Cognitive Deficits In Schizophrenia Research Articles

M41 - Pleiotropic Effects of Schizophrenia And Cognitive LOCI: A Meta-Analytic Approach

Background Cognitive deficits are a key feature of schizophrenia. The genetic architecture underlying cognition is investigated. A novel method of using cross-phenotype meta-analysis to elucidate overlapping genetic substrates between established schizophrenia loci and cognitive loci was conducted. Methods 895 healthy controls and 648 schizophrenia subjects with intact cognitive data were included in the discovery dataset after standard genome-wide QC procedures. The markers were imputed via Minimac (MACH) to the 1000 genomes phase 1 reference panel. Strict post-imputation filtering of rsq > .9 was carried out. Publicly available leave-one-out summary statistics from the PGC2 schizophrenia working group were employed for meta-analysis. Meta-Analysis for cognition and schizophrenia was conducted in METAL. Results 51 markers were found to be enriched for the cognition-schizophrenia cross-phenotype meta-analysis (33.6%; p Discussion Cross-phenotype meta-analysis revealed voltage-gated ion channels, calcium channels, and metal-ion transport pathways to be implicated in both schizophrenia and cognition. Areas of the brain with which these candidate genes are involved are also known regions that have been reported to be associated with cognitive deficits in schizophrenia. Results from the current analysis support evidence that has previously been reported in both schizophrenia and cognitive literature. The results provide potential biological insights to the understanding of cognitive impairments found in schizophrenia. Further research is necessary to replicate the current findings and to understand if there might be potential approaches to modify cognition via targeting the above mentioned biological pathways.

Feasibility of Online Neuromodulation Using Transcranial Alternating Current Stimulation in Schizophrenia

Abnormalities in resting and event-related brain oscillations are known to be associated with cognitive deficits in schizophrenia. Transcranial alternating current stimulation (tACS) modulates these rhythms across the neuronal circuits and could have a potential therapeutic role in psychiatric disorders. In this report, we describe, for the first time, application of online tACS in a schizophrenia patient with working memory deficits. This case report supports the feasibility and potential utility of online tACS in schizophrenia, which needs further systematic research.

T66 - The Neuregulin-1 Gene Is Associated With Schizotypy In The General Population

Background It is believed that the personality characteristics and symptoms observed in schizophrenia lie on a continuum, with subclinical symptoms referred to as schizotypy. The continuum theory of schizophrenia recognises schizotypy as a suitable model for investigating schizophrenia: individuals with high levels of schizotypy demonstrate similar symptoms, cognitive profiles and neuroimaging findings to schizophrenia, albeit in a more subtle manner, without the potential confounding factors associated with schizophrenia. Both schizophrenia and schizotypy have been shown to be influenced by genetic factors. Neuregulin-1 (NRG1), involved in neuronal development, migration, myelination and synaptic plasticity, has been identified as a promising candidate gene for schizophrenia risk. Several NRG1 single nucleotide polymorphisms (SNPs) have been associated with schizophrenia and cognitive deficits, though only one SNP has been previously associated with schizotypy. The aim of this study was to examine the link between NRG1 and schizotypy across the schizotypy/schizophrenia continuum. Methods Participants were 200 adults (83 patients with schizophrenia and 117 healthy controls) who were assessed for schizotypy factors using the Oxford-Liverpool Inventory of Feelings and Experience (O-LIFE). The factors assessed were unusual experiences (UnEx), introvertive anhedonia (InAn) and cognitive disorganisation (CogDis), which are thought to reflect the positive, negative and cognitive symptoms of schizophrenia respectively. Participants were also genotyped for five NRG1 SNPs; rs10503929, rs3924999, rs2466058, rs35753505 and rs6994992. A MANOVA was conducted with schizotypy factors as dependent variables and participant group as independent variables to observe differences between patients and controls. Another MANOVA was conducted with schizotypy factors as dependent variables and NRG1 SNPs as independent variables to observe differences and interactions of the NRG1 SNPs on schizotypy across the continuum. Results Confirming previous findings, schizotypy scores were significantly higher in the patient group as compared to controls (p Discussion This is the first study to demonstrate an association between NRG1 and schizotypy across the continuum, in particular CogDis. From this, it can be inferred that genetic variation in NRG1 may be a contributing factor to cognitive deficits in the clinical population, consistent with previous findings. As individual SNPs were not significantly associated with schizotypy but significant interactions were observed, this study also demonstrates the heterogeneity of schizophrenia. This finding contributes to the literature associating NRG1 with cognitive deficits in schizophrenia and supports the use of schizotypy as a model for schizophrenia.

