Effects of N-acetylaspartylglutamate (NAAG) peptidase inhibition on release of glutamate and dopamine in prefrontal cortex and nucleus accumbens in phencyclidine model of schizophrenia

The "glutamate" theory of schizophrenia emerged from the observation that phencyclidine (PCP), an open channel antagonist of the NMDA subtype of glutamate receptor, induces schizophrenia-like behaviors in humans. PCP also induces a complex set of behaviors in animal models of this disorder. PCP also increases glutamate and dopamine release in the medial prefrontal cortex and nucleus accumbens, brain regions associated with expression of psychosis. Increased motor activation is among the PCP-induced behaviors that have been widely validated as models for the characterization of new antipsychotic drugs. The peptide transmitter N-acetylaspartylglutamate (NAAG) activates a group II metabotropic receptor, mGluR3. Polymorphisms in this receptor have been associated with schizophrenia. Inhibitors of glutamate carboxypeptidase II, an enzyme that inactivates NAAG following synaptic release, reduce several behaviors induced by PCP in animal models. This research tested the hypothesis that two structurally distinct NAAG peptidase inhibitors, ZJ43 and 2-(phosphonomethyl)pentane-1,5-dioic acid, would elevate levels of synaptically released NAAG and reduce PCP-induced increases in glutamate and dopamine levels in the medial prefrontal cortex and nucleus accumbens. NAAG-like immunoreactivity was found in neurons and presumptive synaptic endings in both regions. These peptidase inhibitors reduced the motor activation effects of PCP while elevating extracellular NAAG levels. They also blocked PCP-induced increases in glutamate but not dopamine or its metabolites. The mGluR2/3 antagonist LY341495 blocked these behavioral and neurochemical effects of the peptidase inhibitors. The data reported here provide a foundation for assessment of the neurochemical mechanism through which NAAG achieves its antipsychotic-like behavioral effects and support the conclusion NAAG peptidase inhibitors warrant further study as a novel antipsychotic therapy aimed at mGluR3.     

Reversing neural circuit and behavior deficit in mice exposed to maternal inflammation by Zika virus

Zika virus (ZIKV) infection during pregnancy is linked to various developmental brain disorders. Infants who are asymptomatic at birth might have postnatal neurocognitive complications. However, animal models recapitulating these neurocognitive phenotypes are lacking, and the circuit mechanism underlying behavioral abnormalities is unknown. Here, we show that ZIKV infection during mouse pregnancy induces maternal immune activation (MIA) and leads to autistic‐like behaviors including repetitive self‐grooming and impaired social memory in offspring. In the medial prefrontal cortex (mPFC), ZIKV‐affected offspring mice exhibit excitation and inhibition imbalance and increased cortical activity. This could be explained by dysregulation of inhibitory neurons and synapses, and elevated neural activity input from mPFC‐projecting ventral hippocampus (vHIP) neurons. We find structure alterations in the synaptic connections and pattern of vHIP innervation of mPFC neurons, leading to hyperconnectivity of the vHIP‐mPFC pathway. Decreasing the activity of mPFC‐projecting vHIP neurons with a chemogenetic strategy rescues social memory deficits in ZIKV offspring mice. Our studies reveal a hyperconnectivity of vHIP to mPFC projection driving social memory deficits in mice exposed to maternal inflammation by ZIKV.     

Characterization of interactions between phencyclidine and amphetamine in rodent prefrontal cortex and striatum: implications in NMDA/glycine-site-mediated dopaminergic dysregulation and dopamine transporter function

N-Methyl-D-aspartate (NMDA) antagonists induced behavioral and neurochemical changes in rodents that serve as animal models of schizophrenia. Chronic phencyclidine (PCP, 15 mg/(kg day) for 3 weeks via Alzet osmotic pump) administration enhances the amphetamine (AMPH)-induced dopamine (DA) efflux in prefrontal cortex (PFC), similar to that observed in schizophrenia. NMDA/glycine-site agonists, such as glycine (GLY), administered via dietary supplementation, reverse the enhanced effect. The present study investigated mechanisms of glycine-induced reversal of PCP-induced stimulation of AMPH-induced DA release, using simultaneous measurement of DA and AMPH in brain microdialysate, as well as peripheral and tissue AMPH levels. PCP treatment, by itself, increased peripheral and central AMPH levels, presumably via interaction with hepatic enzymes (e.g. cytochrome P450 CYP2C11). GLY (16% diet) had no effect on peripheral AMPH levels in the presence of PCP. Nevertheless, GLY significantly reduced extracellular/tissue AMPH ratios in both PFC and striatum (STR), especially following PCP administration, suggesting a feedback mediated effect on the dopamine transporter. GLY also inhibited acute AMPH (5 mg/kg)-induced DA release in PFC, but not STR. These findings suggest that GLY may modulate DA release in brain by producing feedback regulation of dopamine transporter function, possibly via potentiation of NMDA-stimulated GABA release and presynaptic GABAB receptor activation. The present studies also demonstrate pharmacokinetic interaction between AMPH and PCP, which may be of both clinical and research relevance.     

