Alternations of NMDA and GABAB Receptor Function in Development: A Potential Animal Model of Schizophrenia

Schizophrenia is a debilitating mental disorder that affects up to 3% of the world population. The behavioral symptoms are categorized into positive and negative symptoms, which appear during late adolescence/early adulthood. Unfortunately, the underlying cellular and molecular mechanisms of the disease are poorly understood. Several hypotheses exist to explain mechanisms contributing to these behavioral alterations. One model proposes that a reduced function of the NMDA glutamate receptor on specific GABAergic interneurons may be responsible for deficits in schizophrenia. Post-mortem investigations provide evidence of reductions in both glutamate and GABA-related proteins in patients with schizophrenia. Further, GABAergic interneurons that are activated by glutamate via NMDA receptors are important for oscillatory activity involved with sensory processing and cognitive function. Alterations in the function of NMDA receptors on GABAeric interneurons are implicated in regulating neural network activity and, if disrupted, could potentially lead to altered brain function and deficits seen in schizophrenia. Several investigations have demonstrated reduction in NMDA receptor function or GABA receptor function induces deficits consistent with schizophrenia. Recent approaches have also focused on changes in NMDA or GABA function related to schizophrenia as a neurodevelopmental disorder. This approach suggests that alterations in either system during brain development may result in behavioral deficits later in life. The purpose of the below studies was to determine if changes in NMDA receptor function or alterations in downstream GABA receptor function during development in rodent pups results in behavioral or biochemical alterations in adulthood that are relevant to schizophrenia. The data reveal that altering these receptor systems in development produce deficits in adulthood. Changes in sensorimotor gating, spatial learning and memory, and differential expression of multiple GABA related proteins in the brain tissue were observed in these animals

A link between NMDA receptor hypofunction and GABAergic inhibition in the modulation of cognition: a comparison of neural and cognitive changes in rat models of NMDA receptor hypofunction and of prefrontal and hippocampal neural disinhibition