Supplemental Material for Evidence of Systematic Attenuation in the Measurement of Cognitive Deficits in Schizophrenia

Supplemental Material for Evidence of Systematic Attenuation in the Measurement of Cognitive Deficits in Schizophrenia

Schizophrenia: Basic and Clinical.

Schizophrenia is a chronic severe mental disorder characterized by psychosis, cognitive impairments, and social and motivational deficits. It is associated with a progressive loss of cortical volume after onset of psychosis; nevertheless, cortical atrophy correlates with the cognitive impairments and the negative symptoms but not with the psychosis. The cortical atrophy is not primarily due to neuronal degeneration but rather to neuronal atrophy and loss of glutamatergic synapses. A downregulation of the presynaptic markers for the parvalbumin-expressing GABAergic interneurons that provide recurrent inhibition to cortical pyramidal neurons is another consistent pathologic feature. Antipsychotic drugs continue after 50 years to be the mainstay of treatment although these drugs, with the possible exception of clozapine, have negligible effects on cognition and negative symptoms. Pharmacologic challenge studies, postmortem analyses and a recent sufficiently powered genome-wide association study and copy number variant studies provide compelling evidence that NMDA receptor hypofunction is an important pathophsysiologic feature of schizophrenia. Silencing the gene encoding serine racemase, the enzyme that synthesizes the cortical-limbic NMDA receptor co-agonist, D-serine, replicates the dendritic and GABAergic pathology and cognitive deficits of schizophrenia in mice. Pharmacologic strategies to overcome NMDA receptor hypofunction hold promise of treating the disabling cognitive and negative symptoms.

The relationship between cognitive impairment in schizophrenia and metabolic syndrome: a systematic review and meta-analysis.

Individuals with schizophrenia are at greater risk for metabolic syndrome (MetS) which is associated with cognitive deficits in the general population. MetS might be potentially an important contributing factor to cognitive impairment in schizophrenia. In the current systematic review and meta-analysis, the findings of 18 studies investigating the association between MetS (and its components) with cognitive impairment in schizophrenia are reviewed. Co-morbidity of MetS (d = 0.28) and diabetes mellitus (d = 0.28) were both associated with more severe cognitive deficits in schizophrenia. There was also evidence for a significant relationship between cognitive impairment in schizophrenia and each of the components of MetS including hypertension, dyslipidemia, abdominal obesity and diabetes. MetS is significantly associated with cognitive impairment in schizophrenia and can potentially contribute to functional decline observed in some patients with schizophrenia throughout the course of illness.

Stimulating cognition in schizophrenia: A controlled pilot study of the effects of prefrontal transcranial direct current stimulation upon memory and learning

BackgroundSchizophrenia is characterized by prominent cognitive deficits, impacting on memory and learning; these are strongly associated with the prefrontal cortex. Objective/hypothesisTo combine two interventions, transcranial direct current stimulation (tDCS) over the prefrontal cortex and cognitive training, to examine change in cognitive performance in patients with schizophrenia. MethodsA double blind, sham-controlled pilot study of 49 patients with schizophrenia, randomized into real or sham tDCS stimulation groups. Subjects participated in 4 days of cognitive training (days 1, 2, 14, 56) with tDCS applied at day-1 and day-14. The primary outcome measure was change in accuracy on working memory and implicit learning tasks from baseline. The secondary outcome measure was the generalization of learning to non-trained task, indexed by the CogState neuropsychological battery. Data analysis was conducted using multilevel modelling and multiple regressions. Results24 participants were randomized to real tDCS and 25 to sham. The working memory task demonstrated a significant mean difference in performance in the tDCS treatment group: at day-2 (b = 0.68, CI 0.14–1.21; p = 0.044) and at day-56 (b = 0.71, 0.16–1.26; p = 0.044). There were no significant effects of tDCS on implicit learning. Trend evidence of generalization onto untrained tasks of attention and vigilance task (b = 0.40, 0.43–0.77; p = 0.058) was found. ConclusionsThis is the first study to show a significant longer-term effect of tDCS on working memory in schizophrenia. Given the current lack of effective therapies for cognitive deficits, tDCS may offer an important novel approach to modulating brain networks to ameliorate cognitive deficits in schizophrenia.

GSK-3β Interacts with Dopamine D1 Receptor to Regulate Receptor Function: Implication for Prefrontal Cortical D1 Receptor Dysfunction in Schizophrenia.

