Importance:Dopaminergic dysregulation has been considered the final common pathway for pathophysiology of schizophrenia and related disorders (SRD). However, this model does not adequately explain treatment resistance, cognitive impairment, negative symptoms, and marked biological heterogeneity across patients. Objective:To examine whether SRD are best conceptualized as resulting from a final common dopaminergic pathway or from several partially independent neurochemical mechanisms and to evaluate the implications of these models for treatment development. Evidence Review:Neuroimaging, postmortem and genetic investigations, pharmacologic challenge paradigms, clinical trials, and animal models published between 1980 and 2025 were synthesized. Studies were identified through expert knowledge and targeted searches of PubMed and related databases. Systematic reviews, meta-analyses, and multimodal convergent findings were emphasized. Evidence was appraised qualitatively with attention to consistency, specificity, and translational relevance. Findings:Positive psychotic symptoms are strongly linked to increased presynaptic dopaminergic activity in the associative striatum, which predicts response to dopamine D2 receptor antagonists. However, approximately one-third of patients exhibit treatment resistance and show no increase in striatal dopamine synthesis capacity. Increasing evidence implicates glutamatergic, gamma-aminobutyric acid (GABA)ergic, serotonergic, cholinergic, endocannabinoid, and opioidergic systems, as well as nonneurotransmitter processes including oxidative stress, mitochondrial dysfunction, and neuroinflammation. The efficacy of the muscarinic M1/M4-preferring agonist xanomeline-trospium, which lacks direct D2 receptor antagonism, suggests that nondopaminergic mechanisms can reduce psychotic symptoms. Neurochemically distinct subgroups within SRD may cut across overlapping clinical phenotypes. Conclusions and Relevance:Dopaminergic hyperactivity may be a key mechanism for core psychotic symptoms in many patients, but it is unlikely that dopamine dysregulation is a universal final common pathway across symptom domains. A pluralistic model-recognizing multiple interacting neurochemical and cellular processes-may better account for heterogeneity and translational failures. Future development of novel treatments may depend on biomarker-informed stratification, mechanism-based clinical trials, and integration of molecular, circuit-level, and clinical phenotypes.

The prefrontal cortex (PFC) is critical for regulating stress responses through top-down control over limbic and subcortical structures. The PFC undergoes a prolonged developmental process that only reaches maturation during adulthood, causing it to be highly sensitive to environmental insults during neurodevelopment, such as adolescence. During this critical period, synaptic pruning, the maturation of inhibitory GABAergic interneurons, and the refinement of dopaminergic transmission collectively establish the excitatory-inhibitory balance necessary for adaptive behavior. Impairment of the PFC due to developmental disruptions increases susceptibility to maladaptive stress responses. These responses can, in turn, contribute to the development of major depressive disorder and schizophrenia. In depression, a dysfunctional PFC fails to effectively inhibit the amygdala, which contributes to hyperactivity in stress-related circuits, hypodopaminergic states, and anhedonia. In schizophrenia, a neurodevelopmental PFC dysfunction would precipitate hippocampal circuit disruption driven by stress. The inability of an immature PFC to regulate the amygdala response to stress would trigger an increased excitatory drive to the ventral hippocampus, which is proposed to underlie the excessive limbic drive, hippocampal hyperactivity, and a hyperdopaminergic state. In addition, the activation of the mesocortical dopaminergic system by stress facilitates the PFC response to stress, both during adulthood and adolescence. A dopamine (DA)-induced unregulated stress response disrupts the excitatory and inhibitory transmission within the PFC, which plays a critical role in its function. Understanding the interplay between stress and PFC activity/maturation to regulate the circuit toward adaptive or maladaptive outcomes offers critical insights for early intervention and prevention. Early changes in the PFC could underlie vulnerability to unregulated stress response and its consequent effect in contributing to schizophrenia and depression. In this way, early intervention may limit the impact and prevent further circuit dysregulation leading to pathological states.

