Site-specific inhibition of the thalamic reticular nucleus induces distinct modulations in sleep architecture.

The thalamic reticular nucleus (TRN) is crucial for the modulation of sleep-related oscillations. The caudal and rostral subpopulations of the TRN exert diverse activities, which arise from their interconnectivity with all thalamic nuclei, as well as other brain regions. Despite the recent characterization of the functional and genetic heterogeneity of the TRN, the implications of this heterogeneity for sleep regulation have not been assessed. Here, using a combination of optogenetics and electrophysiology in C57BL/6 mice, we demonstrate that caudal and rostral TRN modulations are associated with changes in cortical alpha and delta oscillations and have distinct effects on sleep stability. Tonic silencing of the rostral TRN elongates sleep episodes, while tonic silencing of the caudal TRN fragments sleep. Overall, we show evidence of distinct roles exerted by the rostral and caudal TRN in sleep regulation and oscillatory activity.

16p11.2 deletion mice exhibit compromised fronto-temporal connectivity, GABAergic dysfunction, and enhanced attentional ability.

Autism spectrum disorders are more common in males, and have a substantial genetic component. Chromosomal 16p11.2 deletions in particular carry strong genetic risk for autism, yet their neurobiological impact is poorly characterised, particularly at the integrated systems level. Here we show that mice reproducing this deletion (16p11.2 DEL mice) have reduced GABAergic interneuron gene expression (decreased parvalbumin mRNA in orbitofrontal cortex, and male-specific decreases in Gad67 mRNA in parietal and insular cortex and medial septum). Metabolic activity was increased in medial septum, and in its efferent targets: mammillary body and (males only) subiculum. Functional connectivity was altered between orbitofrontal, insular and auditory cortex, and between septum and hippocampus/subiculum. Consistent with this circuit dysfunction, 16p11.2 DEL mice showed reduced prepulse inhibition, but enhanced performance in the continuous performance test of attentional ability. Level 1 autistic individuals show similarly heightened performance in the equivalent human test, also associated with parietal, insular-orbitofrontal and septo-subicular dysfunction. The data implicate cortical and septal GABAergic dysfunction, and resulting connectivity changes, as the cause of pre-attentional and attentional changes in autism.

The schizophrenia risk gene Map2k7 regulates responding in a novel contingency-shifting rodent touchscreen gambling task.

In schizophrenia, subjects show reduced ability to evaluate and update risk/reward contingencies, showing correspondingly suboptimal performance in the Iowa gambling task. JNK signalling gene variants are associated with schizophrenia risk, and JNK modulates aspects of cognition. We therefore studied the performance of mice hemizygous for genetic deletion of the JNK activator MKK7 (Map2k7+/- mice) in a touchscreen version of the Iowa gambling task, additionally incorporating a novel contingency-switching stage. Map2k7+/- mice performed slightly better than wild-type (WT) littermates in acquisition and performance of the task. Although Map2k7+/- mice adapted well to subtle changes in risk/reward contingencies, they were profoundly impaired when the positions of 'best' and 'worst' choice selections were switched, and still avoided the previous 'worst' choice location weeks after the switch. This demonstrates a precise role for MKK7-JNK signalling in flexibility of risk/reward assessment and suggests that genetic variants affecting this molecular pathway may underlie impairment in this cognitive domain in schizophrenia. Importantly, this new contingency shift adaptation of the rodent touchscreen gambling task has translational utility for characterising these cognitive subprocesses in models of neuropsychiatric disorders.

Enzymatic Degradation of Cortical Perineuronal Nets Reverses GABAergic Interneuron Maturation.

