Neural changes following cognitive remediation therapy for schizophrenia

Patients with schizophrenia experience cognitive impairments that relate to poorer social functioning even after amelioration of positive symptoms. Pharmacological treatment and cognitive remediation are the two important therapeutic approaches for cognitive impairment in schizophrenia. Cognitive remediation therapy (CRT) for schizophrenia improves cognitive functioning and induces neuroplasticity, but different approaches and durations of CRT and different neuroimaging devices have led to varying results in meta‐analyses. The objective of this review was to explore the impact of CRT on neurobiology. Several studies have provided evidence of increased activation in the frontal brain regions, such as the prefrontal cortex, anterior cingulate cortex, and parietal and occipital regions during working memory or executive function tasks after CRT. Two studies have shown alterations in resting‐state connectivity between the prefrontal cortex and temporal regions. Two studies have reported that CRT induces changes in gray matter volume in the hippocampus. Further, one study observed that patients who had received CRT had elevated fractional anisotropy in the basal ganglia. We conclude that neuroimaging studies assessing CRT in patients with schizophrenia showed functional, structural, and connectivity changes that were positively correlated with cognitive improvements despite heterogeneous CRT approaches. Future studies that combine multiple modalities are required to address the differences, effects of intrinsic motivation, and pharmacological augmentation of CRT. Further understanding of the biological basis might lead to predictions of the CRT response in patients with schizophrenia and contribute to identification of schizophrenia patients for future interventions.     

Common and distinct networks underlying reward valence and processing stages: a meta-analysis of functional neuroimaging studies

To better understand the reward circuitry in human brain, we conducted activation likelihood estimation (ALE) and parametric voxel-based meta-analyses (PVM) on 142 neuroimaging studies that examined brain activation in reward-related tasks in healthy adults. We observed several core brain areas that participated in reward-related decision making, including the nucleus accumbens (NAcc), caudate, putamen, thalamus, orbitofrontal cortex (OFC), bilateral anterior insula, anterior cingulate cortex (ACC) and posterior cingulate cortex (PCC), as well as cognitive control regions in the inferior parietal lobule and prefrontal cortex (PFC). The NAcc was commonly activated by both positive and negative rewards across various stages of reward processing (e.g., anticipation, outcome, and evaluation). In addition, the medial OFC and PCC preferentially responded to positive rewards, whereas the ACC, bilateral anterior insula, and lateral PFC selectively responded to negative rewards. Reward anticipation activated the ACC, bilateral anterior insula, and brain stem, whereas reward outcome more significantly activated the NAcc, medial OFC, and amygdala. Neurobiological theories of reward-related decision making should therefore take distributed and interrelated representations of reward valuation and valence assessment into account.     

Prefrontal-Thalamic Anatomical Connectivity and Executive Cognitive Function in Schizophrenia

Background

Executive cognitive functions, including working memory, cognitive flexibility, and inhibition, are impaired in schizophrenia. Executive functions rely on coordinated information processing between the prefrontal cortex (PFC) and thalamus, particularly the mediodorsal nucleus. This raises the possibility that anatomical connectivity between the PFC and mediodorsal thalamus may be 1) reduced in schizophrenia and 2) related to deficits in executive function. The current investigation tested these hypotheses.

Imaging genetic liability to schizophrenia: systematic review of FMRI studies of patients' nonpsychotic relatives

