John Talpos

NMDA receptors, cognition and schizophrenia--testing the validity of the NMDA receptor hypofunction hypothesis.

Cognitive dysfunction is core to schizophrenia, and remains poorly treated by existing therapies. A prominent hypothesis suggests that many symptoms arise from N-methyl-d-aspartate receptor (NMDAR) hypofunction. Subsequently, there has emerged a widespread use of many preclinical and clinical NMDAR antagonist models in the search for novel treatments. Clinically, ketamine is broadly purported to induce cognitive symptoms similar to those of schizophrenia. Preclinically, acute, subchronic and neonatal NMDAR antagonist administration models are all utilised in this context, as well as NMDAR transgenic animals. In this review, key strengths and weaknesses of each of these approaches are described with regard to their ability to recapitulate the deficits seen in patients. Given the breadth of literature and vogue for research in this topic, instances of NMDAR antagonist effects in the desired domains can readily be found preclinically. However, it is surprisingly difficult to identify any single aspect of cognitive function that possesses complete translational integrity. That is, there does not seem to be an NMDAR antagonist regimen proven to engage NMDARs equivalently in humans and animals that reliably produces the same cognitive effects in each species. This is likely due to the diverse range of techniques and models used by preclinical researchers, a paucity of research describing pharmacokinetic-pharmacodynamic relationships of NMDAR antagonist regimens, little capability to measure target engagement, and the lack of harmonized procedures between preclinical and clinical studies. Realizing the potential of the NMDAR hypofunction hypothesis to model cognitive impairment in schizophrenia will require some of these issues to be addressed.

Assessing behavioural and cognitive domains of autism spectrum disorders in rodents: current status and future perspectives

The establishment of robust and replicable behavioural testing paradigms with translational value for psychiatric diseases is a major step forward in developing and testing etiology-directed treatment for these complex disorders. Based on the existing literature, we have generated an inventory of applied rodent behavioural testing paradigms relevant to autism spectrum disorders (ASD). This inventory focused on previously used paradigms that assess behavioural domains that are affected in ASD, such as social interaction, social communication, repetitive behaviours and behavioural inflexibility, cognition as well as anxiety behaviour. A wide range of behavioural testing paradigms for rodents were identified. However, the level of face and construct validity is highly variable. The predictive validity of these paradigms is unknown, as etiology-directed treatments for ASD are currently not on the market. To optimise these studies, future efforts should address aspects of reproducibility and take into account data about the neurodevelopmental underpinnings and trajectory of ASD. In addition, with the increasing knowledge of processes underlying ASD, such as sensory information processes and synaptic plasticity, phenotyping efforts should include multi-level automated analysis of, for example, representative task-related behavioural and electrophysiological read-outs.

A touch-screen based paired-associates learning (PAL) task for the rat may provide a translatable pharmacological model of human cognitive impairment

The use of touch-screen equipped operant boxes is an increasingly popular approach for modeling human cognition in the rodent. However little data is currently available describing the effects of pharmacological manipulations on touch-screen based tasks. Owing to the relationship between performance on visual-spatial paired associates learning (PAL) with schizophrenia and Alzheimers disease one task of specific interest is the touch-screen PAL task developed for rodents (J. Talpos et al., 2009). The goal of this study was to profile a range of the commonly used pharmacological models of schizophrenia and Alzheimers disease to investigate the sensitivity of PAL to these models of disease. Male Lister hooded rats were trained on PAL until stable performance was obtained. The effects of PCP, ketamine, amphetamine, LSD, scopolamine, and biperiden (recently proposed as an alternative to scopolamine) were then tested on animals performing the PAL task. While all compounds influenced responding during PAL, only PCP and amphetamine impaired performance with minimal changes in secondary measures (response latencies, trials completed). Surprisingly ketamine did not cause a change in percent correct despite being an NMDA antagonist, indicating that not all NMDA antagonists are equal in the touch-screen platform. This finding is in agreement with existing literature showing differential effects of NMDA antagonists on a wide variety of behavioral assays include tasks of attention, memory, and cognitive flexibility (Gilmour et al., 2009; Dix et al., 2010; Smith et al., 2011). Moreover biperiden showed no benefit when compared to scopolamine, highlighting the current lack of an effective pharmacological model of cholinergic dysfunction in the touch-screen platform. These data demonstrate that performance on PAL can be disrupted by common pharmacological disease models, suggesting that PAL may have the sensitivity to serve as a translational test for the study of cognition in humans.