Perineuronal nets (PNNs) are specialised extracellular matrix structures which preferentially enwrap fast-spiking (FS) parvalbumin interneurons and have diverse roles in the cortex. PNN maturation coincides with closure of the critical period of cortical plasticity. We have previously demonstrated that BDNF accelerates interneuron development in a c-Jun-NH2-terminal kinase (JNK)-dependent manner, which may involve upstream thousand-and-one amino acid kinase 2 (TAOK2). Chondroitinase-ABC (ChABC) enzymatic digestion of PNNs reportedly reactivates 'juvenile-like' plasticity in the adult CNS. However, the mechanisms involved are unclear. We show that ChABC produces an immature molecular phenotype in cultured cortical neurons, corresponding to the phenotype prior to critical period closure. ChABC produced different patterns of PNN-related, GABAergic and immediate early (IE) gene expression than well-characterised modulators of mature plasticity and network activity (GABAA-R antagonist, bicuculline, and sodium-channel blocker, tetrodotoxin (TTX)). ChABC downregulated JNK activity, while this was upregulated by bicuculline. Bicuculline, but not ChABC, upregulated Bdnf expression and ERK activity. Furthermore, we found that BDNF upregulation of semaphorin-3A and IE genes was TAOK mediated. Our data suggest that ChABC heightens structural flexibility and network disinhibition, potentially contributing to 'juvenile-like' plasticity. The molecular phenotype appears to be distinct from heightened mature synaptic plasticity and could relate to JNK signalling. Finally, we highlight that BDNF regulation of plasticity and PNNs involves TAOK signalling.

Mice lacking melatonin MT2 receptors exhibit attentional deficits, anxiety and enhanced social interaction.

BACKGROUND: Aside from regulating circadian rhythms, melatonin also affects cognitive processes, such as alertness, and modulates the brain circuitry underlying psychiatric diseases, such as depression, schizophrenia and bipolar disorder, via mechanisms that are not fully clear. In particular, while melatonin MT1 receptors are thought primarily to mediate the circadian effects of the hormone, the contribution of the MT2 receptor to melatonin actions remains enigmatic. AIMS: To characterise the contribution of MT2 receptors to melatonin's effects on cognition and anxiety/sociability. METHODS: Mice with a genetic deletion of the MT2 receptor, encoded by the Mtnr1b gene, were compared with wild-type littermates for performance in a translational touchscreen version of the continuous performance task (CPT) to assess attentional processes and then monitored over 3 days in an ethological home-cage surveillance system. RESULTS: Mtnr1b knockout (KO) mice were able to perform at relatively normal levels in the CPT. However, they showed consistent evidence of more liberal/risky responding strategies relative to control mice, with increases in hit rates and false alarm rates, which were maintained even when the cognitive demands of the task were increased. Assessment in the home-cage monitoring system revealed that female Mtnr1b KO mice have increased anxiety levels, whereas male Mtnr1b KO mice show increased sociability. CONCLUSIONS: The results confirm that the MT2 receptor plays a role in cognition and also modulates anxiety and social interactions. These data provide new insights into the functions of endogenous melatonin and will inform future drug development strategies focussed on the MT2 receptor.

Impaired working memory, cognitive flexibility and reward processing in mice genetically lacking Gpr88: Evidence for a key role for Gpr88 in multiple cortico-striatal-thalamic circuits.

The GPR88 orphan G protein-coupled receptor is expressed throughout the striatum, being preferentially localised in medium spiny neurons. It is also present in lower densities in frontal cortex and thalamus. Rare mutations in humans suggest a role in cognition and motor function, while common variants are associated with psychosis. Here we evaluate the influence of genetic deletion of GPR88 upon performance in translational tasks interrogating motivation, reward evaluation and cognitive function. In an automated radial arm maze 'N-back' working memory task, Gpr88 KO mice showed impaired correct responding, suggesting a role for GPR88 receptors in working memory circuitry. Associative learning performance was similar to wild-type controls in a touchscreen task but performance was impaired at the reversal learning stage, suggesting cognitive inflexibility. Gpr88 KO mice showed higher breakpoints, reduced latencies and lengthened session time in a progressive ratio task consistent with enhanced motivation. Simultaneously, locomotor hyperactivity was apparent in this task, supporting previous findings of actions of GPR88 in a cortico-striatal-thalamic motor loop. Evidence for a role of GPR88 in reward processing was demonstrated in a touchscreen-based equivalent of the Iowa gambling task. Although both Gpr88 KO and wild-type mice showed a preference for an optimum contingency choice, Gpr88 KO mice selected more risky choices at the expense of more advantageous lower risk options. Together these novel data suggest that striatal GPR88 receptors influence activity in a range of procedures integrated by prefrontal, orbitofrontal and anterior cingulate cortico-striatal-thalamic loops leading to altered cognitive, motivational and reward evaluation processes.