There is a growing literature on brain activity in the nonpsychotic first-degree relatives of patients with schizophrenia as measured using functional imaging. This systematic review examined 20 studies in 4 domains of cognition, including cognitive control (7 samples), working memory (5 samples), long-term memory (4 samples), and language (4 samples). While the literature was widely divergent, these studies did consistently find activation differences between patients' relatives and controls. The most consistent increases in activation within hemisphere were found in right ventral prefrontal cortex (PFC) and right parietal cortex. Abnormal activity, defined as significant increases or decreases in activation relative to controls irrespective of hemisphere, was found in about two-thirds of contrasts in the cerebellum, dorsal prefrontal, lateral temporal, and parietal cortices, and thalamus, with basal ganglia and ventral PFC showing abnormalities in approximately half of those contrasts. Anterior cingulate was generally spared in patients' relatives. The diversity of findings in studies of patients' relatives may derive from differences between the cognitive demands across studies. We identify avenues for building a more accurate and cumulative literature, including symmetrical inclusion criteria for relatives and controls, recording in-scanner responses, using both a priori and whole-brain tests, explicitly reporting threshold values, reporting main effects of task, reporting effect sizes, and quantifying the risk of false negatives. While functional imaging in the relatives of schizophrenia patients remains a promising methodology for understanding the impact of the unexpressed genetic liability to schizophrenia, no single region or mechanism of abnormalities has yet emerged.     

The SIGMAR1 gene is associated with a risk of schizophrenia and activation of the prefrontal cortex

Several studies have identified the possible involvement of sigma non-opioid intracellular receptor 1 (SIGMAR1) in the pathogenesis of schizophrenia. The Gln2Pro polymorphism in the SIGMAR1 gene has been extensively examined for an association with schizophrenia. However, findings across multiple studies have been inconsistent. We performed a meta-analysis of the association between the functional Gln2Pro polymorphism and schizophrenia using combined samples (1254 patients with schizophrenia and 1574 healthy controls) from previously published studies and our own additional samples (478 patients and 631 controls). We then used near-infrared spectroscopy to analyze the effects of the Gln2Pro genotype, a schizophrenia diagnosis and the interaction between genotype and diagnosis on activation of the prefrontal cortex (PFC) during a verbal fluency task (127 patients and 216 controls). The meta-analysis provided evidence of an association between Gln2Pro and schizophrenia without heterogeneity across studies (odds ratio = 1.12, p = 0.047). Consistent with previous studies, patients with schizophrenia showed lower bilateral activation of the PFC when compared to controls (p < 0.05). We provide evidence that Pro carriers, who are more common among patients with schizophrenia, have significantly lower activation of the right PFC compared to subjects with the Gln/Gln genotype (p = 0.013). These data suggest that the SIGMAR1 polymorphism is associated with an increased risk of schizophrenia and differential activation of the PFC.     

Neurofunctional correlates of vulnerability to psychosis: a systematic review and meta-analysis

An understanding of the neurobiological correlates of vulnerability to psychosis is fundamental to research on schizophrenia. We systematically reviewed data from studies published from 1992 to 2006 on the neurocognitive correlates (as measured by fMRI) of increased vulnerability to psychosis. We also conducted a meta-analysis of abnormalities of activation in the prefrontal cortex (PFC) in high-risk and first episode subjects, and reviewed neuroimaging studies of high-risk subjects that used PET, SPECT and MRS. Twenty-four original fMRI papers were identified, most of which involved tasks that engaged the PFC. In fMRI studies, vulnerability to psychosis was associated with medium to large effect sizes when prefrontal activation was contrasted with that in controls. Relatives of patients affected with psychosis, the co-twins of patients and subjects with an At Risk Mental State (ARMS) appear to share similar neurocognitive abnormalities. Furthermore, these are qualitatively similar but less severe than those observed in the first episode of illness. These abnormalities have mainly been described in the prefrontal and anterior cingulated cortex, the basal ganglia, hippocampus and cerebellum.     

Semantic strategy training increases memory performance and brain activity in patients with prefrontal cortex lesions

Objective

Memory deficit is a frequent cognitive disorder following acquired prefrontal cortex lesions. In the present study, we investigated the brain correlates of a short semantic strategy training and memory performance of patients with distinct prefrontal cortex lesions using fMRI and cognitive tests.