Abstract Recent evidence suggests that psychosis involves glutamatergic dysfunction and altered activity/connectivity within corticolimbic circuitry. While altered relationships between corticolimbic glutamatergic metabolite levels and resting-state functional connectivity (FC) have been described in schizophrenia and first-episode psychosis (FEP), whether these disruptions are also present prior to psychosis onset remains unclear. We measured Glx (glutamate + glutamine) levels in the anterior cingulate cortex (ACC) and hippocampus with magnetic resonance spectroscopy (MRS), and resting-state FC between corticolimbic regions of interest (ACC, hippocampus, amygdala and nucleus accumbens (NAc)) in antipsychotic-naïve participants at clinical high-risk for psychosis (CHR-P, n=22), compared to healthy controls (HC, n=23) and FEP participants (n=10). Primary analyses compared corticolimbic Glx-FC interactions between CHR-P and HC groups. FEP individuals were included in secondary Glx comparisons but were excluded from FC analyses due to insufficient sample size after quality control. There was a significant interaction between group and ACC Glx for FC between the NAc and the bilateral amygdala and hippocampus (p-FDR=0.021), which was driven by a significant negative association in the CHR-P group (p-FDR=0.005). Complementary seed-to-whole-brain analyses revealed additional negative associations between ACC Glx and FC with the left middle temporal gyrus, and between hippocampal Glx and FC with the parahippocampal and temporal fusiform cortices in CHR-P individuals, which were absent in HC. FEP showed higher Glx than HC across both regions (p=0.015), but there were no significant Glx differences between CHR-P and HC. These data suggest that increased risk for psychosis is associated with altered relationships between corticolimbic connectivity and glutamatergic function.

OBJECTIVE:Preclinical evidence suggests that modulating neural excitation through administration of diazepam, a positive allosteric modulator of GABAA receptors, can prevent the emergence of behavioral and neurobiological alterations relevant to psychosis in adulthood. DESIGN AND PARTICIPANTS:Here, we examine this neurochemical mechanism in individuals at clinical high risk for psychosis in a randomized, double-blind, placebo-controlled crossover study. Twenty-four individuals (15 female and 9 male) aged 18-35 were scanned twice using proton magnetic resonance spectroscopy to measure anterior cingulate cortex Glx (glutamate and glutamine) levels, once after a single dose of diazepam (5 mg) and once after placebo. RESULTS:Mixed-effects model analyses revealed that diazepam reduced anterior cingulate cortex Glx levels compared to placebo (t(20.8) = -2.14, P = .04). The effect of diazepam on Glx levels was greater in older individuals at clinical high risk for psychosis (t(12) = -4.36, P = .001). CONCLUSION:These findings suggest that pharmacological modulation of GABAA receptors can alter Glx changes in and support a novel therapeutic mechanism of benefit for individuals at clinical high risk of psychosis.

The discovery of antipsychotic drugs more than 65 years ago revolutionized the treatment of schizophrenia that was initially based on serendipitous findings with chlorpromazine. This later led to the dopamine (DA) hypothesis, linking hyperdopaminergic states to psychosis. While D2-based antipsychotics effectively reduce positive symptoms, they fail to address cognitive and negative deficits. Preclinical studies have provided critical insights into schizophrenia pathophysiology and treatment. These studies show that hippocampal hyperactivity and loss of parvalbumin GABAergic (gamma-aminobutyric acidergic) neuron inhibition drive DA system dysregulation, which leads to pathological hyper-responsivity to stimuli. Antipsychotic drugs induce depolarization block in DA neurons that normalizes DA hyperactivity but does not correct upstream hippocampal dysfunction. Preclinical models have also identified potential novel treatments targeting the hippocampal hyperexcitability, including GABA α5-positive allosteric modulators and evenamide. These compounds may have the ability to restore hippocampal inhibition, normalize positive symptom-related DA activity, and improve cognitive and negative symptoms without D2-associated side effects. Clinical trial failures of novel agents, such as pomaglumetad, may be a product of prior D2 antagonist exposure leading to postsynaptic supersensitivity rather than lack of efficacy. This evidence underscores the importance of patient treatment history and the design of trials that account for prior antipsychotic exposure when evaluating new compounds. Targeting upstream pathology in the hippocampus offers a promising approach for developing more effective, side effect-sparing treatments for schizophrenia.

The hippocampus has long been recognized for its central role in memory and navigation. However more recent studies have shown that this structure is also involved in the pathophysiology of major psychiatric disorders. Specifically, the ventral/anterior portion of the hippocampus is a mediator of stress-induced circuit dysfunction in neuropathology. The hippocampus is comprised of a number of neurotransmissions, especially inhibitory, not unlike the neocortex, but is also vulnerable to disruption particularly in the juvenile stage. The disruption occurs via alterations in activity but also in rhythmicity, which is essential for gating information flow in its target structures. In this review, we show how stress-related disorders involve hippocampal dysfunction, and how this can impact the dopamine system as well as other circuits that lead to pathologies such as schizophrenia, depression and post-traumatic stress disorder. As such, the hippocampus may be an effective target for treatment and prevention of multiple pathological conditions.