BDNF and JNK Signaling Modulate Cortical Interneuron and Perineuronal Net Development: Implications for Schizophrenia-Linked 16p11.2 Duplication Syndrome.

Schizophrenia (SZ) is a neurodevelopmental disorder caused by the interaction of genetic and environmental risk factors. One of the strongest genetic risk variants is duplication (DUP) of chr.16p11.2. SZ is characterized by cortical gamma-amino-butyric acid (GABA)ergic interneuron dysfunction and disruption to surrounding extracellular matrix structures, perineuronal nets (PNNs). Developmental maturation of GABAergic interneurons, and also the resulting closure of the critical period of cortical plasticity, is regulated by brain-derived neurotrophic factor (BDNF), although the mechanisms involved are unknown. Here, we show that BDNF promotes GABAergic interneuron and PNN maturation through JNK signaling. In mice reproducing the 16p11.2 DUP, where the JNK upstream activator Taok2 is overexpressed, we find that JNK is overactive and there are developmental abnormalities in PNNs, which persist into adulthood. Prefrontal cortex parvalbumin (PVB) expression is reduced, while PNN intensity is increased. Additionally, we report a unique role for TAOK2 signaling in the regulation of PVB interneurons. Our work implicates TAOK2-JNK signaling in cortical interneuron and PNN development, and in the responses to BDNF. It also demonstrates that over-activation of this pathway in conditions associated with SZ risk causes long-lasting disruption in cortical interneurons.

Drug-responsive autism phenotypes in the 16p11.2 deletion mouse model: a central role for gene-environment interactions.

There are no current treatments for autism, despite its high prevalence. Deletions of chromosome 16p11.2 dramatically increase risk for autism, suggesting that mice with an equivalent genetic rearrangement may offer a valuable model for the testing of novel classes of therapeutic drug. 16p11.2 deletion (16p11.2 DEL) mice and wild-type controls were assessed using an ethological approach, with 24 h monitoring of activity and social interaction of groups of mice in a home-cage environment. The ability of the excitation/inhibition modulator N-acetyl cysteine (NAC) and the 5-HT1B/1D/1F receptor agonist eletriptan to normalise the behavioural deficits observed was tested. 16p11.2 DEL mice exhibited largely normal behaviours, but, following the stress of an injection, showed hyperlocomotion, reduced sociability, and a strong anxiolytic phenotype. The hyperactivity and reduced sociability, but not the suppressed anxiety, were effectively attenuated by both NAC and eletriptan. The data suggest that 16p11.2 DEL mice show an autism-relevant phenotype that becomes overt after an acute stressor, emphasising the importance of gene-environmental interactions in phenotypic analysis. Further, they add to an emerging view that NAC, or 5-HT1B/1D/1F receptor agonist treatment, may be a promising strategy for further investigation as a future treatment.

Temporal dissociation of phencyclidine: Induced locomotor and social alterations in rats using an automated homecage monitoring system - implications for the 3Rs and preclinical drug discovery.