Methods

Twenty-one adult patients with post-acute prefrontal cortex (PFC) lesions, twelve with left dorsolateral PFC (LPFC) and nine with bilateral orbitofrontal cortex (BOFC) were assessed before and after a short cognitive semantic training using a verbal memory encoding paradigm during scanning and neuropsychological tests outside the scanner.

Results

After the semantic strategy training both groups of patients showed significant behavioral improvement in verbal memory recall and use of semantic strategies. In the LPFC group, greater activity in left inferior and medial frontal gyrus, precentral gyrus and insula was found after training. For the BOFC group, a greater activation was found in the left parietal cortex, right cingulated and precuneus after training.

Conclusion

The activation of these specific areas in the memory and executive networks following cognitive training was associated to compensatory brain mechanisms and application of the semantic strategy.     

Meta-analysis of neuroimaging studies of the Wisconsin card-sorting task and component processes

A quantitative meta-analysis using the activation likelihood estimation (ALE) method was used to investigate the brain basis of the Wisconsin Card-Sorting Task (WCST) and two hypothesized component processes, task switching and response suppression. All three meta-analyses revealed distributed frontoparietal activation patterns consistent with the status of the WCST as an attention-demanding executive task. The WCST was associated with extensive bilateral clusters of reliable cross-study activity in the lateral prefrontal cortex, anterior cingulate cortex, and inferior parietal lobule. Task switching revealed a similar, although less robust, frontoparietal pattern with additional clusters of activity in the opercular region of the ventral prefrontal cortex, bilaterally. Response-suppression tasks, represented by studies of the go/no-go paradigm, showed a large and highly right-lateralized region of activity in the right prefrontal cortex. The activation patterns are interpreted as reflecting a neural fractionation of the cognitive components that must be integrated during the performance of the WCST.     

Resting-State Brain Activity in Schizophrenia and Major Depression: A Quantitative Meta-Analysis

Intrinsic activity of the brain during resting-state is not random and is currently discussed as a neural reflection of self-referential processing. Self-reference is typically reduced in schizophrenia as a disorder of the self while extensive self-attribution of, eg, negative thoughts is characteristic for major depression. However, a quantitative meta-analysis targeting the resting-state brain activity in both disorders is lacking. Here, we predict primarily abnormal resting-state activity in brain regions related to self-referential processing. By means of activation likelihood estimation (ALE) on functional magnetic resonance imaging and positron emission tomography studies, we investigated concurrence of hyperactivation and hypoactivation in resting-state measurements of schizophrenic and depressed patients compared with healthy controls. We found hypoactivation in ventromedial prefrontal cortex (vmPFC), left hippocampus, posterior cingulate cortex, lower precueus and the precuneus, and hyperactivation in bilateral lingual gyrus of schizophrenic patients. In major depression, we found hyperactivation in vmPFC, left ventral striatum, and left thalamus and hypoactivation in left postcentral gyrus, left fusiform gyrus, and left insula. An overall ALE analysis confirmed the proximity of hypoactivation in schizophrenia and hyperactivation in major depression in the vmPFC.The opposing resting-state activity in vmPFC for the 2 disorders is in line with the different expression of dysfunctional self-reference as core characteristics of schizophrenia and major depression. The vmPFC has previously been identified as a crucial area for self-referential processing and may represent a target to increase the diagnostic validity of resting-state activity for disorders with dysfunctions of the self.     

A neurobehavioral systems analysis of adult rats exposed to methylazoxymethanol acetate on E17: implications for the neuropathology of schizophrenia.