Schizophrenia is a neurodevelopmental disorder often accompanied by heightened anxiety. The methylazoxymethanol acetate (MAM) rodent model has demonstrated that prenatal MAM exposure disrupts neurodevelopment and leads to schizophrenia-like deficits, including increased anxiety-like behaviors. While previous research has focused primarily on male subjects, this study investigates anxiety-like behaviors and parvalbumin (PV) interneuron and perineuronal net (PNN) expression in the basolateral amygdala (BLA), thalamic reticular nucleus (TRN), and ventral hippocampus (vHIP) in female MAM rats across postnatal development (PD31-PD75). We found that female MAM rats exhibited increased anxiety-like behaviors in adulthood (PD75), as evidenced by reduced time spent and entries in the open arms of the elevated plus maze and increased center exploration in the open field test. At PD31, an increase in the open arms time and margin exploration was observed in female MAM rats. Interestingly, a baseline hyperlocomotion was observed at PD31 and PD51 in the MAM condition. The TRN also showed reduced PNN density at PD31 and PV density at PD51 which indicates a possible deficit in inhibitory control. Interestingly, in contrast to prior work in males, the BLA did not show alterations in PV or PNN densities that would contribute to increased anxiety, suggesting a different mechanism of anxiety regulation in females compared to males. These findings highlight sex-specific neurodevelopmental alterations following prenatal MAM exposure, emphasizing the need for further research on female models of schizophrenia. Understanding these differences may improve targeted therapeutic strategies for anxiety and psychosis risk in schizophrenia.

BACKGROUND:Genetic liability for schizophrenia has been associated with cognitive deficits and clinical phenotypes during neurodevelopment. However, the possible role of executive function (EF) as a mediator between the polygenic risk score for schizophrenia (PRS-SZ) and subsequent outcomes, including transdiagnostic general psychopathology (the p-factor), has yet to be examined. In this study, we investigated whether EF mediates the effect of PRS-SZ on psychopathology and functional phenotypes in a community-based youth sample. STUDY DESIGN:We analyzed cross-sectional data from 698 participants (aged 6-14) of the Brazilian High-Risk Cohort. PRS-SZ was calculated using summary statistics from the Psychiatric Genetics Consortium (PGC-3). EF was assessed through working memory, inhibitory control, and time processing tasks, condensed into a single latent EF trait. Independent linear models were tested to examine direct associations between PRS-SZ and EF, general psychopathology, anxiety symptoms, psychotic experiences (PE), and school performance. Mediation models were applied to evaluate EF as a mediator of the associations between PRS-SZ and each outcome. STUDY RESULTS:PRS-SZ predicted lower EF scores (β = -0.091, t = -2.435, p = 0.015). No direct associations were found between PRS-SZ and the other measures. EF mediated the association between PRS-SZ and general psychopathology (p-factor) (Effect = 0.0079, BootSE = 0.0049, LLCI = 0.0004, ULCI = 0.0191), anxiety symptoms (Effect = 0.0075, BootSE = 0.0047, LLCI = 0.0001, ULCI = 0.0182), and school performance (Effect = -0.0167, BootSE = 0.0077, LLCI = -0.0327, ULCI = -0.0028), but not PE. CONCLUSIONS:PRS-SZ was associated with poorer EF, which in turn mediated its associations with increased general psychopathology (p-factor) and anxiety symptoms, and reduced school performance in this community youth sample. EF may represent a hub through which PRS-SZ contributes to negative behavioral and functional outcomes.