BACKGROUND: Rodent behavioural assays are widely used to delineate the mechanisms of psychiatric disorders and predict the efficacy of drug candidates. Conventional behavioural paradigms are restricted to short time windows and involve transferring animals from the homecage to unfamiliar apparatus which induces stress. Additionally, factors including environmental perturbations, handling and the presence of an experimenter can impact behaviour and confound data interpretation. To improve welfare and reproducibility these issues must be resolved. Automated homecage monitoring offers a more ethologically relevant approach with reduced experimenter bias. AIM: To evaluate the effectiveness of an automated homecage system at detecting locomotor and social alterations induced by phencyclidine (PCP) in group-housed rats. PCP is an N-methyl-D-aspartate (NMDA) receptor antagonist commonly utilised to model aspects of schizophrenia. METHODS: Rats housed in groups of three were implanted with radio frequency identification (RFID) tags. Each homecage was placed over a RFID reader baseplate for the automated monitoring of the social and locomotor activity of each individual rat. For all rats, we acquired homecage data for 24 h following administration of both saline and PCP (2.5 mg/kg). RESULTS: PCP resulted in significantly increased distance travelled from 15 to 60 min post injection. Furthermore, PCP significantly enhanced time spent isolated from cage mates and this asociality occured from 60 to 105 min post treatment. CONCLUSIONS: Unlike conventional assays, in-cage monitoring captures the temporal duration of drug effects on multiple behaviours in the same group of animals. This approach could benefit psychiatric preclinical drug discovery through improved welfare and increased between-laboratory replicability.

16p11 Duplication Disrupts Hippocampal-Orbitofrontal-Amygdala Connectivity, Revealing a Neural Circuit Endophenotype for Schizophrenia.

Chromosome 16p11.2 duplications dramatically increase risk for schizophrenia, but the mechanisms remain largely unknown. Here, we show that mice with an equivalent genetic mutation (16p11.2 duplication mice) exhibit impaired hippocampal-orbitofrontal and hippocampal-amygdala functional connectivity. Expression of schizophrenia-relevant GABAergic cell markers (parvalbumin and calbindin) is selectively decreased in orbitofrontal cortex, while somatostatin expression is decreased in lateral amygdala. When 16p11.2 duplication mice are tested in cognitive tasks dependent on hippocampal-orbitofrontal connectivity, performance is impaired in an 8-arm maze "N-back" working memory task and in a touchscreen continuous performance task. Consistent with hippocampal-amygdala dysconnectivity, deficits in ethologically relevant social behaviors are also observed. Overall, the cellular/molecular, brain network, and behavioral alterations markedly mirror those observed in schizophrenia patients. Moreover, the data suggest that 16p11.2 duplications selectively impact hippocampal-amygdaloid-orbitofrontal circuitry, supporting emerging ideas that dysfunction in this network is a core element of schizophrenia and defining a neural circuit endophenotype for the disease.

Map2k7 Haploinsufficiency Induces Brain Imaging Endophenotypes and Behavioral Phenotypes Relevant to Schizophrenia.

c-Jun N-terminal kinase (JNK) signaling contributes to functional plasticity in the brain and cognition. Accumulating evidence implicates a role for MAP kinase kinase 7 (MAP2K7), a JNK activator encoded by the Map2k7 gene, and other JNK pathway components in schizophrenia (ScZ). Mice haploinsufficient for Map2k7 (Map2k7+/- mice) display ScZ-relevant cognitive deficits, although the mechanisms are unclear. Here we show that Map2k7+/- mice display translationally relevant alterations in brain function, including hippocampal and mesolimbic system hypermetabolism with a contrasting prefrontal cortex (PFC) hypometabolism, reminiscent of patients with ScZ. In addition Map2k7+/- mice show alterations in functional brain network connectivity paralleling those reported in early ScZ, including PFC and hippocampal hyperconnectivity and compromised mesolimbic system functional connectivity. We also show that although the cerebral metabolic response to ketamine is preserved, the response to dextroamphetamine (d-amphetamine) is significantly attenuated in Map2k7+/- mice, supporting monoamine neurotransmitter system dysfunction but not glutamate/NMDA receptor (NMDA-R) dysfunction as a consequence of Map2k7 haploinsufficiency. These effects are mirrored behaviorally with an attenuated impact of d-amphetamine on sensorimotor gating and locomotion, whereas similar deficits produced by ketamine are preserved, in Map2k7+/- mice. In addition, Map2k7+/- mice show a basal hyperactivity and sensorimotor gating deficit. Overall, these data suggest that Map2k7 modifies brain and monoamine neurotransmitter system function in a manner relevant to the positive and cognitive symptoms of ScZ.

