the hippocampus and prefrontal cortex of rats, promote neuronal cell proliferation, and improve neuronal cell morphology. Traditional Chinese medicine has good effects in psychopathology, positive and negative symptoms, and PANSS total score. Disruption of lncRNA expression may be one of the biological factors contributing to the pathogenesis of schizophrenia and is closely related to its mechanism. Prepulse inhibition, reflecting sensory gating function, is an important factor affecting perceptual and cognitive functions in patients with schizophrenia. Gender, smoking amount, and relapse frequency may influence prepulse inhibition deficit in these patients. Traditional Chinese medicine shows potential in improving prepulse inhibition deficit. The acidic polysaccharides from Poria cocos, a natural traditional Chinese medicine, can promote the regeneration of neuronal cells, effectively improve the damage to the structure and function of neurons in the hippocampal CA3 area and prefrontal cortex. When used in combination with other traditional Chinese medicines, it could offer new approaches for treating schizophrenia.

The Natural Protoalkaloid Methyl-2-Amino-3-Methoxybenzoate (MAM) Alleviates Positive as well as Cognitive Symptoms in Rat and Mouse Schizophrenia Models.

The development of new antipsychotics with pro-cognitive properties and less side effects represents a priority in schizophrenia drug research. In this study, we present for the first time a preclinical exploration of the effects of the promising natural atypical antipsychotic Methyl-2-Amino-3- Methoxybenzoate (MAM), a brain-penetrable protoalkaloid from the seed of the plant Nigella damascena. Using animal models related to hyperdopaminergic activity, namely the pharmacogenetic apomorphine (D2/D1 receptor agonist)-susceptible (APO-SUS) rat model and pharmacologically induced mouse and rat models of schizophrenia, we found that MAM reduced gnawing stereotypy and climbing behaviours induced by dopaminergic agents. This predicts antipsychotic activity. In line, MAM antagonized apomorphine-induced c-Fos and NPAS4 mRNA levels in post-mortem brain nucleus accumbens and dorsolateral striatum of APO-SUS rats. Furthermore, phencyclidine (PCP, an NMDA receptor antagonist) and 2,5-Dimethoxy-4-iodoamphetamine (DOI, a 5HT2A/2C receptor agonist) induced prepulse inhibition deficits, reflecting the positive symptoms of schizophrenia, which were rescued by treatment with MAM and atypical antipsychotics alike. Post-mortem brain immunostaining revealed that MAM blocked the strong activation of both PCP- and DOI-induced c-Fos immunoreactivity in a number of cortical areas. Finally, during a 28-day subchronic treatment regime, MAM did not induce weight gain, hyperglycemia, hyperlipidemia or hepato- and nephrotoxic effects, side effects known to be induced by atypical antipsychotics. MAM also did not show any cataleptic effects. In conclusion, its brain penetrability, the apparent absence of preclinical side effects, and its ability to antagonize positive and cognitive symptoms associated with schizophrenia make MAM an exciting new antipsychotic drug that deserves clinical testing.

Different levels of prepulse inhibition among patients with first-episode schizophrenia, bipolar disorder and major depressive disorder.

Deficits in prepulse inhibition may be a common feature in first-episode schizophrenia, bipolar disorder (BD) and major depressive disorder (MDD). We sought to explore the levels and viability of prepulse inhibition to differentiate first-episode schizophrenia, BD and MDD in patient populations. We tested patients with first-episode schizophrenia, BD or MDD and healthy controls using prepulse inhibition paradigms, namely perceived spatial co-location (PSC-PPI) and perceived spatial separation (PSS-PPI). We included 53 patients with first-episode schizophrenia, 30 with BD and 25 with MDD, as well as 82 healthy controls. The PSS-PPI indicated that the levels of prepulse inhibition were smallest to largest, respectively, in the first-episode schizophrenia, BD, MDD and control groups. Relative to the healthy controls, the prepulse inhibition deficits in the first-episode schizophrenia group were significant (p < 0.001), but the prepulse inhibitions were similar between patients with BD and healthy controls, and between patients with MDD and healthy controls. The receiver operating characteristic curve analysis showed that PSS-PPI (area under the curve [AUC] 0.73, p < 0.001) and latency (AUC 0.72, p < 0.001) were significant for differentiating patients with first-episode schizophrenia or BD from healthy controls. The demographics of the 4 groups were not ideally matched. We did not perform cognitive assessments. The possible confounding effect of medications on prepulse inhibition could not be eliminated. The level of prepulse inhibition among patients with first-episode schizophrenia was the lowest, with levels among patients with BD, patients with MDD and healthy controls increasingly higher. The PSS-PPI paradigm was more effective than PSC-PPI to recognize deficits in prepulse inhibition. These results provide a basis for further research on biological indicators that can assist differential diagnoses in psychosis.