Stress is a major risk factor for psychiatric disorders, with the timing of exposure critically shaping its neural and behavioral consequences. Here, we investigated how stress during adolescence or adulthood affects neuronal activity and oscillatory dynamics in the medial prefrontal cortex (mPFC) of rats. Animals were exposed to a combined footshock and restraint stress protocol during adolescence (postnatal days [PNDs] 31 to 40) or adulthood (PNDs 65 to 74). In vivo electrophysiological recordings of putative glutamate pyramidal neurons, Gamma-Aminobutyric Acid (GABA) interneurons, and local field potentials were performed 1 to 2 and 5 to 6 wk post-stress to evaluate both short- and long-term effects. Adolescent stress induced increases in pyramidal neuron firing rates and sustained elevations in interneuron burst activity that persisted into adulthood, accompanied by long-lasting reductions in mPFC gamma oscillations. These alterations point to enduring disruptions in excitatory-inhibitory balance and impaired network coordination. In contrast, adult stress produced no persistent changes in pyramidal neuron activity but caused transient increases in interneuron excitability and selective reductions in theta oscillatory power, suggesting temporary inhibitory dysfunction. These findings highlight adolescence as a critical window during which stress triggers enduring, cell-type-specific changes in cortical circuitry, whereas changes induced by adult stress are transient, potentially reflecting recovery mechanisms. Collectively, our results underscore the importance of developmental timing in determining stress outcomes, providing mechanistic insight into how adolescent stress may contribute to long-lasting cortical dysfunction and psychiatric disease risk, and informing the timing of potential preventive or therapeutic interventions.

Dysfunction in the GABAergic system has been described in schizophrenia, including decreased expression of α5 subunit-containing GABAA receptors (α5-GABAARs) in patients with schizophrenia. This study explores the therapeutic potential of positive allosteric modulators (PAMs) of the α5-GABAAR to reduce the hyperdopaminergic state produced by the neurodevelopmental methylazoxymethanol acetate (MAM) model of schizophrenia. Male offspring rats generated from pregnant females injected with saline or MAM at gestational day 17 were used for the electrophysiological recordings as adults. In vivo electrophysiological recordings were performed to assess the effects of 10 mg/kg of the novel α5-GABAAR-preferring PAM alogabat on dopamine (DA) neuron activity in the ventral tegmental area (VTA); a dose shown to produce sustained, ≥80% α5-GABAAR occupancy over a time period of 0.5-3.5 h post-dose. A less extensive confirmatory study was also performed with a second α5-GABAAR PAM, Compound 100. The primary outcome was that at a dose of 10 mg/kg, which corresponded to an α5-GABAAR occupancy of ≥80% for alogabat and 70% for Compound 100, reversed the increased number of spontaneously active DA neurons in MAM rats. Alogabat data showed that these effects were driven by a reduction in the central and lateral (but not medial) portions of the VTA; regions that project to the associative striatum. These findings suggest that selective targeting of α5-GABAARs may help normalize aberrant DA activity. The study highlights α5-GABAARs as a promising therapeutic target, potentially addressing positive symptoms by restoring excitatory-inhibitory balance in a key region of the brain implicated in the pathophysiology of schizophrenia.

A great deal is known about the use, benefits, and side effects of clozapine in treatment-resistant schizophrenia (TRS). However, why clozapine is more effective than other antipsychotics in TRS remains unclear. In this article, we address this question. Patients with TRS show glutamate abnormalities, and clozapine has widespread effects on glutamate. However, these actions have not been proven to be different from those of other antipsychotics. Immune dysfunction is also reported in TRS, and clozapine has anti-inflammatory actions, but these have not been correlated with clinical improvement. Currently, there is a great deal of interest in muscarinic abnormalities in psychosis. Unlike most antipsychotics, clozapine has important effects on muscarinic receptors, particularly M1 and M4, and its major metabolite, N-desmethylclozapine, is a full agonist at M1. These effects are likely crucial to clozapine's effectiveness. In addition, clozapine's lower dopamine D2 receptor occupancy has been postulated to allow gradual resolution of dopamine receptor supersensitivity in the minority of patients with TRS who initially respond to antipsychotics but become resistant following long-term dopamine blockade. However, this hypothesis remains controversial. Clozapine's multireceptor profile enables it to have beneficial actions on the nonpsychotic symptoms common in TRS; its ability to bind to histamine H1, serotonin 5-HT1A, and GABAB (gamma-aminobutyric acid B) receptors offers an explanation for its anxiolytic actions, while effects on 5-HT1A, 5-HT2A, and 5-HT7 receptors likely underlie its antidepressant properties. Clozapine shares these properties with olanzapine and quetiapine, but its affinity for muscarinic receptors may be the mechanism by which it is more effective in TRS.