BACKGROUND: As a test of plausibility for the hypothesis that schizophrenia can result from abnormal brain, especially cerebral cortical, development, these studies examined whether, in the rat, disruption of brain development initiated on embryonic day (E) 17, using the methylating agent methylazoxymethanol acetate (MAM), leads to a schizophrenia-relevant pattern of neural and behavioral pathology. Specifically, we tested whether this manipulation leads to disruptions of frontal and limbic corticostriatal circuit function, while producing schizophrenia-like, region-dependent reductions in gray matter in cortex and thalamus. METHODS: In offspring of rats administered MAM (22 mg/kg) on E17 or earlier (E15), regional size, neuron number and neuron density were determined in multiple brain regions. Spontaneous synaptic activity at prefrontal cortical (PFC) and ventral striatal (vSTR) neurons was recorded in vivio. Finally, cognitive and sensorimotor processes mediated by frontal and limbic corticostriatal circuits were assessed. RESULTS: Adult MAM-E17-exposed offspring showed selective histopathology: size reductions in mediodorsal thalamus, hippocampus, and parahippocampal, prefrontal, and occipital cortices, but not in sensory midbrain, cerebellum, or sensorimotor cortex. The prefrontal, perirhinal, and occipital cortices showed increased neuron density with no neuron loss. The histopathology was accompanied by a disruption of synaptically-driven "bistable membrane states" in PFC and vSTR neurons, and, at the behavioral level, cognitive inflexibility, orofacial dyskinesias, sensorimotor gating deficits and a post-pubertal-emerging hyper-responsiveness to amphetamine. Earlier embryonic MAM exposure led to microcephaly and a motor phenotype. CONCLUSIONS: The "MAM-E17" rodent models key aspects of neuropathology in circuits that are highly relevant to schizophrenia.     

Plasticity of the primate prefrontal cortex.

Cortical plasticity refers to flexible and long-lasting changes in neuronal circuitry and information processing, which is caused by learning and experience. Although cortical plasticity can be observed in every cortex of the brain, the plasticity of the prefrontal cortex (PFC) is particularly important because the PFC is involved in various cognitive functions, and its plasticity could lead to adaptive changes in the use of other brain regions. Cortical plasticity occurs at several levels, from functional molecules to the organization of large areas of the brain. Here, the authors focus mainly on the development and remodeling of the functional and structural organization of the primate PFC. They discuss how the columnar modules of the PFC develop in the immature brain, how these modules form a "cognitive field" that is responsible for a specific cognitive function, how the cognitive field could be reorganized by training in the mature brain, and how monoaminergic systems contribute to these various levels of plasticity. They suggest that monoaminergic systems, especially the dopaminergic system, are involved in various levels of cortical plasticity, such as behavioral learning and learning-dependent cortical remodeling, thereby contributing to the reorganization of the cognitive field in the primate PFC.     

Event-related fMRI studies of episodic encoding and retrieval: Meta-analyses using activation likelihood estimation

The recent surge in event-related fMRI studies of episodic memory has generated a wealth of information about the neural correlates of encoding and retrieval processes. However, interpretation of individual studies is hampered by methodological differences, and by the fact that sample sizes are typically small. We submitted results from studies of episodic memory in healthy young adults, published between 1998 and 2007, to a voxel-wise quantitative meta-analysis using activation likelihood estimation [Laird, A. R., McMillan, K. M., Lancaster, J. L., Kochunov, P., Turkeltaub, P. E., & Pardo, J. V., et al. (2005). A comparison of label-based review and ALE meta-analysis in the stroop task. Human Brain Mapping, 25, 6–21]. We conducted separate meta-analyses for four contrasts of interest: episodic encoding success as measured in the subsequent-memory paradigm (subsequent Hit vs. Miss), episodic retrieval success (Hit vs. Correct Rejection), objective recollection (e.g., Source Hit vs. Item Hit), and subjective recollection (e.g., Remember vs. Know). Concordance maps revealed significant cross-study overlap for each contrast. In each case, the left hemisphere showed greater concordance than the right hemisphere. Both encoding and retrieval success were associated with activation in medial-temporal, prefrontal, and parietal regions. Left ventrolateral prefrontal cortex (PFC) and medial-temporal regions were more strongly involved in encoding, whereas left superior parietal and dorsolateral and anterior PFC regions were more strongly involved in retrieval. Objective recollection was associated with activation in multiple PFC regions, as well as multiple posterior parietal and medial-temporal areas, but not hippocampus. Subjective recollection, in contrast, showed left hippocampal involvement. In summary, these results identify broadly consistent activation patterns associated with episodic encoding and retrieval, and subjective and objective recollection, but also subtle differences among these processes.     