Activation of dopamine D1 receptors blocks phencyclidine-induced neurotoxicity by enhancing N-methyl-D-aspartate receptor-mediated synaptic strength

Early postnatal blockade of NMDA receptors by phencyclidine (PCP) causes cortical apoptosis in animals. This is associated with the development of schizophrenia-like behaviors in rats later in life. Recent studies show that the mechanism involves a loss of neurotrophic support from the phosphoinositol-3 kinase/Akt pathway, which is normally maintained by synaptic NMDA receptor activation. Here we report that activation of dopamine D1 receptors (D1R) with dihydrexidine (DHX) prevents PCP-induced neurotoxicity in cortical neurons by enhancing the efficacy of NMDAergic synapses. DHX increases serine phosphorylation of the NR1 subunit through protein kinase A activation and tyrosine phosphorylation of the NR2B subunit via Src kinase. DHX enhances recruitment of NR1 and NR2B, but not NR2A, into synapses. DHX also facilitated the synaptic response in cortical slices and this was blocked by an NR2B antagonist. DHX pre-treatment of rat pups prior to PCP on postnatal days 7, 9 and 11 inhibited PCP-induced caspase-3 activation on PN11 and deficits in pre-pulse inhibition of acoustic startle measured on PN 26-28. In summary, these data demonstrate that PCP-induced deficits in NMDA receptor function, neurotoxicity and subsequent behavioral deficits may be prevented by D1R activation in the cortex and further, it is suggested that D1R activation may be beneficial in treating schizophrenia.     

NE-100, a novel sigma receptor ligand: Effect on phencyclidine-induced behaviors in rats,dogs and monkeys

Phencyclidine (PCP)-induced psychosis is a useful animal model for studies on schizophrenia. N, N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)-phenyl]-ethylamine monohydrochloride (NE-100) had no effect on conditioned avoidance responses (CAR) in rats, whereas, the PCP-induced impairment of avoidance inhibition was attenuated by NE-100. The PCP-induced ataxia or decrased attention in rhesus monkeys was to some extent overcome by NE-100. In dogs, PCP-induced either head-weaving behavior or ataxia, effects which were blocked by NE-100. Administration of PCP led to an increase in beta-2 and a decrease in delta relative power (RP) activity in cortical background spectral electroencephalographics (ECoG) in dogs. While NE-100 in itself showed no significant change in beta-2 and delta RP, NE-100 did block the PCP-induced beta-2 increase and delta decrease. These findings indicate that NE-100 attenuates the effect of PCP in experimental animals. This drug is being considered as a therapeutic for the treatment of patients in the schizophrenia.     

Spatial learning and action planning in a prefrontal cortical network model

The interplay between hippocampus and prefrontal cortex (PFC) is fundamental to spatial cognition. Complementing hippocampal place coding, prefrontal representations provide more abstract and hierarchically organized memories suitable for decision making. We model a prefrontal network mediating distributed information processing for spatial learning and action planning. Specific connectivity and synaptic adaptation principles shape the recurrent dynamics of the network arranged in cortical minicolumns. We show how the PFC columnar organization is suitable for learning sparse topological-metrical representations from redundant hippocampal inputs. The recurrent nature of the network supports multilevel spatial processing, allowing structural features of the environment to be encoded. An activation diffusion mechanism spreads the neural activity through the column population leading to trajectory planning. The model provides a functional framework for interpreting the activity of PFC neurons recorded during navigation tasks. We illustrate the link from single unit activity to behavioral responses. The results suggest plausible neural mechanisms subserving the cognitive "insight" capability originally attributed to rodents by Tolman & Honzik. Our time course analysis of neural responses shows how the interaction between hippocampus and PFC can yield the encoding of manifold information pertinent to spatial planning, including prospective coding and distance-to-goal correlates.     