JNK signalling mediates aspects of maternal immune activation: importance of maternal genotype in relation to schizophrenia risk.

BACKGROUND: Important insight into the mechanisms through which gene-environmental interactions cause schizophrenia can be achieved through preclinical studies combining prenatal immune stimuli with disease-related genetic risk modifications. Accumulating evidence associates JNK signalling molecules, including MKK7/MAP2K7, with genetic risk. We tested the hypothesis that Map2k7 gene haploinsufficiency in mice would alter the prenatal immune response to the viral mimetic polyriboinosinic-polyribocytidylic acid (polyI:C), specifically investigating the impact of maternal versus foetal genetic variants. METHODS: PolyI:C was administered to dams (E12.5), and cytokine/chemokine levels were measured 6 h later, in maternal plasma, placenta and embryonic brain. RESULTS: PolyI:C dramatically elevated maternal plasma levels of most cytokines/chemokines. Induction of IL-1ß, IL-2, IL-10, IL-12, TNF-α and CXCL3 was enhanced, while CCL5 was suppressed, in Map2k7 hemizygous (Hz) dams relative to controls. Maternal polyI:C administration also increased embryonic brain chemokines, influenced by both maternal and embryonic genotype: CCL5 and CXCL10 levels were higher in embryonic brains from Map2k7 dams versus control dams; for CCL5, this was more pronounced in Map2k7 Hz embryos. Placental CXCL10 and CXCL12 levels were also elevated by polyI:C, the former enhanced and the latter suppressed, in placentae from maternal Map2k7 Hzs relative to control dams receiving polyI:C. CONCLUSIONS: The results demonstrate JNK signalling as a mediator of MIA effects on the foetus. Since both elevated CXCL10 and supressed CXCL12 compromise developing GABAergic interneurons, the results support maternal immune challenge contributing to schizophrenia-associated neurodevelopmental abnormalities. The influence of Map2k7 on cytokine/chemokine induction converges the genetic and environmental aspects of schizophrenia, and the overt influence of maternal genotype offers an intriguing new insight into modulation of embryonic neurodevelopment by genetic risk.

Distortion of protein analysis in primary neuronal cultures by serum albumin from culture medium: A methodological approach to improve target protein quantification.

BACKGROUND: Primary neuronal cultures underpin diverse neuroscience experiments, including various protein analysis techniques, such as Western blotting, whereby protein extraction from cultured neurons is required. During immunoblotting experiments, we encountered problems due to a highly-abundant protein of 65-70 KDa present in the cell extracts, that interfered with total protein estimation, and immunodetection of target proteins of similar size. Previous research has suggested that serum proteins, specifically albumin, contained within commonly-used culture media, can bind to, or be adsorbed by, generic cell culture plasticware. This residual albumin may then be extracted along with cell proteins. NEW METHOD: We made simple modifications to wash steps of traditional cell lysis/extraction protocols. RESULTS: We report that a substantial amount of albumin, accumulated from the standard culture media, is extracted from primary neuronal cultures along with the cellular contents. This contamination can be reduced, without changing the culture conditions, by modifying wash procedures. COMPARISON WITH EXISTING METHODS: Accumulated albumin from neuronal culture media, in amounts equivalent to cellular contents, can distort data from total protein assays and from the immunoreactive signal from nearby bands on Western blots. By altering wash protocols during protein extraction, these problems can be ameliorated. CONCLUSIONS: We suggest that the standard extended culture periods for primary neuronal cultures, coupled with the requirement for successive medium changes, may leave them particularly susceptible to cumulative albumin contamination from the culture media used. Finally, we propose the implementation of simple alterations to wash steps in protein extraction protocols which can ameliorate this interference.