N-acetylcysteine during critical neurodevelopmental periods prevents behavioral and neurochemical deficits in the Poly I:C rat model of schizophrenia

Schizophrenia is a chronic neurodevelopmental disorder with an inflammatory/prooxidant component. N-acetylcysteine (NAC) has been evaluated in schizophrenia as an adjuvant to antipsychotics, but its role as a preventive strategy has not been sufficiently explored. We aimed to evaluate the potential of NAC administration in two-time windows before the onset of symptoms in a schizophrenia-like maternal immune stimulation (MIS) rat model. Pregnant Wistar rats were injected with Poly I:C or Saline on gestational day (GD) 15. Three different preventive approaches were evaluated: 1) NAC treatment during periadolescence in the offspring (from postnatal day [PND] 35 to 49); 2) NAC treatment during pregnancy after MIS challenge until delivery (GD15–21); and 3) NAC treatment throughout all pregnancy (GD1–21). At postnatal day (PND) 70, prepulse inhibition (PPI) and anxiety levels were evaluated. In vivo magnetic resonance (MR) imaging was acquired on PND100 to assess structural changes in gray and white matter, and brain metabolite concentrations. Additionally, inflammation and oxidative stress (IOS) markers were measured ex vivo in selected brain regions. MIS offspring showed behavioral, neuroanatomical, and biochemical alterations. Interestingly, NAC treatment during periadolescence prevented PPI deficits and partially counteracted some biochemical imbalances. Moreover, NAC treatments during pregnancy not only replicated the beneficial outcomes reported by the treatment in periadolescence, but also prevented some neuroanatomical deficits, including reductions in hippocampal and corpus callosum volumes. This study suggests that early reduction of inflammation and prooxidation could help prevent the onset of schizophrenia-like symptoms, supporting the importance of anti-IOS compounds in ameliorating this disorder.

Acute ketamine induces neuronal hyperexcitability and deficits in prepulse inhibition by upregulating IL-6

Acute ketamine administration results in psychotic symptoms similar to those observed in schizophrenia and is regarded as a pharmacological model of schizophrenia. Accumulating evidence suggests that patients with schizophrenia show increased IL-6 levels in the blood and cerebrospinal fluid and that IL-6 levels are associated with the severity of psychotic symptoms. In the present study, we found that a single ketamine exposure led to increased expression of IL-6 and IL-6Rα, decreased dendritic spine density, increased expression and currents of T-type calcium channels, and increased neuron excitability in the hippocampal CA1 area 12 h after exposure. Acute ketamine administration also led to impaired prepulse inhibition (PPI) 12 h after administration. Additionally, we found that the expression of signaling molecules IKKα/β, NF-κB, JAK2, and STAT3 was upregulated 12 h after a single ketamine injection. The decreases in dendritic spine density, the increases in calcium currents and neuron excitability, and the impairments in PPI were ameliorated by blocking IL-6 or IL-6Rα. Our findings show that blocking IL-6 or its receptor may protect hippocampal neurons from hyperexcitability, thereby ameliorating ketamine-induced psychotic effects. Our study provides additional evidence that targeting IL-6 and its receptor is a potential strategy for treating psychotic symptoms in acute ketamine-induced psychosis and schizophrenia.

Behavioral and transcriptional effects of repeated electroconvulsive seizures in the neonatal MK-801-treated rat model of schizophrenia.