The Mediodorsal Thalamus: An Essential Partner of the Prefrontal Cortex for Cognition

Deficits in cognition are a core feature of many psychiatric conditions, including schizophrenia, where the severity of such deficits is a strong predictor of long-term outcome. Impairment in cognitive domains such as working memory and behavioral flexibility has typically been associated with prefrontal cortex (PFC) dysfunction. However, there is increasing evidence that the PFC cannot be dissociated from its main thalamic counterpart, the mediodorsal thalamus (MD). Since the causal relationships between MD-PFC abnormalities and cognitive impairment, as well as the neuronal mechanisms underlying them, are difficult to address in humans, animal models have been employed for mechanistic insight. In this review, we discuss anatomical, behavioral, and electrophysiological findings from animal studies that provide a new understanding on how MD-PFC circuits support higher-order cognitive function. We argue that the MD may be required for amplifying and sustaining cortical representations under different behavioral conditions. These findings advance a new framework for the broader involvement of distributed thalamo-frontal circuits in cognition and point to the MD as a potential therapeutic target for improving cognitive deficits in schizophrenia and other disorders.     

Hyperfrontality and hypoconnectivity during refreshing in schizophrenia

Anomalous activations of the prefrontal cortex (PFC) and posterior cerebral areas have been reported in previous studies of working memory in schizophrenia. Several interpretations have been reported: e.g., neural inefficiency, the use of different strategies and differences in the functional organization of the cerebral cortex. To better understand these abnormal activations, we investigated the cerebral bases of a working memory component process, namely refreshing (i.e., thinking briefly of a just-activated representation). Fifteen patients with schizophrenia and 15 control subjects participated in this functional magnetic resonance imaging (fMRI) study. Participants were told that whenever they saw a word on the screen, they had to read it silently to themselves (read and repeat conditions), and when they saw a dot, they had to think of the just-previous word (refresh condition). The refresh condition (in comparison with the read condition) was associated with significantly increased activation in the left inferior frontal gyrus and significantly decreased connectivity within the prefrontal cortex and between the prefrontal and parietal cortices in patients with schizophrenia in comparison with control subjects. These results suggest that prefrontal dysfunctions in schizophrenia might be related to a defective ability to initiate (rather than to execute) specific cognitive processes.     

Working memory functioning in schizophrenia patients and their first-degree relatives: cognitive functioning shedding light on etiology

There is accumulating evidence for involvement of the prefrontal cortex (PFC) in the pathophysiology of schizophrenia. A primary function supported by the PFC is working memory (WM). Findings from WM studies in schizophrenia can provide insight into the nature of clinical symptoms and cognitive deficits associated with this disorder, as well as begin to suggest areas of underlying neuropathology. To date, studies have not adequately investigated different WM domains (e.g., verbal, spatial, or object) or processing requirements (e.g., maintenance, monitoring, or manipulation), shown to be associated with distinct patterns of neural activation, in schizophrenia patients and their well relatives. Accordingly, this study evaluated the performance of schizophrenia patients, their first-degree biological relatives, and nonpsychiatric controls on a comprehensive battery of WM tasks and investigated the association among WM deficits and schizophrenia-spectrum psychopathology. The findings indicate that schizophrenia patients are consistently impaired on WM tasks, irrespective of WM domain or processing requirements. In contrast, their unaffected relatives are only impaired on WM tasks with higher central executive processing requirements. This pattern of WM performance may further implicate DLPFC dysfunction in the liability for schizophrenia and has implications for future cognitive, genetic, and neurodevelopmental research.     