NAAG peptidase inhibition reduces locomotor activity and some stereotypes in the PCP model of schizophrenia via group II mGluR

Phencyclidine (PCP) administration elicits positive and negative symptoms that resemble those of schizophrenia and is widely accepted as a model for the study of this human disorder. Group II metabotropic glutamate receptor (mGluR) agonists have been reported to reduce the behavioral and neurochemical effects of PCP. The peptide neurotransmitter, N-acetylaspartylglutamate (NAAG), is a selective group II agonist. We synthesized and characterized a urea-based NAAG analogue, ZJ43. This novel compound is a potent inhibitor of enzymes, glutamate carboxypeptidase II (K(i) = 0.8 nM) and III (K(i) = 23 nM) that deactivate NAAG following synaptic release. ZJ43 (100 microM) does not directly interact with NMDA receptors or metabotropic glutamate receptors. Administration of ZJ43 significantly reduced PCP-induced motor activation, falling while walking, stereotypic circling behavior, and head movements. To test the hypothesis that this effect of ZJ43 was mediated by increasing the activation of mGluR3 via increased levels of extracellular NAAG, the group II mGluR selective antagonist LY341495 was co-administered with ZJ43 prior to PCP treatment. This antagonist completely reversed the effects of ZJ43. Additionally, LY341495 alone increased PCP-induced motor activity and head movements suggesting that normal levels of NAAG act to moderate the effect of PCP on motor activation via a group II mGluR. These data support the view that NAAG peptidase inhibitors may represent a new therapeutic approach to some of the components of schizophrenia that are modeled by PCP.     

The effect of non-competitive NMDA receptor antagonist MK-801 on neuronal activity in rodent prefrontal cortex: an animal model for cognitive symptoms of schizophrenia

Schizophrenia affects about 1% of the world population and is a major socio-economical problem in ours societies. Cognitive symptoms are particularly resistant to current treatments and are believed to be closely related to an altered function of prefrontal cortex (PFC). Particularly, abnormalities in the plasticity processes in the PFC are a candidate mechanism underlying cognitive symptoms, and the recent evidences in patients are in line with this hypothesis. Animal pharmacological models of cognitive symptoms, notably with non-competitive NMDA receptor antagonists such as MK-801, are commonly used to investigate the underlying cellular and molecular mechanisms of schizophrenia. However, it is still unknown whether in these animal models, impairments in plasticity of PFC neurons are present. In this article, we briefly summarize the current knowledge on the effect of non-competitive NMDA receptor antagonist MK-801 on medial PFC (mPFC) neuronal activity and then introduce a form of plasticity found after acute exposure to MK-801, which was accompanied by cognitive deficits. These observations suggest a potential correlation between cognitive deficits and the aberrant plasticity in the mPFC in the animal model of schizophrenia.     

Computerized cognitive training restores neural activity within the reality monitoring network in schizophrenia

Schizophrenia patients suffer from severe cognitive deficits, such as impaired reality monitoring. Reality monitoring is the ability to distinguish the source of internal experiences from outside reality. During reality monitoring tasks, schizophrenia patients make errors identifying "I made it up" items, and even during accurate performance, they show abnormally low activation of the medial prefrontal cortex (mPFC), a region that supports self-referential cognition. We administered 80 hr of computerized training of cognitive processes to schizophrenia patients and found improvement in reality monitoring that correlated with increased mPFC activity. In contrast, patients in a computer games control condition did not show any behavioral or neural improvements. Notably, recovery in mPFC activity after training was associated with improved social functioning 6 months later. These findings demonstrate that a serious behavioral deficit in schizophrenia, and its underlying neural dysfunction, can be improved by well-designed computerized cognitive training, resulting in better quality of life.     