Re-evaluating the PCP challenge as a pre-clinical model of impaired cognitive flexibility in schizophrenia.

NMDA-R antagonists are a popular translational pharmacological challenge to induce cognitive deficits associated with schizophrenia. Amongst their many cognitive and non-cognitive effects is an ability to impair cognitive flexibility in general, and reversal learning in particular. Here, we test the hypothesis that the NMDA-R antagonist phencyclidine when given acutely selectively effects reversal learning by simultaneously measuring reversal learning and baseline responding, or acquisition and baseline responding, under identical conditions. Animals were trained to simultaneously perform two different visual discriminations in a touch-screen equipped operant box. Accordingly the reward contingencies associated with one pair could be altered, while the second pair acted as an experimental control. As such, the effect of a manipulation on reversal learning, stimuli acquisition, or baseline responding can be more accurately evaluated through the use of a double visual discrimination. A similar approach was also used to investigate the influence of sub-chronic phencyclidine administration on cognitive flexibility. Phencyclidine (1mg/kg) given before testing caused a slowing in acquisition and reversal learning, while having a minimal effect on secondary measures. Sub-chronic phencyclidine administration had no significant effect on any of the measures used within this study. While acute phencyclidine impairs reversal learning, it is clear from these results that other aspects of cognition (learning/relearning) are also impaired, potentially questioning the specificity of acute phencyclidine in conjunction with reversal learning paradigms as a model of impaired cognitive flexibility.

Strain-dependent effects on acquisition and reversal of visual and spatial tasks in a rat touchscreen battery of cognition.

AIM The use of touch-screen equipped operant boxes is an increasingly popular method for modeling human cognition in the rodent. A concern of this approach is that the dependence upon vision may limit the strains of rats that can be tested in the apparatus. This is of particular concern because of the increased availability of genetically modified rats that are disproportionately on an albino background and may have compromised vision. Here we test pigmented and albino strains of rats on three touch-screen tasks of learning and memory that may require different levels of visual ability. In tests where albino animals have similar levels of performance as the pigmented rats we also tested common pharmacological models of cognitive impairment to determine the generalizability of these challenges across strains. By doing this work we hope to determine the robustness of common models of pharmacological impairment in albino rats. METHODS We tested four strains of rats (albino: Wistar and Sprague Dawley, pigmented: Long Evans and Lister Hooded) in three touchscreen-based tasks of cognition with differing visual requirements: visual discrimination (VD) acquisition and reversal learning, and the more spatial and less visually demanding, automated spatial search task (AST). Furthermore, we tested the effects of the muscarinic antagonist scopolamine and the non-competitive NMDAR antagonist MK801 on performance of the four strains in AST. Finally, visual acuity was also assessed via a movement detection test. RESULTS The rate of acquisition (% correct) in albino rats was significantly slower than in pigmented rats. Wistar rats were significantly slower to acquire the task, and showed differences in reversal learning when compared to the pigmented strains. Moreover, SD rats performed so badly during the acquisition phase of the VD that they failed to reach inclusion criteria (80% correct responses over 3-sessions) for the reversal phase. In contrast, no effect of strain was found in AST. Some of these differences can likely be attributed to differences in visual acuity as albino animals appeared to have reduced visual acuity when compared to the pigmented animals as previously reported in the literature. Pharmacological challenge with scopolamine or MK801 induced dissociable effects between compounds, but generally comparable impairments in all four strains. CONCLUSIONS Albino animals showed a clear impairment on tasks that are dependent upon intact vision, while no impairment was observed in the visually less demanding spatial task. Despite a published report to the contrary, these results demonstrate that albino strains may not be appropriate for use in touchscreen tasks that are dependent upon a visual discrimination. Furthermore, the spatial search task showed distinct impairment profiles as a result of treatment with either MK-801 or scopolamine. While an interaction did exist between strain and treatment, the dissociation between MK-801 and scopolamine was consistent across 3 of 4 strains. These results highlight the importance of selecting the appropriate strain for use in tasks of visual learning and memory and also demonstrate the potential robustness of pharmacological models of cognitive impairment across strains.