fMRI study of maintenance and manipulation processes within working memory in first-episode schizophrenia

OBJECTIVE: Working memory, a critical cognitive capacity that is affected in schizophrenia, can be divided into maintenance and manipulation processes. Previous behavioral research suggested that manipulation is more affected than maintenance in patients with chronic schizophrenia. In this study of first-episode schizophrenia patients, the authors evaluated the extent to which the two working memory processes are affected early in the course of schizophrenia. METHOD: Study subjects were 11 first-episode schizophrenia patients and 11 matched healthy comparison subjects. Each group performed two verbal working memory tasks while undergoing functional magnetic resonance imaging. One task required maintenance of information; the other required manipulation of information in addition to maintenance. RESULTS: Under behaviorally matched conditions, both groups activated a predominantly left-sided frontal-parietal network. The manipulation plus maintenance task elicited activation of greater magnitude and spatial extent. With both tasks, patients showed less bilateral dorsolateral prefrontal cortex activation and greater ventrolateral prefrontal cortex activation, relative to the comparison subjects. A group-by-task interaction was observed for activation at the left dorsolateral and ventrolateral prefrontal cortex. The increase in activation when patients engaged in the manipulation plus maintenance task was disproportionately less in the dorsolateral prefrontal cortex and greater in the ventrolateral prefrontal cortex. CONCLUSIONS: These functional neuroanatomical findings add support to earlier suggestions that manipulation of information is selectively more affected than maintenance of information in persons with schizophrenia. They also suggest the presence of interacting regions of dysfunctional and compensatory prefrontal responses in the dorsolateral and ventrolateral prefrontal cortex, respectively, that are more prominent when information is manipulated. This disrupted prefrontal network is present relatively early in the course of schizophrenia.     

Differences in neuroanatomical sites of apoD elevation discriminate between schizophrenia and bipolar disorder

We previously demonstrated that apolipoprotein D (apoD) levels are elevated in the dorsolateral prefrontal cortex and caudate obtained postmortem from subjects with schizophrenia and bipolar disorder compared to controls, suggesting a focal compensatory response to neuropathology associated with psychiatric disorders. We have now extended those studies by measuring apoD protein levels in additional brain regions from post-mortem samples of schizophrenic and bipolar disorder subjects using an enzyme-linked immunosorbent assay. Increased apoD levels were observed in the lateral prefrontal cortex (Brodmann Area 46) in both schizophrenia (46%) and bipolar disorder (111%), and in the orbitofrontal cortex (Brodmann Area 11) (44.3 and 37.9% for schizophrenia and bipolar disorder, respectively). However, differences between the disease groups were observed in other brain regions. In subjects with schizophrenia, but not bipolar disorder, apoD levels were significantly elevated in the amygdala (42.8%) and thalamus (31.7%), while in bipolar disorder, but not schizophrenia, additional increases were detected in the parietal cortex (Brodmann Area 40; 123%) and the cingulate cortex (Brodmann Area 24; 57.7%). These data demonstrate that there is anatomical overlap in the pathophysiologies of schizophrenia and bipolar disorder, as well as areas of pathology that distinguish the two disorders.     

The neuronal correlates of intranasal trigeminal function—an ALE meta-analysis of human functional brain imaging data