NMDA receptor (NMDAR) hypofunction and impaired GABAergic inhibition, so-called neural disinhibition, in the hippocampus and prefrontal cortex, have both been implicated in the pathophysiology of schizophrenia. Moreover, it has been suggested that NMDAR hypofunction and neural disinhibition are mechanistically linked and may converge on a common pathological hub. NMDAR hypofunction in rodents has been reported to mimic certain aspects of cognitive deficits associated with schizophrenia, alongside pathological reductions in hippocampal and prefrontal GABAergic markers. Given the importance of GABAergic inhibition in the hippocampus and prefrontal cortex for a range of cognitive functions, hippocampal and prefrontal neural disinhibition may underlie some of the cognitive deficits found in rodent models of NMDAR hypofunction. Here, we examined the overarching hypothesis that NMDAR hypofunction impairs cognition by causing neural disinhibition in the hippocampus and prefrontal cortex. In chapter 1, we reviewed the current evidence for this hypothesis, which demonstrated a compelling case for neural disinhibition in acute and neurodevelopmental models of NMDAR hypofunction. However, importantly, studies investigating the impact of sub-chronic NMDAR hypofunction on GABAergic function were equivocal in support of the hypothesis, and the role of these processes in mediating cognition on the watermaze delayed-matching-to-place (DMP) and novel object recognition (NOR) task, respectively, had not been investigated. In subsequent chapters, we aimed to address the hypothesis experimentally, by comparing and examining the cognitive and neural changes in rat models of sub-chronic NMDAR hypofunction and regional neural disinhibition. In chapter 2, we examined the impact of NMDAR hypofunction, caused by sub-chronic treatment with phencyclidine (scPCP), in rats on the watermaze DMP task. Sub-chronic PCP treatment did not disrupt hippocampal rapid place learning performance. This contrasts with the marked impairments observed following acute pharmacological hippocampal disinhibition and suggests that hippocampal disinhibition is not a pronounced feature of the scPCP model. In chapter 3, we used high throughput simple western analysis to determine the protein levels of key GABAergic biomarkers, GAD67 and parvalbumin, in the brains of the scPCP treated rats used for behavioural studies in chapter 2. No changes in GAD67 or parvalbumin protein expression were found in the prefrontal cortex or dorsal region of the hippocampus. In the intermediate to ventral hippocampus, GAD67 was found to be reduced in female, but not male, rats, suggesting that scPCP treatment may have sex-specific neuropathological effects. Importantly, however, in the scPCP treated rats which underwent watermaze DMP testing, parvalbumin was found to be increased in the intermediate to ventral hippocampus. Overall, our investigations into GABAergic protein expression changes following NMDAR hypofunction revealed limited evidence for neural disinhibition in the prefrontal cortex and hippocampus. In chapter 4, we investigated whether scPCP treatment results in functional alterations to hippocampal neural activity. Using evoked in vivo recordings under urethane anaesthesia, we applied low frequency train stimulation to the subiculum or CA3 region, with the aim of examining instances of reverberatory responses as a measure of the overall excitability of hippocampal circuits. This study revealed evidence of reverberation in both treatment groups, indicating intact fibre pathways in scPCP treated rats. However, a preliminary analysis did not indicate clear-cut changes in hippocampal excitability following scPCP treatment. Finally, in chapter 5, we investigated whether neural disinhibition in the medial prefrontal cortex, dorsal or ventral hippocampus may account for the NOR deficits reported widely in the scPCP model. Neural disinhibition or functional inhibition was induced in rats via local infusion of picrotoxin or muscimol, respectively, and NOR performance compared using a within-subjects design. We found that hippocampal, but not prefrontal, GABAergic inhibition was required for intact NOR. This finding suggests that hippocampal GABAergic deficits may contribute, in part, to NOR deficits found in NMDAR hypofunction models. Thus, the experiments reported in chapters 2-5 provide limited evidence for a link between NMDAR hypofunction and neural disinhibition in the hippocampus and prefrontal cortex in the modulation of cognition. The finding that hippocampal, but not prefrontal, GABAergic inhibition is required for intact NOR performance suggests that hippocampal GABAergic impairments could contribute to scPCP-induced NOR deficits. However, the lack of a watermaze DMP impairment in scPCP treated rats, combined with weak post-mortem evidence for reduced GABAergic markers, does not support a marked impairment of hippocampal GABA function in scPCP treated rats. Overall, our findings do not support that scPCP treatment leads to pronounced hippocampal disinhibition or that neural disinhibition in the prefrontal cortex or hippocampus plays a major role in cognitive deficits caused by sub-chronic NMDAR hypofunction

A link between NMDA receptor hypofunction and GABAergic inhibition in the modulation of cognition: a comparison of neural and cognitive changes in rat models of NMDA receptor hypofunction and of prefrontal and hippocampal neural disinhibition