Schizophrenia spectrum disorders (SSD) involve disturbances in the integration of perception, emotion and cognition. The corticolimbic system is an interacting set of cortical and subcortical brain regions critically involved in this process. Understanding how neural circuitry and molecular mechanisms within this corticolimbic system may contribute to the development of not only positive symptoms but also negative and cognitive deficits in SSD has been a recent focus of intense research, as the latter are not adequately treated by current antipsychotic medications and are more strongly associated with poorer functioning and long-term outcomes. This review synthesises recent developments examining corticolimbic dysfunction in the pathophysiology of SSD, with a focus on neuroimaging advances and related novel methodologies that enable the integration of data across different scales. We then integrate how these findings may inform the identification of novel therapeutic and preventive targets for SSD symptomatology. A range of pharmacological interventions have shown initial promise in correcting corticolimbic dysfunction and improving negative, cognitive and treatment-resistant symptoms. We discuss current challenges and opportunities for improving the still limited translation of these research findings into clinical practice. We argue how our knowledge of the role of corticolimbic dysfunction can be improved by combining multiple research modalities to examine hypotheses across different spatial and temporal scales, combining neuroimaging with experimental interventions and utilising large-scale consortia to advance biomarker identification. Translation of these findings into clinical practice will be aided by consideration of optimal intervention timings, biomarker-led patient stratification, and the development of more selective medications.

Disrupted gamma-aminobutyric acid (GABA) neurotransmission may contribute to the pathophysiology of schizophrenia. Reductions in hippocampal GABAergic neurons have been found in schizophrenia, and increased hippocampal perfusion has been described in schizophrenia and in people at clinical high-risk for psychosis (CHRp). We have also found decreases in hippocampal GABAA receptors containing the α5 subunit (GABAARα5) in a well-validated neurodevelopmental rat model of relevance for schizophrenia. Positive allosteric modulation of these receptors in the hippocampus using a specific compound was shown to reverse the behavioural and neurophysiological phenotypes of this model. However, whether GABAARα5 availability is dysregulated in the psychosis spectrum at the regional or network levels is unknown. We addressed this issue by using [11C]Ro15-4513 and positron emission tomography (PET) in 22 individuals at CHRp, 10 people with a first-episode psychosis (FEP) and 23 healthy controls (HC). We quantified GABAARα5 availability in the hippocampus and across the brain, and employed a perturbation covariance method to assess individual molecular covariance deviations in CHRp and FEP groups compared to the HC group. Hippocampal GABAARα5 availability was not significantly different between groups (F(2,50) = 0.25, p = 0.78). However, network analysis identified significant deviations in GABAARα5 covariance between groups, both across all regions (all p < 0.001, pairwise Cohen’s d = 0.07–0.5) and relative to the hippocampus (all p < 0.001, pairwise Cohen’s d = 0.01–0.67). These findings suggest that individuals at clinical high-risk for psychosis and people with early psychosis may show alterations to the brain-wide organisation of the GABAARα5 system, rather than changes at a regional level.

Preclinical evidence suggests that diazepam enhances hippocampal γ-aminobutyric acid (GABA) signalling and normalises a psychosis-relevant cortico-limbic-striatal circuit. Hippocampal network dysconnectivity, particularly from the CA1 subfield, is evident in people at clinical high-risk for psychosis (CHR-P), representing a potential treatment target. This study aimed to forward-translate this preclinical evidence. In this randomised, double-blind, placebo-controlled study, 18 CHR-P individuals underwent resting-state functional magnetic resonance imaging twice, once following a 5 mg dose of diazepam and once following a placebo. They were compared to 20 healthy controls (HC) who did not receive diazepam/placebo. Functional connectivity (FC) between the hippocampal CA1 subfield and the nucleus accumbens (NAc), amygdala, and ventromedial prefrontal cortex (vmPFC) was calculated. Mixed-effects models investigated the effect of group (CHR-P placebo/diazepam vs. HC) and condition (CHR-P diazepam vs. placebo) on CA1-to-region FC. In the placebo condition, CHR-P individuals showed significantly lower CA1-vmPFC (Z = 3.17, PFWE = 0.002) and CA1-NAc (Z = 2.94, PFWE = 0.005) FC compared to HC. In the diazepam condition, CA1-vmPFC FC was significantly increased (Z = 4.13, PFWE = 0.008) compared to placebo in CHR-P individuals, and both CA1-vmPFC and CA1-NAc FC were normalised to HC levels. In contrast, compared to HC, CA1-amygdala FC was significantly lower contralaterally and higher ipsilaterally in CHR-P individuals in both the placebo and diazepam conditions (lower: placebo Z = 3.46, PFWE = 0.002, diazepam Z = 3.33, PFWE = 0.003; higher: placebo Z = 4.48, PFWE < 0.001, diazepam Z = 4.22, PFWE < 0.001). This study demonstrates that diazepam can partially restore hippocampal CA1 dysconnectivity in CHR-P individuals, suggesting that modulation of GABAergic function might be useful in the treatment of this clinical group.