Electroconvulsive therapy (ECT) is an effective treatment modality for schizophrenia. However, its antipsychotic-like mechanism remains unclear. To gain insight into the antipsychotic-like actions of ECT, this study investigated how repeated treatments of electroconvulsive seizure (ECS), an animal model for ECT, affect the behavioral and transcriptomic profile of a neurodevelopmental animal model of schizophrenia. Two injections of MK-801 or saline were administered to rats on postnatal day 7 (PN7), and either repeated ECS treatments (E10X) or sham shock was conducted daily from PN50 to PN59. Ultimately, the rats were divided into vehicle/sham (V/S), MK-801/sham (M/S), vehicle/ECS (V/E), and MK-801/ECS (M/E) groups. On PN59, prepulse inhibition and locomotor activity were tested. Prefrontal cortex transcriptomes were analyzed with mRNA sequencing and network and pathway analyses, and quantitative real-time polymerase chain reaction (qPCR) analyses were subsequently conducted. Prepulse inhibition deficit was induced by MK-801 and normalized by E10X. In M/S vs. M/E model, Egr1, Mmp9, and S100a6 were identified as center genes, and interleukin-17 (IL-17), nuclear factor kappa B (NF-κB), and tumor necrosis factor (TNF) signaling pathways were identified as the three most relevant pathways. In the V/E vs. V/S model, mitophagy, NF-κB, and receptor for advanced glycation end products (RAGE) pathways were identified. qPCR analyses demonstrated that Igfbp6, Btf3, Cox6a2, and H2az1 were downregulated in M/S and upregulated in M/E. E10X reverses the behavioral changes induced by MK-801 and produces transcriptional changes in inflammatory, insulin, and mitophagy pathways, which provide mechanistic insight into the antipsychotic-like mechanism of ECT.

Metergoline Shares Properties with Atypical Antipsychotic Drugs Identified by Gene Expression Signature Screen

Novel approaches are required to find new treatments for schizophrenia and other neuropsychiatric disorders. This study utilised a combination of in vitro transcriptomics and in silico analysis with the BROAD Institute’s Connectivity Map to identify drugs that can be repurposed to treat psychiatric disorders. Human neuronal (NT2-N) cells were treated with a combination of atypical antipsychotic drugs commonly used to treat psychiatric disorders (such as schizophrenia, bipolar disorder, and major depressive disorder), and differential gene expression was analysed. Biological pathways with an increased gene expression included circadian rhythm and vascular endothelial growth factor signalling, while the adherens junction and cell cycle pathways were transcriptionally downregulated. The Connectivity Map (CMap) analysis screen highlighted drugs that affect global gene expression in a similar manner to these psychiatric disorder treatments, including several other antipsychotic drugs, confirming the utility of this approach. The CMap screen specifically identified metergoline, an ergot alkaloid currently used to treat seasonal affective disorder, as a drug of interest. In mice, metergoline dose-dependently reduced MK-801- or methamphetamine-induced locomotor hyperactivity confirming the potential of metergoline to treat positive symptoms of schizophrenia in an animal model. Metergoline had no effects on prepulse inhibition deficits induced by MK-801 or methamphetamine. Taken together, metergoline appears a promising drug for further studies to be repurposed as a treatment for schizophrenia and possibly other psychiatric disorders.

Effects of Icariin and Its Metabolites on GPCR Regulation and MK-801-Induced Schizophrenia-Like Behaviors in Mice.

Icariin, a major bioactive compound found in the Epimedium genus, has been reported to exert protective effects against neurodegenerative disorders. In the current study, we aimed to investigate the regulatory effect of icariin and its active metabolites (icariside II and icaritin) against prime G-protein-coupled receptor targets, considering their association with neuronal disorders. Icariside II exhibited selective agonist activity towards the dopamine D3 receptor (D3R), with half-maximal effective concentrations of 13.29 μM. Additionally, they effectively inhibited the specific binding of radioligands to D3R. Molecular docking analysis revealed that icariside II potentially exerts its agonistic effect through hydrogen-bonding interaction with Asp110 of the D3R, accompanied by negative binding energy. Conversely, icaritin demonstrated selective antagonist effects on the muscarinic acetylcholine M2 receptor (M2R). Radioligand binding assay and molecular docking analysis identified icaritin as an orthosteric ligand for M2R. Furthermore, all three compounds, icariin and its two metabolites, successfully mitigated MK-801-induced schizophrenia-like symptoms, including deficits in prepulse inhibition and social interaction, in mice. In summary, these findings highlight the potential of icariin and its metabolites as promising lead structures for the discovery of new drugs targeting cognitive and neurodegenerative disorders.