Disruption of the Zdhhc9 intellectual disability gene leads to behavioural abnormalities in a mouse model.

Protein S-acylation is a widespread post-translational modification that regulates the trafficking and function of a diverse array of proteins. This modification is catalysed by a family of twenty-three zDHHC enzymes that exhibit both specific and overlapping substrate interactions. Mutations in the gene encoding zDHHC9 cause mild-to-moderate intellectual disability, seizures, speech and language impairment, hypoplasia of the corpus callosum and reduced volume of sub-cortical structures. In this study, we have undertaken behavioural phenotyping, magnetic resonance imaging (MRI) and isolation of S-acylated proteins to investigate the effect of disruption of the Zdhhc9 gene in mice in a C57BL/6 genetic background. Zdhhc9 mutant male mice exhibit a range of abnormalities compared with their wild-type littermates: altered behaviour in the open-field test, elevated plus maze and acoustic startle test that is consistent with a reduced anxiety level; a reduced hang time in the hanging wire test that suggests underlying hypotonia but which may also be linked to reduced anxiety; deficits in the Morris water maze test of hippocampal-dependent spatial learning and memory; and a 36% reduction in corpus callosum volume revealed by MRI. Surprisingly, membrane association and S-acylation of H-Ras was not disrupted in either whole brain or hippocampus of Zdhhc9 mutant mice, suggesting that other substrates of this enzyme are linked to the observed changes. Overall, this study highlights a key role for zDHHC9 in brain development and behaviour, and supports the utility of the Zdhhc9 mutant mouse line to investigate molecular and cellular changes linked to intellectual disability and other deficits in the human population.

Deconstructing Schizophrenia: Advances in Preclinical Models for Biomarker Identification.

Schizophrenia is considered to develop as a consequence of genetic and environmental factors impacting on brain neural systems and circuits during vulnerable neurodevelopmental periods, thereby resulting in symptoms in early adulthood. Understanding of the impact of schizophrenia risk factors on brain biology and behaviour can help in identifying biologically relevant pathways that are attractive for informing clinical studies and biomarker development. In this chapter, we emphasize the importance of adopting a reciprocal forward and reverse translation approach that is iteratively updated when additional new information is gained, either preclinically or clinically, for offering the greatest opportunity for discovering panels of biomarkers for the diagnosis, prognosis and treatment of schizophrenia. Importantly, biomarkers for identifying those at risk may inform early intervention strategies prior to the development of schizophrenia.Given the emerging nature of this approach in the field, this review will highlight recent research of preclinical biomarkers in schizophrenia that show the most promise for informing clinical needs with an emphasis on relevant imaging, electrophysiological, cognitive behavioural and biochemical modalities. The implementation of this reciprocal translational approach is exemplified firstly by the production and characterization of preclinical models based on the glutamate hypofunction hypothesis, genetic and environmental risk factors for schizophrenia (reverse translation), and then the recent clinical recognition of the thalamic reticular thalamus (TRN) as an important locus of brain dysfunction in schizophrenia as informed by preclinical findings (forward translation).

The thalamic reticular nucleus: a functional hub for thalamocortical network dysfunction in schizophrenia and a target for drug discovery.

The thalamus (comprising many distinct nuclei) plays a key role in facilitating sensory discrimination and cognitive processes through connections with the cortex. Impaired thalamocortical processing has long been considered to be involved in schizophrenia. In this review we focus on the thalamic reticular nucleus (TRN) providing evidence for it being an important communication hub between the thalamus and cortex and how it may play a key role in the pathophysiology of schizophrenia. We first highlight the functional neuroanatomy, neurotransmitter localisation and physiology of the TRN. We then present evidence of the physiological roles of the TRN in relation to oscillatory activity, cognition and behaviour. Next we discuss the role of the TRN in rodent models of risk factors for schizophrenia (genetic and pharmacological) and provide evidence for TRN deficits in schizophrenia. Finally we discuss new drug targets for schizophrenia in relation to restoring TRN circuitry dysfunction.