Phencyclidine animal models of schizophrenia: approaches from abnormality of glutamatergic neurotransmission and neurodevelopment

In humans, phencyclidine (PCP), a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, reproduces a schizophrenia-like psychosis including positive symptoms, negative symptoms and cognitive dysfunction. Thus, the glutamatergic neuronal dysfunction hypothesis is one of the main explanatory hypotheses and PCP-treated animals have been utilized as an animal model of schizophrenia. The adult rodents treated with PCP repeatedly exhibit hyperlocomotion as an index of positive symptoms, a social behavioral deficit in a social interaction test and enhanced immobility in a forced swimming test as indices of negative symptoms. They also show a sensorimotor gating deficits and cognitive dysfunctions in several learning and memory tests. Some of these behavioral changes endure after withdrawal from repeated PCP treatment. Furthermore, repeated PCP treatment induces some neurochemical and neuroanatomical changes. On the other hand, the exposure to viral or environmental insult in the second trimester of pregnancy increases the probability of subsequently developing schizophrenia as an adult. NMDA receptor has been implicated in controlling the structure and plasticity of developing brain circuitry. Based on neurodevelopment hypothesis of schizophrenia, schizophrenia model rats treated with PCP at the perinatal stage is developed. Perinatal PCP treatment impairs neuronal development and induces long-lasting schizophrenia-like behaviors in adult period. Many findings suggest that these PCP animal models would be useful for evaluating novel therapeutic candidates and for confirming pathological mechanisms of schizophrenia.     

Antipsychotic drugs reverse the AMPA receptor-stimulated release of 5-HT in the medial prefrontal cortex

The prefrontal cortex (PFC) is involved in the pathophysiology of schizophrenia. PFC neuronal activity is modulated by monoaminergic receptors for which antipsychotic drugs display moderate-high affinity, such as 5-HT(2A) and alpha(1)-adrenoceptors. Conversely, PFC pyramidal neurons project to and modulate the activity of raphe serotonergic neurons and serotonin (5-HT) release. Under the working hypothesis that atypical antipsychotic drugs may partly exert their action in PFC, we assessed their action on the in vivo 5-HT release evoked by increasing glutamatergic transmission in rat medial PFC (mPFC). This was achieved by applying S-AMPA in mPFC (reverse dialysis) or by disinhibiting thalamic excitatory afferents to mPFC with bicuculline. The application of haloperidol, chlorpromazine, clozapine and olanzapine in mPFC by reverse dialysis (but not reboxetine or diazepam) reversed the S-AMPA-evoked local 5-HT release. Likewise, the local (in mPFC) or systemic administration of these antipsychotic drugs reversed the increased prefrontal 5-HT release produced by thalamic disinhibition. These effects were shared by the 5-HT(2A) receptor antagonist M100907 and the alpha(1)-adrenoceptor antagonist prazosin. However, raclopride (DA D2 antagonist) had very modest effects. These results suggest that, besides their action in limbic striatum, antipsychotic drugs may attenuate glutamatergic transmission in PFC, possibly by interacting with 5-HT(2A) and/or alpha(1)-adrenoceptors.     

Differential effects of phencyclidine application on secretogranin II expression in organotypic slices of rat prefrontal cortex

Phencyclidine (PCP) is a non-competitive NMDA glutamate receptor antagonist that induces psychotomimetic effects in humans and experimental animals. Chronic PCP exposure elicits signs of persistently altered frontal brain activity and related behaviors which are also seen in patients with schizophrenia. Secretogranin II (sg II) belongs to the chromogranin family of proteins that exist in large dense core vesicles in nervous tissue. In the brain, 90% of sg II is processed to the small peptide secretoneurin. We previously detected differential effects of single-dose and subchronic PCP administration on sg II expression in the rat prefrontal cortex (PFC). In the present study, we applied PCP to organotypic PFC slices. PCP application for 28 h induced decreased tissue and culture medium secretoneurin content. In contrast, incubation with the adenylate cyclase activator forskolin caused significantly increased secretoneurin levels after 8 h. PCP for 4 h followed by 24 h without PCP resulted in increased culture medium secretoneurin content but no change in tissue levels. sg II mRNA expression was decreased after 28 h PCP application in cortical neurons. Immunohistochemical and TUNEL staining profiles indicated that the alterations were not due to neurodegeneration. PCP for 5 days changed neither the secretoneurin tissue or culture medium levels, nor the sg II mRNA expression. These results demonstrate that PCP modulates sg II expression in PFC tissue in the absence of afferent inputs and that the nature of these changes is dependent upon the duration of exposure to and/or withdrawal from PCP.     