MK-801 and amphetamine result in dissociable profiles of cognitive impairment in a rodent paired associates learning task with relevance for schizophrenia

RationalePaired associates learning (PAL) has been suggested to be predictive of functional outcomes in first episode psychosis and of conversion from mild cognitive impairment to Alzheimer’s disease. An automated touch screen-based rodent PAL (rPAL) task has been developed and is sensitive to manipulations of the dopaminergic and glutamatergic system. Accordingly, rPAL when used with pharmacological models of schizophrenia, like NMDA receptor blockade with MK-801 or dopaminergic stimulation with amphetamine, may have utility as a translational model of cognitive impairment in schizophrenia.ObjectiveThe purpose of this study was to determine if amphetamine- and MK-801-induced impairment represent distinct models of cognitive impairment by testing their sensitivity to common antipsychotics and determine the relative contributions of D1 versus D2 receptors on performance of PAL.MethodRats were trained in rPAL and were then treated with MK-801, amphetamine, risperidone, haloperidol, quinpirole, SK-82958, or SCH-23390 alone and in combination.ResultsWhile both amphetamine and MK-801 caused clear impairments in accuracy, MK-801 induced a profound “perseverative” type behavior that was more pronounced when compared to amphetamine. Moreover, amphetamine-induced impairments, but not the effects of MK-801, could be reversed by antipsychotics as well as the D1 receptor antagonist SCH-23390, suggesting a role for both the D1 and D2 receptor in the amphetamine impairment model.ConclusionsThese data suggest that amphetamine and MK-801 represent dissociable models of impairment in PAL, dependent on different underlying neurobiology. The ability to distinguish dopaminergic versus glutamatergic effects on performance in rPAL makes it a unique and useful tool in the modeling of cognitive impairments in schizophrenia.

Dissociable effects of NR2A and NR2B NMDA receptor antagonism on cognitive flexibility but not pattern separation

RationaleN-methyl-d-aspartate (NMDA) receptors play crucial roles in learning and memory, but the role of each NMDA receptor subtype in a specific cognitive process is unclear. Non-selective blockers of NMDA receptor are used to model the cognitive impairment in schizophrenia and Alzheimer’s disease. Counter-intuitively selective NR2A and 2B NMDA receptor antagonists are thought to have pro-cognitive properties. These seemingly contrasting findings might in part be the result of different compounds and behavioral measures used across studies.ObjectiveWe compared the effect of NVP-AAM077 (NR2A antagonist), CP 101-606 (NR2B antagonist), and MK-801 (non-selective antagonist) in a series of touch screen tasks that can be used to measure spatial cognition and cognitive flexibility.MethodsNVP-AAM077, CP 101-606, and MK-801 were administered prior to testing, in adult male Lister-hooded rats trained in tasks of location discrimination, paired associate learning (PAL), and trial unique non-match to location (TUNL).ResultsResults showed that MK-801 impaired performance on all the tasks. In contrast, CP 101-606 only impaired reversal learning in location discrimination and had minimal effect on working memory in TUNL and caused a modest improvement in accuracy in PAL and acquisition of a spatial discrimination. NVP-AAM077 had little effect on performance across tasks, although these data allude to a potential enhancement of acquisition of a spatial location and impairments in spatial reversal learning in a separation-dependent manner.ConclusionsThese data demonstrated that non-selective NMDA antagonism will disrupt numerous aspects of cognitive function. However, selective antagonism is capable of impairing or enhancing cognitive function in a task-dependent fashion.