Functional brain connectivity phenotypes for schizophrenia drug discovery.

While our knowledge of the pathophysiology of schizophrenia has increased dramatically, this has not translated into the development of new and improved drugs to treat this disorder. Human brain imaging and electrophysiological studies have provided dramatic new insight into the mechanisms of brain dysfunction in the disease, with a swathe of recent studies highlighting the differences in functional brain network and neural system connectivity present in the disorder. Only recently has the value of applying these approaches in preclinical rodent models relevant to the disorder started to be recognised. Here we highlight recent findings of altered functional brain connectivity in preclinical rodent models and consider their relevance to those alterations seen in the brains of schizophrenia patients. Furthermore, we highlight the potential translational value of using the paradigm of functional brain connectivity phenotypes in the context of preclinical schizophrenia drug discovery, as a means both to understand the mechanisms of brain dysfunction in the disorder and to reduce the current high attrition rate in schizophrenia drug discovery.

Risk genes for schizophrenia: translational opportunities for drug discovery.

Despite intensive research over many years, the treatment of schizophrenia remains a major health issue. Current and emerging treatments for schizophrenia are based upon the classical dopamine and glutamate hypotheses of disease. Existing first and second generation antipsychotic drugs based upon the dopamine hypothesis are limited by their inability to treat all symptom domains and their undesirable side effect profiles. Third generation drugs based upon the glutamate hypothesis of disease are currently under evaluation but are more likely to be used as add on treatments. Hence there is a large unmet clinical need. A major challenge in neuropsychiatric disease research is the relatively limited knowledge of disease mechanisms. However, as our understanding of the genetic causes of the disease evolves, novel strategies for the development of improved therapeutic agents will become apparent. In this review we consider the current status of knowledge of the genetic basis of schizophrenia, including methods for identifying genetic variants associated with the disorder and how they impact on gene function. Although the genetic architecture of schizophrenia is complex, some targets amenable to pharmacological intervention can be discerned. We conclude that many challenges lie ahead but the stratification of patients according to biobehavioural constructs that cross existing disease classifications but with common genetic and neurobiological bases, offer opportunities for new approaches to effective drug discovery.

Subanesthetic ketamine treatment promotes abnormal interactions between neural subsystems and alters the properties of functional brain networks.

Acute treatment with subanesthetic ketamine, a non-competitive N-methyl-D-aspartic acid (NMDA) receptor antagonist, is widely utilized as a translational model for schizophrenia. However, how acute NMDA receptor blockade impacts on brain functioning at a systems level, to elicit translationally relevant symptomatology and behavioral deficits, has not yet been determined. Here, for the first time, we apply established and recently validated topological measures from network science to brain imaging data gained from ketamine-treated mice to elucidate how acute NMDA receptor blockade impacts on the properties of functional brain networks. We show that the effects of acute ketamine treatment on the global properties of these networks are divergent from those widely reported in schizophrenia. Where acute NMDA receptor blockade promotes hyperconnectivity in functional brain networks, pronounced dysconnectivity is found in schizophrenia. We also show that acute ketamine treatment increases the connectivity and importance of prefrontal and thalamic brain regions in brain networks, a finding also divergent to alterations seen in schizophrenia. In addition, we characterize how ketamine impacts on bipartite functional interactions between neural subsystems. A key feature includes the enhancement of prefrontal cortex (PFC)-neuromodulatory subsystem connectivity in ketamine-treated animals, a finding consistent with the known effects of ketamine on PFC neurotransmitter levels. Overall, our data suggest that, at a systems level, acute ketamine-induced alterations in brain network connectivity do not parallel those seen in chronic schizophrenia. Hence, the mechanisms through which acute ketamine treatment induces translationally relevant symptomatology may differ from those in chronic schizophrenia. Future effort should therefore be dedicated to resolve the conflicting observations between this putative translational model and schizophrenia.