NMDA receptor (NMDAR) hypofunction and impaired GABAergic inhibition, so-called neural disinhibition, in the hippocampus and prefrontal cortex, have both been implicated in the pathophysiology of schizophrenia. Moreover, it has been suggested that NMDAR hypofunction and neural disinhibition are mechanistically linked and may converge on a common pathological hub. NMDAR hypofunction in rodents has been reported to mimic certain aspects of cognitive deficits associated with schizophrenia, alongside pathological reductions in hippocampal and prefrontal GABAergic markers. Given the importance of GABAergic inhibition in the hippocampus and prefrontal cortex for a range of cognitive functions, hippocampal and prefrontal neural disinhibition may underlie some of the cognitive deficits found in rodent models of NMDAR hypofunction. Here, we examined the overarching hypothesis that NMDAR hypofunction impairs cognition by causing neural disinhibition in the hippocampus and prefrontal cortex. In chapter 1, we reviewed the current evidence for this hypothesis, which demonstrated a compelling case for neural disinhibition in acute and neurodevelopmental models of NMDAR hypofunction. However, importantly, studies investigating the impact of sub-chronic NMDAR hypofunction on GABAergic function were equivocal in support of the hypothesis, and the role of these processes in mediating cognition on the watermaze delayed-matching-to-place (DMP) and novel object recognition (NOR) task, respectively, had not been investigated. In subsequent chapters, we aimed to address the hypothesis experimentally, by comparing and examining the cognitive and neural changes in rat models of sub-chronic NMDAR hypofunction and regional neural disinhibition. In chapter 2, we examined the impact of NMDAR hypofunction, caused by sub-chronic treatment with phencyclidine (scPCP), in rats on the watermaze DMP task. Sub-chronic PCP treatment did not disrupt hippocampal rapid place learning performance. This contrasts with the marked impairments observed following acute pharmacological hippocampal disinhibition and suggests that hippocampal disinhibition is not a pronounced feature of the scPCP model. In chapter 3, we used high throughput simple western analysis to determine the protein levels of key GABAergic biomarkers, GAD67 and parvalbumin, in the brains of the scPCP treated rats used for behavioural studies in chapter 2. No changes in GAD67 or parvalbumin protein expression were found in the prefrontal cortex or dorsal region of the hippocampus. In the intermediate to ventral hippocampus, GAD67 was found to be reduced in female, but not male, rats, suggesting that scPCP treatment may have sex-specific neuropathological effects. Importantly, however, in the scPCP treated rats which underwent watermaze DMP testing, parvalbumin was found to be increased in the intermediate to ventral hippocampus. Overall, our investigations into GABAergic protein expression changes following NMDAR hypofunction revealed limited evidence for neural disinhibition in the prefrontal cortex and hippocampus. In chapter 4, we investigated whether scPCP treatment results in functional alterations to hippocampal neural activity. Using evoked in vivo recordings under urethane anaesthesia, we applied low frequency train stimulation to the subiculum or CA3 region, with the aim of examining instances of reverberatory responses as a measure of the overall excitability of hippocampal circuits. This study revealed evidence of reverberation in both treatment groups, indicating intact fibre pathways in scPCP treated rats. However, a preliminary analysis did not indicate clear-cut changes in hippocampal excitability following scPCP treatment. Finally, in chapter 5, we investigated whether neural disinhibition in the medial prefrontal cortex, dorsal or ventral hippocampus may account for the NOR deficits reported widely in the scPCP model. Neural disinhibition or functional inhibition was induced in rats via local infusion of picrotoxin or muscimol, respectively, and NOR performance compared using a within-subjects design. We found that hippocampal, but not prefrontal, GABAergic inhibition was required for intact NOR. This finding suggests that hippocampal GABAergic deficits may contribute, in part, to NOR deficits found in NMDAR hypofunction models. Thus, the experiments reported in chapters 2-5 provide limited evidence for a link between NMDAR hypofunction and neural disinhibition in the hippocampus and prefrontal cortex in the modulation of cognition. The finding that hippocampal, but not prefrontal, GABAergic inhibition is required for intact NOR performance suggests that hippocampal GABAergic impairments could contribute to scPCP-induced NOR deficits. However, the lack of a watermaze DMP impairment in scPCP treated rats, combined with weak post-mortem evidence for reduced GABAergic markers, does not support a marked impairment of hippocampal GABA function in scPCP treated rats. Overall, our findings do not support that scPCP treatment leads to pronounced hippocampal disinhibition or that neural disinhibition in the prefrontal cortex or hippocampus plays a major role in cognitive deficits caused by sub-chronic NMDAR hypofunction

The effect of schizotypy on spatial learning in an environment with a distinctive shape

In two experiments, participants completed the Oxford-Liverpool Inventory of Feelings and Experiences measuring schizotypal traits across four dimensions (unusual experiences, cognitive disorganization, introvertive anhedonia, and impulsive non-conformity). They then took part in a virtual navigation task where they were required to learn about the position of a hidden goal with reference to geometric cues of a rectangular arena or rely on colored wall panels to find the hidden goal in a square-shaped arena. Unusual experience and cognitive disorganization were significant predictors of the use of geometric cues, but no significant predictors were found for the use of wall panels. Implications to hippocampal function and the clinical domain are considered

Place conditioning in humans: opportunities for translational research

Rationale Translational research, especially research that bridges studies with humans and nonhuman species, is critical to advancing our understanding of human disorders such as addiction. This advancement requires reliable and rigorous models to study the underlying constructs contributing to the maladaptive behavior. Objective In this commentary, we address some of the challenges of conducting translational research by examining a single procedure, place conditioning. Place conditioning is commonly used with laboratory animals to study the conditioned rewarding effects of drugs, and recent studies indicate that a similar procedure can be used in humans. Results We discuss the opportunities and challenges of making the procedure comparable across species, as well as discuss the benefits of more systematically applying the procedure to humans. Conclusion We argue that the capacity of humans to report verbally on their internal experiences (perceptions, affective states, likes and dislikes) add an important dimension to the understanding of the procedures used in laboratory animals