Opposing effects of glutamatergic and GABAergic pharmacological manipulations on a visual perception task with relevance to schizophrenia

RationaleNumerous psychiatric disorders and neurodegenerative diseases have been associated with differences in visual perception, and it has been proposed that the treatment of these differences may represent a novel means to treat disorders like schizophrenia. Unfortunately, few methods exist to study visual perception in pre-clinical species.ObjectiveThe purpose of the present study was to adapt a task of visual integration by proximity with relevance to schizophrenia to a rodent touchscreen environment to determine the effects of glutamatergic and GABAergic compounds. In this way, we could evaluate the effects of common models of cognitive impairment, as well as the effects of net excitation versus inhibition, on a task of visual integration.MethodRats were trained to perform a visual discrimination where the stimuli were composed of rows of dots differing only in there horizontal and vertical proximity. Once stable performance had been achieved, animals were tested under the influence of glutamatergic or GABAergic drugs (ketamine, MK-801, PCP, memantine, chlordiazepoxide, or diazepam) while attempting to perform a visual discrimination with altered stimuli.ResultsKetamine appeared to impair perceptual grouping in this paradigm, while the GABA agonist chlordiazepoxide enhanced grouping even in the presence of non-selective effects.ConclusionsIn general, these findings support the theory that NMDA antagonists may disrupt visual grouping by proximity and highlight a potential beneficial effect of enhanced GABA activity in perception. However, additional research will be required to confirm the stimulus selectivity of this effect, and the clinical significance of this approach.

Do wholes become more than the sum of their parts in the rodent (Rattus Norvegicus) visual system? A test case with the configural superiority effect.

The rodent has been used to model various aspects of the human visual system, but it is unclear to what extent human visual perception can be modelled in the rodent. Research suggests rodents can perform invariant object recognition tasks in a manner comparable to humans. There is further evidence that rodents also make use of certain grouping cues, but when performing a shape discrimination they have a tendency to rely much more on local image cues than human participants. In the current work, we exploit the fact that humans sometimes discriminate better between whole shapes, rather than the parts from which they are constructed, to ask whether rodents show a classic Configural Superiority Effect. Using touchscreen‐equipped operant boxes, rats were trained to discriminate ‘part’ or ‘whole’ images based off of those used by J. R. Pomerantz et al. ( ) J Exp Psychol Hum Percept Perform, 3, 422–435. Here, we show that rats show no advantage for wholes and that they perform better when presented with simpler image parts, a pattern of effect opposite to what was seen in humans when highly comparable stimuli were used. These results add to our understanding of the similarities and differences between the human and rodent visual system, and suggest that the rodent visual system may not compute part whole relationships in a way comparable to humans. These results are significant from both a comparative anatomy perspective, and of particular relevance for those wishing to use rodents to model visuo‐perceptual deficits associated with human psychiatric disorders.

Evaluating aged mice in three touchscreen tests that differ in visual demands: Impaired cognitive function and impaired visual abilities

HighlightsAge‐related impairments in the performance of three touchscreen‐based behavioral assays were demonstrated in mice.Neither Visual Discrimination nor Automated Search Task performance was correlated with visual acuity.The automated search task was translated to mice for the first time.Touchscreen‐based operant paradigms were effective at evaluating age‐related cognitive decline. Abstract Normal aging is often accompanied by reductions in cognitive abilities as well as impairments in visual acuity in men and mice. In preclinical models of human cognition this concomitance can make it difficult to assess the relative contributions of declined vision and cognitive ability on behavioral measures of cognition. To assess the influence of age on cognition and the impact of visual decline on the performance of touchscreen‐based behavioral paradigms in mice, aged (11, 12, 16, 17, 19 and 21 months old) male C57BL/6J mice were compared to young (3 or 4 months old) male C57BL/6J mice using three tests of cognition as well as an assessment of visual acuity. Performance of a Visual Discrimination, Spatial Reversal, and an Automated Search Task were all affected by age. However, there was no relationship between reduced visual acuity and the observed performance impairments. Moreover, the visual acuity of animals with profound cognitive impairments overlapped with those showing normal cognitive ability. Despite the potential confound of impaired visual ability, it appears that the touchscreen approach might be particularly effective in studying age‐related cognitive decline. This approach will increase the utility of aged mice as a model of decreased cognitive flexibility and may be particularly important for the study of age‐related disorders such as Alzheimer’s disease.