Abstract Background Stress is a major risk factor for psychiatric disorders, particularly when occuring during the sensitive period of adolescence. We showed previously that male rats exposed to major stressors during prepuberty exhibit amygdala-driven loss of parvalbumin neurons in the ventral hippocampus, hippocampal hyperactivity, and an increase in ventral tegmental area (VTA) dopamine (DA) neuron activity. In contrast, we now find that female rats are resilient to the effects of prepubertal stress, but are uniquely sensitive to postpubertal (PostP) stress that impacts the system via a unique pathway involving the nucleus reuniens. Aims & Objectives Using a combined stress paradigm, we examine the mechanism by which PostP stress in females activates medial VTA DA neuron activity, which are the DA neurons projecting to the affect-associated ventral nucleus accumbens.Method: Female rats were subjected to a combination of footshock/restraint stress during PostP (PD41-50). single-unit extracellular recordings of RE neurons 1-2 and 5-6 weeks were done after stress. RTN local field potentials were recorded in the RTN for at PD41, PD51, PD61, and PD85. Low (30-50Hz) and high gamma (60-120Hz) were analyzed. Immunohistochemistry analysis of PV/PNN content was evaluated in the posterior RTN one week after PostP stress (PD61). Another cohort of female rats received a retrograde inhibitory AAV-DREADDs virus (AAVrg-hSyn-hM4D(Gi)-mCherry, 500nL) at PD 31 followed by a cannula implantation in the nucleus reunions. Females were injected with Clozapine N-oxide (CNO, 1mM/200nL) in the nucleus reunions 15 min before stress during PD41-50. The rats were recorded for DA activity in the VTA during adulthood (PD>65). Results Although female rats failed to show activation of the amygdala after PostP stress, another region that also projects to ventral hippocampal parvalbumin neurons, the nucleus reuniens, shows selective activation 1-2 weeks and 5-6 weeks after PostP stress only in females. This is accompanied by a loss of parvalbumin interneurons in the ventral hippocampus. This loss of hippocampal parvalbumin neurons leads to ventral hippocampal activation and DA neuron overdrive; an effect that is attenuated by inhibition of the reuniens-hippocampal pathway via inhibitory retrograde DREADD injection into the ventral hippocampus and CNO injection into the nucleus reuniens. One region that potently regulates primary thalamic nuclei, including the nucleus reuniens, is the reticular nucleus of the thalamus (RTN), a region consisting of parvalbumin-containing GABAergic neurons. We found that after postpubertal stress there is first an activation of low gamma oscillations one day after stress (consistent with parvalbumin neuron overdrive) followed one week later by a loss of parvalbumin neurons in the region of the RTN associated with the nucleus reuniens. Discussion & Conclusion These data support that female rats that are resilient to prepubertal stress but show sensitivity to PostP stress that leads to parvalbumin loss in the RTN, decreased RTN inhibition of the nucleus reuniens, parvalbumin loss in the ventral hippocampus, and activation of the affect-related ventromedial striatum. These data are consistent with human studies, in which, females tend to be exposed more often to PostP stress in terms of e.g. sexual abuse, and are more susceptible to affect-related disorders.