Prostorová paměť u lidí a její poruchy: Od animálních modelů ke schizofrenii

Spatial memory is often studied using spatial tasks originally developed for animals, such as the Morris water maze and the Carousel maze tasks. Both tasks have an important role in the process of identification of brain areas crucial for spatial memory, and also in pharmacological research of animal models of neuropsychiatric diseases. In recent years considerable attention has been devoted to the research and treatment of cognitive impairment in schizophrenia. Comparative research addressing cognitive abilities of both animals and patients in similar tasks, could therefore lead to verification of the predictive and face validity of animal models of this complex disorder. The aim of this study was to create virtual analogues of these tasks, which would allow this comparative approach. This thesis first describes the experiment testing the performance of an animal model of schizophrenia induced by the application of dizocilpine (MK-801) in reversal version of both mentioned spatial tasks, in order to assess mental flexibility and learning abilities affected in schizophrenia. Other two experiments present the findings of the two virtual analogues tested in the first episode of schizophrenia patients. Our results confirm the presence of deficits in spatial memory and mental flexibility, functions dependent on...Ke studiu prostorové paměti se často využívají úlohy původně vytvořené pro zvířata, jako Morrisovo vodní bludiště a Kolotočové bludiště. Tyto úlohy prokázaly svůj význam nejen s ohledem na identifikaci neurofyziologických podkladů prostorové paměti, ale také ve farmakologickém výzkumu u animálních modelů neuropsychiatrických onemocnění. V této souvislosti se v posledních letech věnuje značná pozornost zejména modelování kognitivního deficitu u schizofrenie a možnostem jeho terapie. Komparativní výzkum srovnávající schopnosti modelových zvířat a pacientů v podobných úlohách umožňuje ověřit fenomenologickou a prediktivní validitu animálních modelů. Cílem této práce bylo vytvořit virtuální (počítačové) analogie dvou behaviorálních úloh, které by podobné srovnání umožnily. Tato dizertační práce nejdříve popisuje experiment posuzující výkon potkanů v animálním modelu schizofrenie, vyvolaným aplikací dizocilpinu (MK-801), v reverzních variantách dvou prostorových úloh (v měnících se prostorových podmínkách) ve snaze otestovat mentální flexibilitu, schopnost značně narušenou u schizofrenie. Následující dva experimenty pak prezentují nálezy virtuálních analogií obou úloh testovaných u pacientů po první epizodě schizofrenního onemocnění. Naše nálezy potvrdily deficit prostorové paměti a mentální flexibility u...3. lékařská fakultaThird Faculty of Medicin

Hippocampus

The hippocampus is a bicortical structure with extensive fiber connections with multiple brain regions. It is involved in several functions, such as learning, memory, attention, emotion, and more. This book covers various aspects of the hippocampus including cytoarchitecture, functions, diseases, and treatment. It highlights the most advanced findings in research on the hippocampus. It discusses circuits, pattern formation process of grid cells, and zinc dynamics of the hippocampus. The book also addresses the tau pathology and circRNAs related to Alzheimer’s disease and potential treatment strategies. It is a useful resource for general readers, students, and researchers

Cognitive mechanisms associated with clinical and non-clinical psychotic experiences