Differential expression of parvalbumin in neonatal phencyclidine‐treated rats and socially isolated rats

Decreased parvalbumin expression is a hallmark of the pathophysiology of schizophrenia and has been associated with abnormal cognitive processing and decreased network specificity. It is not known whether this decrease is due to reduced expression of the parvalbumin protein or degeneration of parvalbumin‐positive interneurons (PV⁺ interneurons). In this study, we examined PV⁺ expression in two rat models of cognitive dysfunction in schizophrenia: the environmental social isolation (SI) and pharmacological neonatal phencyclidine (neoPCP) models. Using a stereological method, the optical fractionator, we counted neurons, PV⁺ interneurons, and glial cells in the medial prefrontal cortex (mPFC) and hippocampus (HPC). In addition, we quantified the mRNA level of parvalbumin in the mPFC. There was a statistically significant reduction in the number of PV⁺ interneurons (p = 0.021) and glial cells (p = 0.024) in the mPFC of neonatal phencyclidine rats, but not in SI rats. We observed no alterations in the total number of neurons, hippocampal PV⁺ interneurons, parvalbumin mRNA expression or volume of the mPFC or HPC in the two models. Thus, as the total number of neurons remains unchanged following phencyclidine (PCP) treatment, we suggest that the decreased number of counted PV⁺ interneurons represents a reduced parvalbumin protein expression below immunohistochemical detection limit rather than a true cell loss. Furthermore, these results indicate that the effect of neonatal PCP treatment is not limited to neuronal populations.     

Molecular validation of the acute phencyclidine rat model for schizophrenia: identification of translational changes in energy metabolism and neurotransmission

Administration of the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist phencyclidine (PCP) to rodents is widely used as preclinical model for schizophrenia. Most studies on this model employ methods investigating behavior and brain abnormalities. However, little is known about the corresponding peripheral effects. In this study, we analyzed changes in brain and serum molecular profiles, together with alterations in behavior after acute PCP treatment of rats. Furthermore, abnormalities in peripheral protein expression of first and recent onset antipsychotic free schizophrenia patients were assessed for comparison with the preclinical model. PCP treatment induced hyperlocomotion and stereotypic behavior, which have been related to positive symptoms of schizophrenia. Multiplex immunoassay profiling of serum revealed molecular abnormalities similar to those seen in first and recent onset, antipsychotic free schizophrenia patients. Also, increased insulin levels were detected after administration of a glucose tolerance test (GTT), consistent with previous studies showing changes in insulin signaling in patients with schizophrenia. Finally, schizophrenia-relevant alterations in brain molecules were found in the hippocampus and to a lesser extent in the frontal cortex using liquid-chromatography mass spectrometry and (1)H nuclear magnetic resonance spectroscopy. In conclusion, this study identified behavioral and molecular alterations in the acute PCP rat model, which are also observed in human schizophrenia. We propose that the corresponding changes in serum in both animals and patients may have utility as surrogate markers in this model to facilitate discovery and development of novel drugs for treatment of certain pathological features of schizophrenia.     

The role of dopamine in the nucleus accumbens in analgesia

Opioid and psychostimulant drugs have long been used for the relief of chronic pain in the clinical situation. Animal studies confirm that these drugs alleviate persistent or tonic pain. Little is known, however, about the neural systems underlying the suppression of tonic pain except that they are different from those mediating the suppression of phasic (i.e., sharp and short-lasting) pain. Although spinal and brainstem-descending pain suppression mechanisms play a role in mediating the inhibition of tonic pain, it appears that this response is additionally mediated by the activation of mechanisms lying rostral to the brainstem. Recent studies suggest that the activation of mesolimbic dopamine (DA) neurons, arising from the cell bodies of the ventral tegmental area (VTA) and projecting to the nucleus accumbens (NAcc), plays an important role in mediating the suppression of tonic pain. Other studies suggest that this pain-suppression system involving the activation of mesolimbic DA neurons is naturally triggered by exposure to stress, through the endogenous release of opioids and substance P (SP) in the midbrain.     