Background Hippocampal hyperactivity in early psychosis may result from excitation-inhibition imbalance within corticolimbic regions. Preclinical evidence suggests that positive allosteric modulation of hippocampal inhibitory γ-aminobutyric acid receptors (α5-GABAAR) attenuates hippocampal hyperactivity, striatal hyperdopaminergia, and psychosis-relevant behaviours. Here, we investigated whether hippocampal hyperactivity and α5-GABAAR network covariance are perturbed in people at clinical high risk for psychosis (CHR-P) and with first-episode psychosis (FEP). Method Twenty-four individuals at CHR-P, 24 healthy controls (HC), and 10 FEP, underwent simultaneous PET-MRI to quantify regional cerebral blood flow (rCBF) with arterial spin labelling and α5-GABAAR availability with [11C]Ro15-4513 PET. Individual deviations in corticolimbic rCBF and α5-GABAAR covariance were calculated using a perturbation analysis approach based on a HC-derived reference. Permutation tests and Pearson's correlations assessed group differences and symptom relationships. Results For rCBF, absolute deviations were greater at hippocampal edges (F=5.763, p=.006) in CHR-P (p=.016) and FEP (p=.002). For α5-GABAAR, absolute deviations did not differ from HC across the network (p=.145) or at hippocampal edges (p=.245). However, negative covariance deviations (reduced covariance vs HC) were greater for rCBF (F=4.006, p=.032) and α5-GABAAR across the network (F=6.265, p=.026), and for hippocampal edges for rCBF (F=4.471, p=.015; CHR-P) and α5-GABAAR (F=3.14, p=.047; CHR). In CHR-P, rCBF deviations correlated with positive symptoms (r=-.516, p=.001); in FEP, α5-GABAAR deviations correlated with general symptoms (r=.722, p=.018). No rCBF-α5-GABAAR covariance correlations were observed. Conclusions Early psychosis involves alterations in corticolimbic network organization in both neural activity and α5-GABAAR availability, driven by negative deviations. Individualized covariance perturbation provides a promising approach for detecting network-level dysfunction psychosis. ### Competing Interest Statement GM has received consulting fees from Boehringer Ingelheim, and speaker fees from Johnson & Johnson. AAG has received research support from Merck & Newron, Honoraria/consulting from Alkermes, Lundbeck, Roche, Takeda, Newron, & Merck, Speaker's bureau from Bristol-Meyers-Squibb. ### Funding Statement SRK was supported by a grant from Mental Health Research UK and the Schizophrenia Research Fund. This research was funded by the Wellcome Trust & The Royal Society [Sir Henry Dale Fellowship 202397/Z/16/Z to GM]. MV is supported by EU funding within the MUR PNRR National Center for HPC, BIG DATA AND QUANTUM COMPUTING (Project no. CN00000013 CN1), the Ministry of University and Research within the Complementary National Plan PNC DIGITAL LIFELONG PREVENTION - DARE (Project no PNC0000002_DARE), and by Fondo per il Programma Nazionale di Ricerca e Progetti di Rilevante Interesse Nazionale (PRIN), (Project no 2022RXM3H7). JJS is part-funded by the National Institute for Health and Care Research (NIHR) Maudsley Biomedical Research Centre (BRC). This manuscript also represents independent research partly funded by the NIHR Maudsley BRC at South London and Maudsley NHS Foundation Trust and King's College London. Furthermore, OOD is supported by a grant from NIHR Maudsley BRC at South London and Maudsley NHS Foundation Trust and King's College London. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: London/Surrey Research Ethics Committee gave approval for this work (17/LO/1130) I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors

Schizophrenia is characterized by positive, negative, and cognitive symptoms. However, current D2-based antipsychotic drugs only address primarily positive symptoms. Limbic hippocampus hyperexcitability is a key pathological state of schizophrenia, representing an ideal therapeutic target. Evenamide is a selective voltage-gated sodium channel blocker that reduces neuronal hyperexcitability. We examined the effect of acute evenamide treatment on the hyperdopaminergic state, hippocampal hyperexcitability, social deficits, and recognition memory in the methylazoxymethanol acetate (MAM) neurodevelopmental model. Male and female Sprague-Dawley offspring from dams treated with saline or MAM on gestational day 17 were tested as adults (postnatal day >65). Electrophysiological recordings were made in the ventral tegmental area (VTA) and ventral hippocampus (vHipp) and social approach and novel object recognition were tested. Evenamide (3 mg/kg i.p.) normalized the number of spontaneously active DA neurons in the VTA of female and male MAM rats and reduced pyramidal neuron hyperactivity in the vHipp. The hyperdopaminergic state in the VTA of female and male MAM rats was also rescued by local evenamide injection in the vHipp (1 µM). Systemic evenamide also reversed the recognition memory impairment of female and male MAM rats. For social deficits, only male MAM rats exhibit a reduced social sniffing time that was normalized by evenamide. These findings suggest that evenamide’s efficacy in downregulating the hyperdopaminergic state, social deficits, and recognition memory impairment may result from its ability to attenuate vHipp hyperexcitability. Therefore, evenamide could offer a novel therapeutic strategy that is capable of addressing positive, cognitive, and negative symptoms of schizophrenia.