The studies reported in this thesis were designed to address several important issues in symptom-specific cognitive models of psychosis. The design of these studies was guided by a commitment to the continuity hypothesis of psychosis, which holds that psychotic experiences exist on a continuum stretching into the healthy population. The thesis firstly examines a two-factor cognitive model of persecutory ideation, focusing primarily on the roles of thought suppression, intrusive thoughts, anxiety, social rank, and the jumping to conclusions bias. The thesis then turns to an examination of cognitive factors involved in hallucinations and, in particular, auditory verbal hallucinations. Chapters in this section describe a series of experimental and theoretical studies of the relations between intrusive thoughts and hallucinations, agency and hallucinations, and the role of inner speech in auditory verbal hallucinations. Two-factor models of persecutory delusion (PD) formation propose that in the first stage of PD formation an initial implausible idea is triggered. The second stage of Deformation is then the uncritical adoption of such a thought as a belief, which may be due to cognitive biases such as the jumping to conclusions (JTC) bias often present in those with PDs. The first study (Chapter 1) investigated whether thought suppression, and its interaction with anxiety, was associated with levels of non-clinical persecutory delusion like beliefs (PDLBs). It was hypothesised that thought suppression could play a role in the formation and maintenance of PDLBs through its tendency to lead to intrusive thoughts, and to trigger initial implausible ideas. Consistent with this proposal, thought suppression was positively associated with PDLBs only when anxiety was high. The second study (Chapter 2) examined a prediction of the two-factor model, namely that a second-stage factor, the jumping to conclusions (JTC) bias, should interact with first-stage factors, specifically social anxiety, social rank, anomalous experiences and thought suppression. Consistent with the two-factor model, the JTC bias was found not to be an independent predictor of PDLB levels, but its interaction with social rank was a significant predictor of PDLBs. It was concluded that although evidence was found for the two-factor model, the presence of the JTC bias was neither a sufficient nor necessary condition for PDLB formation. In addition to being postulated to play a role in persecutory delusion formation, intrusive thoughts have been implicated in the formation of hallucinations, and particularly auditory verbal hallucinations (AVHs). The third study (Chapter 3) created a new tool for assessing hypnagogic and hypnopompic (H&H) hallucinations, and showed that the presence of auditory H&H hallucinations, but not visual or felt-presence H&H hallucinations, was associated with a greater tendency to experience intrusions. The fourth study (Chapter 4) developed an extended model of AVHs in which rumination, as well as thought suppression, were proposed to be involved in the formation of AVHs, through their creation of intrusive thoughts. This model was tested in a healthy sample of individuals using structural equation modelling, and the proposed model was found to be a good fit to the data. The study on rumination and AVHs highlighted that agency disruption factors are likely to be involved in leading these self-generated cognitions to be experienced as alien. A theoretical analysis (Chapter 5) was made of the mechanisms likely to be involved in this disruption of agency, involving the concept of a neurocognitive action self-monitoring system (NASS) and a breakdown in the processes leading to the illusion of conscious will. A consideration was also given to how a Vygotskian conception of inner speech could contribute to inner speech models of AVHs. The next study (Chapter 6) then performed an empirical test of the proposal that the disruption of agency in AVHs is associated with a faulty NASS. Subliminal primes were used as a proxy for the predicted state proposed to exist in the NASS, which leads to the experience of agency. It was proposed that those prone to hallucinations would be less able to use primes to enhance their experience of agency, due to deficits in their NASS. A statistically significant trend was found for the more hallucination-prone to be less able to use subliminal primes, but this effect was only found in women. It was concluded that although this was a promising finding, the effect was too small and gender-specific to be practical to test in a clinical sample of patients with AVHs. The proposal that AVHs result from a breakdown in the NASS, specifically a corollary discharge deficit between speech production and reception areas, has been claimed to be supported by electrophysiological event-related potential (ERP) studies. However, only a simplistic conception of inner speech has thus far been investigated in ERP studies, and the potential confounding effects of attention have not been considered. The Nl ERP component response to auditory stimuli during inner speech was studied in as ample of healthy volunteers (Chapter 7). Although dampening of the Nl response was found during all types of inner speech, as compared to a silent baseline condition, dampening was also found during a mental rotation task. It was concluded that dampening of the Nl ERP component during inner speech is due to attention factors, and is not indicative of a corollary discharge mechanism. Finally, a theoretical analysis considers whether inner speech models of AVHs are able to satisfactorily account for the phenomenology of the experience (Chapter 8). It is concluded that subcategorisation of auditory hallucinations may be necessary, with memory-based, inner speech-based, and ictal-based models each accounting for a subcategory of auditory hallucinations. The concept of the dynamic developmental progression of AVHs is introduced and avenues for future research in this area highlighte