Serotonin and Prefrontal Cortex Function: Neurons,Networks, and Circuits

Higher-order executive tasks such as learning, working memory, and behavioral flexibility depend on the prefrontal cortex (PFC), the brain region most elaborated in primates. The prominent innervation by serotonin neurons and the dense expression of serotonergic receptors in the PFC suggest that serotonin is a major modulator of its function. The most abundant serotonin receptors in the PFC, 5-HT1A, 5-HT2A and 5-HT3A receptors, are selectively expressed in distinct populations of pyramidal neurons and inhibitory interneurons, and play a critical role in modulating cortical activity and neural oscillations (brain waves). Serotonergic signaling is altered in many psychiatric disorders such as schizophrenia and depression, where parallel changes in receptor expression and brain waves have been observed. Furthermore, many psychiatric drug treatments target serotonergic receptors in the PFC. Thus, understanding the role of serotonergic neurotransmission in PFC function is of major clinical importance. Here, we review recent findings concerning the powerful influences of serotonin on single neurons, neural networks, and cortical circuits in the PFC of the rat, where the effects of serotonin have been most thoroughly studied.     

Abnormal neural responses to social exclusion in schizophrenia

Social exclusion is an influential concept in politics, mental health and social psychology. Studies on healthy subjects have implicated the medial prefrontal cortex (mPFC), a region involved in emotional and social information processing, in neural responses to social exclusion. Impairments in social interactions are common in schizophrenia and are associated with reduced quality of life. Core symptoms such as delusions usually have a social content. However little is known about the neural underpinnings of social abnormalities. The aim of this study was to investigate the neural substrates of social exclusion in schizophrenia. Patients with schizophrenia and healthy controls underwent fMRI while participating in a popular social exclusion paradigm. This task involves passing a 'ball' between the participant and two cartoon representations of other subjects. The extent of social exclusion (ball not being passed to the participant) was parametrically varied throughout the task. Replicating previous findings, increasing social exclusion activated the mPFC in controls. In contrast, patients with schizophrenia failed to modulate mPFC responses with increasing exclusion. Furthermore, the blunted response to exclusion correlated with increased severity of positive symptoms. These data support the hypothesis that the neural response to social exclusion differs in schizophrenia, highlighting the mPFC as a potential substrate of impaired social interactions.     

Hyper-response to Novelty Increases c-Fos Expression in the Hippocampus and Prefrontal Cortex in a Rat Model of Schizophrenia

Schizophrenia is a debilitating disorder that may have a neurodevelopmental origin. For this reason, animal models based on neonatal insults or manipulations have been extensively used to demonstrate schizophrenia-related behaviors. Among those, the neonatal ventral hippocampus lesion (nVHL) is largely used as a model of schizophrenia-related behavior as it mimics behavioral and neurochemical abnormalities often seen in schizophrenic patients including hyperlocomotion in a novel environment. To investigate the neuroanatomical basis of coding novelty in the nVHL rat, we assessed the behavioral locomotor activity paradigm in a novel environment and measured expression of c-Fos, a marker of neural activation, in brain regions involved in the process of coding novelty or locomotion. Upon reaching adulthood, nVHL rats showed hyperlocomotion in the novel environment paradigm. Moreover, in nVHL rats the expression of c-Fos was greater in the prefrontal cortex (PFC) and CA1 region of the dorsal hippocampus compared to sham rats. Whereas similar expression of c-Fos was observed in the basolateral amygdala, nucleus accumbens and dentate gyrus region of  hippocampus of nVHL and sham rats. These results suggest that the nVHL disrupts the neural activity in the PFC and CA1 region of hippocampus in the process of coding novelty in the rat.     

Early cognitive experience prevents adult deficits in a neurodevelopmental schizophrenia model

Brain abnormalities acquired early in life may cause schizophrenia, characterized by adulthood onset of psychosis, affective flattening, and cognitive impairments. Cognitive symptoms, like impaired cognitive control, are now recognized to be important treatment targets but cognition-promoting treatments are ineffective. We hypothesized that cognitive training during the adolescent period of neuroplastic development can tune compromised neural circuits to develop in the service of adult cognition and attenuate schizophrenia-related cognitive impairments that manifest in adulthood. We report, using neonatal ventral hippocampus lesion rats (NVHL), an established neurodevelopmental model of schizophrenia, that adolescent cognitive training prevented the adult cognitive control impairment in NVHL rats. The early intervention also normalized brain function, enhancing cognition-associated synchrony of neural oscillations between the hippocampi, a measure of brain function that indexed cognitive ability. Adolescence appears to be a critical window during which prophylactic cognitive therapy may benefit people at risk of schizophrenia.