Almost every odor we encounter in daily life has the capacity to produce a trigeminal sensation. Surprisingly, few functional imaging studies exploring human neuronal correlates of intranasal trigeminal function exist, and results are to some degree inconsistent. We utilized activation likelihood estimation (ALE), a quantitative voxel-based meta-analysis tool, to analyze functional imaging data (fMRI/PET) following intranasal trigeminal stimulation with carbon dioxide (CO₂), a stimulus known to exclusively activate the trigeminal system. Meta-analysis tools are able to identify activations common across studies, thereby enabling activation mapping with higher certainty. Activation foci of nine studies utilizing trigeminal stimulation were included in the meta-analysis. We found significant ALE scores, thus indicating consistent activation across studies, in the brainstem, ventrolateral posterior thalamic nucleus, anterior cingulate cortex, insula, precentral gyrus, as well as in primary and secondary somatosensory cortices—a network known for the processing of intranasal nociceptive stimuli. Significant ALE values were also observed in the piriform cortex, insula, and the orbitofrontal cortex, areas known to process chemosensory stimuli, and in association cortices. Additionally, the trigeminal ALE statistics were directly compared with ALE statistics originating from olfactory stimulation, demonstrating considerable overlap in activation. In conclusion, the results of this meta-analysis map the human neuronal correlates of intranasal trigeminal stimulation with high statistical certainty and demonstrate that the cortical areas recruited during the processing of intranasal CO₂ stimuli include those outside traditional trigeminal areas. Moreover, through illustrations of the considerable overlap between brain areas that process trigeminal and olfactory information; these results demonstrate the interconnectivity of flavor processing.     

Alterations of fronto-temporal connectivity during word encoding in schizophrenia

Cognitive deficits, including impaired verbal memory, are prominent in schizophrenia and lead to increased disability. Functional neuroimaging of patients with schizophrenia performing memory tasks has revealed abnormal activation patterns in prefrontal cortex and temporo-limbic regions. Aberrant fronto-temporal interactions thus represent a potential pathophysiological mechanism underlying verbal memory deficits, yet this hypothesis of disturbed connectivity is not tested directly with standard activation studies. We performed within-subject correlations of frontal and temporal timeseries to measure functional connectivity during verbal encoding. Our results confirm earlier findings of aberrant fronto-temporal connectivity in schizophrenia, and extend them by identifying distinct alterations within dorsal and ventral prefrontal cortex. Relative to healthy controls, patients with schizophrenia had reduced connectivity between the dorsolateral prefrontal cortex (DLPFC) and temporal lobe areas including parahippocampus and superior temporal gyrus. In contrast, patients showed increased connectivity between a region of ventrolateral prefrontal cortex (VLPFC) and these same temporal lobe regions. Higher temporal-DLPFC connectivity during encoding was associated with better subsequent recognition accuracy in controls, but not patients. Temporal-VLPFC connectivity was uncorrelated with recognition accuracy in either group. The results suggest that reduced temporal-DLPFC connectivity in schizophrenia could underlie encoding deficits, and increased temporal-VLPFC connectivity may represent an ineffective compensatory effort.     

Transgenic mice overexpressing the extracellular domain of NCAM are impaired in working memory and cortical plasticity

The neural cell adhesion molecule, NCAM, is a pivotal regulator of neural development, with key roles in axonal and dendritic growth and synaptic plasticity. Alterations in NCAM expression or proteolytic cleavage have been linked to human neuropsychiatric disorders such as schizophrenia, bipolar disorder and Alzheimer's disease, and may contribute to cognitive dysfunction. We have generated mice overexpressing the NCAM extracellular (EC) proteolytic cleavage fragment which has been reported to be increased in schizophrenic versus normal brains. These mice show impaired GABAergic innervation and reduced number of apical dendritic spines on pyramidal neurons in the prefrontal cortex (PFC). Here, these NCAM-EC transgenic mice were subjected to behavioral tasks and electrophysiological measurements to determine the impact of structural abnormalities in the PFC on synaptic and cognitive functions. NCAM-EC mice exhibited impaired working memory in a delayed non-match-to-sample task, which requires PFC function, but showed no differences in anxiety, olfactory abilities, or sociability. Transgenic mice displayed impaired long- and short-term potentiation in the PFC but normal synaptic plasticity in the hippocampus, suggesting that the abnormal synaptic innervation in NCAM-EC mice impairs PFC plasticity and alters working memory. These findings may have implications for cognitive dysfunctions observed in neuropsychiatric disorders.