Assessing the Cntnap2 knockout rat prepulse inhibition deficit through prepulse scaling of the baseline startle response curve

Many neurodevelopmental disorders, including autism spectrum disorder (ASD), are associated with changes in sensory processing and sensorimotor gating. The acoustic startle response and prepulse inhibition (PPI) of startle are widely used translational measures for assessing sensory processing and sensorimotor gating, respectively. The Cntnap2 knockout (KO) rat has proven to be a valid model for ASD, displaying core symptoms, including sensory processing perturbations. Here, we used a novel method to assess startle and PPI in Cntnap2 KO rats that allows for the identification of separate scaling components: startle scaling, which is a change in startle amplitude to a given sound, and sound scaling, which reflects a change in sound processing. Cntnap2 KO rats show increased startle due to both an increased overall response (startle scaling) and a left shift of the sound/response curve (sound scaling). In the presence of a prepulse, wildtype rats show a reduction of startle due to both startle scaling and sound scaling, whereas Cntnap2 KO rats show normal startle scaling, but disrupted sound scaling, resulting in the reported PPI deficit. These results validate that startle and sound scaling by a prepulse are indeed two independent processes, with only the latter being impaired in Cntnap2 KO rats. As startle scaling is likely related to motor output and sound scaling to sound processing, this novel approach reveals additional information on the possible cause of PPI disruptions in preclinical models.

Repeated low doses of psilocybin increase resilience to stress, lower compulsive actions, and strengthen cortical connections to the paraventricular thalamic nucleus in rats.

Psilocybin (a classic serotonergic psychedelic drug) has received appraisal for use in psychedelic-assisted therapy of several psychiatric disorders. A less explored topic concerns the use of repeated low doses of psychedelics, at a dose that is well below the psychedelic dose used in psychedelic-assisted therapy and often referred to as microdosing. Psilocybin microdose users frequently report increases in mental health, yet such reports are often highly biased and vulnerable to placebo effects. Here we establish and validate a psilocybin microdose-like regimen in rats with repeated low doses of psilocybin administration at a dose derived from occupancy at rat brain 5-HT2A receptors in vivo. The rats tolerated the repeated low doses of psilocybin well and did not manifest signs of anhedonia, anxiety, or altered locomotor activity. There were no deficits in pre-pulse inhibition of the startle reflex, nor did the treatment downregulate or desensitize the 5-HT2A receptors. However, the repeated low doses of psilocybin imparted resilience against the stress of multiple subcutaneous injections, and reduced the frequency of self-grooming, a proxy for human compulsive actions, while also increasing 5-HT7 receptor expression and synaptic density in the paraventricular nucleus of the thalamus. These results establish a well-validated regimen for further experiments probing the effects of repeated low doses of psilocybin. Results further substantiate anecdotal reports of the benefits of psilocybin microdosing as a therapeutic intervention, while pointing to a possible physiological mechanism.

Impaired erythropoietin-producing hepatocellular B receptors signaling in the prefrontal cortex and hippocampus following maternal immune activation in male rats.

An environmental risk factor for schizophrenia (SZ) is maternal infection, which exerts longstanding effects on the neurodevelopment of offspring. Accumulating evidence suggests that synaptic disturbances may contribute to the pathology of the disease, but the underlying molecular mechanisms remain poorly understood. Erythropoietin-producing hepatocellular B (EphB) receptor signaling plays an important role in synaptic plasticity by regulating the formation and maturation of dendritic spines and regulating excitatory neurotransmission. We examined whether EphB receptors and downstream associated proteins are susceptible to environmental risk factors implicated in the etiology of synaptic disturbances in SZ. Using an established rodent model, which closely imitates the characteristics of SZ, we observed the behavioral performance and synaptic structure of male offspring in adolescence and early adulthood. We then analyzed the expression of EphB receptors and associated proteins in the prefrontal cortex and hippocampus. Maternal immune activation offspring showed significantly progressive cognitive impairment and pre-pulse inhibition deficits together with an increase in the expression of EphB2 receptors and NMDA receptor subunits. We also found changes in EphB receptor downstream signaling, in particular, a decrease in phospho-cofilin levels which may explain the reduced dendritic spine density. Besides, we found that the AMPA glutamate, another glutamate ionic receptor associated with cofilin, decreased significantly in maternal immune activation offspring. Thus, alterations in EphB signaling induced by immune activation during pregnancy may underlie disruptions in synaptic plasticity and function in the prefrontal cortex and hippocampus associated with behavioral and cognitive impairment. These findings may provide insight into the mechanisms underlying SZ.