BACKGROUND:Stress is a significant socio-environmental risk factor for schizophrenia, with its impact varying with age and sex. Male rats are more vulnerable to the long-term effecct of stress during early adolescence, whereas females are more affected during late adolescence, with both demonstrating a stress-induced hyperdopaminergic state and ventral hippocampal hyperexcitability. The nucleus reuniens of the thalamus (RE) plays a crucial role in modulating hippocampal-prefrontal connectivity and dopamine activity. This study investigated the effect of stress during neurodevelopment on RE activity in both sexes. STUDY DESIGN:Sprague-Dawley rats were subjected to a 10-day footshock and restraint stress protocol during early adolescence (Post-natal day [PD] 31-40) or late adolescence (PD41-50) periods. Electrophysiological RE recordings were conducted 1-2 and 5-6 weeks post-stress. STUDY RESULTS:Early adolescence stress did not affect the number of spontaneously active RE neurons in males and females after 1-2 or 5-6 weeks, but it increased the proportion of RE neurons firing in bursts in females. Late adolescence stress increased the number of spontaneously active RE neurons in females at both 1-2 and 5-6 weeks. Females had fewer active RE neurons than males starting earlier in adulthood but not at a younger age (PD47-54). This shows an age-dependent effect on female RE activity. CONCLUSION:Stress had sex-specific effects on RE neuron activity of females, with late adolescence stress increasing the number of spontaneous RE neurons, while early adolescence stress influenced burst firing. Therefore, stress-induced changes in RE activity during adolescence may contribute to females' vulnerability to neuropathology.

Elevated hippocampal perfusion has been observed in people at clinical high risk for psychosis (CHR-P). Preclinical evidence suggests that hippocampal hyperactivity is central to the pathophysiology of psychosis, and that peripubertal treatment with diazepam can prevent the development of psychosis-relevant phenotypes. The present experimental medicine study examined whether diazepam can normalize hippocampal perfusion in CHR-P individuals. Using a randomized, double-blind, placebo-controlled, crossover design, 24 CHR-P individuals were assessed with magnetic resonance imaging (MRI) on two occasions, once following a single oral dose of diazepam (5 mg) and once following placebo. Regional cerebral blood flow (rCBF) was measured using 3D pseudo-continuous arterial spin labeling and sampled in native space using participant-specific hippocampus and subfield masks (CA1, subiculum, CA4/dentate gyrus). Twenty-two healthy controls (HC) were scanned using the same MRI acquisition sequence, but without administration of diazepam or placebo. Mixed-design ANCOVAs and linear mixed-effects models were used to examine the effects of group (CHR-P placebo/diazepam vs. HC) and condition (CHR-P diazepam vs. placebo) on rCBF in the hippocampus as a whole and by subfield. Under the placebo condition, CHR-P individuals (mean [+/- SD] age: 24.1 [+/- 4.8] years, 15 F) showed significantly elevated rCBF compared to HC (mean [+/- SD] age: 26.5 [+/- 5.1] years, 11 F) in the hippocampus (F(1,41) = 24.7, p FDR < 0.001) and across its subfields (all p FDR < 0.001). Following diazepam, rCBF in the hippocampus (and subfields, all p FDR < 0.001) was significantly reduced (t(69) = -5.1, p FDR < 0.001) and normalized to HC levels (F(1,41) = 0.4, p FDR = 0.204). In conclusion, diazepam normalized hippocampal hyperperfusion in CHR-P individuals, consistent with evidence implicating medial temporal GABAergic dysfunction in increased vulnerability for psychosis.

After finishing his postdoc at NYU in the Physiology Department under the direction of Rodolfo Llinas, Dr. Grace started as an Assistant Professor of Psychology and Psychiatry at the University of Pittsburgh in the fall of 1985. He was promoted early in the fall of 1991 to Associate Professor of Behavioral Neuroscience and Psychiatry and to Professor of Neuroscience and Psychiatry in July 2003. In September 2010, he was again promoted to Distinguished Professor of Neuroscience and Professor of Psychiatry and Psychology, his current position. He is the Editor-in-Chief of the International Journal of Neuropsychopharmacology, the journal of the Collegium Internationale Neuropsychopharmacologicum (CINP, International College of Neuropsychopharmacology). Dr. Grace has offered insights into his personal and professional journey.