Impaired dopamine D1 receptor (D1R) function in prefrontal cortex (PFC) is believed to contribute to the PFC hypofunction that has been hypothesized to be associated with negative symptoms and cognitive deficits in schizophrenia. It is therefore critical to understand the mechanisms for modulation of D1R function. To investigate the physical interaction and functional modulation between D1R and GSK-3β. D1R and GSK-3β physically interact in cultured cells and native brain tissues. This direct interaction was found to occur at the S(417)PALS(421) motif in the C-terminus of D1R. Inhibition of GSK-3β impaired D1R activation along with a decrease in D1R-GSK-3β interaction. GSK-3β inhibition reduced agonist-stimulated D1R desensitization and endocytosis, the latter associated with the reduction of membrane translocation of β-arrestin-2. Similarly, inhibition of GSK-3β in rat PFC also resulted in impaired D1R activation and association with GSK-3β. Moreover, in a NMDA antagonist animal model of schizophrenia, we detected a decrease in prefrontal GSK-3β activity and D1R-GSK-3β association and decreased D1R activation in the PFC. The present work identified GSK-3β as a new interacting protein for D1R functional regulation and revealed a novel mechanism for GSK-3β-regulated D1R function which may underlie D1R dysfunction in schizophrenia.

Bacopa monnieri (Brahmi) improved novel object recognition task and increased cerebral vesicular glutamate transporter type 3 in sub-chronic phencyclidine rat model of schizophrenia.

Reduced vesicular glutamate transporter 1 (VGLUT1) and 2 (VGLUT2) indicate glutamatergic hypofunction leading to cognitive impairment in schizophrenia. However, VGLUT3 involvement in cognitive dysfunction has not been reported in schizophrenia. Brahmi (Bacopa monnieri) might be a new treatment and prevention for cognitive deficits in schizophrenia by acting on cerebral VGLUT3 density. We aimed to study cognitive enhancement- and neuroprotective-effects of Brahmi on novel object recognition and cerebral VGLUT3 immunodensity in sub-chronic (2mg/kg, Bid, ip) phencyclidine (PCP) rat model of schizophrenia. Rats were assigned to three groups for cognitive enhancement effect study: Group 1, Control; Group 2, PCP administration; Group 3, PCP+Brahmi. A neuroprotective-effect study was also carried out. Rats were again assigned to three groups: Group 1, Control; Group 2, PCP administration; Group 3, Brahmi+PCP. Discrimination ratio (DR) representing cognitive ability was obtained from a novel object recognition task. VGLUT3 immunodensity was measured in the prefrontal cortex, striatum and cornu ammonis fields 1-3 (CA1-3) using immunohistochemistry. We found reduced DR in the PCP group, which occurred alongside VGLUT3 reduction in all brain areas. PCP+Brahmi showed higher DR score with increased VGLUT3 immunodensity in the prefrontal cortex and striatum. Brahmi+PCP group showed a higher DR score with increased VGLUT3 immunodensity in the prefrontal cortex, striatum and CA1-3. We concluded that reduced cerebral VGLUT3 was involved in cognitive deficit in PCP-administrated rats. Receiving Brahmi after PCP restored cognitive deficit by increasing VGLUT3 in the prefrontal cortex and striatum. Receiving Brahmi before PCP prevented cognitive impairment by elevating VGLUT3 in prefrontal cortex, striatum and CA1-3. Therefore, Brahmi could be a new frontier of restoration and prevention of cognitive deficit in schizophrenia.

Exploring social cognition in schizophrenia.

The aim of the study was to compare social cognition between groups of patients diagnosed with schizophrenia and healthy controls and to replicate two previous studies using tests of social cognition that may be particularly sensitive to social cognitive deficits in schizophrenia. Thirty-eight first-admitted patients with schizophrenia and 38 healthy controls solved 11 "imaginary conversation (i.e., theory of mind)" items, 10 "psychological understanding" items, and 10 "practical understanding" items. Statistical tests were made of unadjusted and adjusted group differences in models adjusting for intelligence and neuropsychological test performance. Healthy controls performed better than patients on all types of social cognitive tests, particularly on "psychological understanding." However, after adjusting for intelligence and neuropsychological test performance, all group differences became nonsignificant. When intelligence and global cognitive functioning is taken into account, schizophrenia patients and healthy controls perform similarly on social cognitive tests.

Cognitive remediation and functional improvement in schizophrenia: Is it a matter of size?

BackgroundCognitive Remediation represents the best available tool to treat cognitive deficits in schizophrenia and evidence suggests an effect also on global functioning. However, the relationship between cognitive and functional improvement is not yet fully elucidated: do cognitive changes need to be of a definite size and/or encompass a certain number of domains in order to impact on daily functioning? This study aims to explore the role of cognitive improvement, evaluated both quantitatively and qualitatively through the use of Italian equivalent scores, on the daily functioning of patients. As secondary goal, the influence of demographic, clinical and neuropsychological variables on functional outcome was also systematically investigated. MethodsOne hundred subjects with a diagnosis of schizophrenia underwent 36 sessions of Cognitive Remediation and were evaluated at baseline and after the training with the Brief Assessment of Cognition in Schizophrenia and the Quality of Life Scale. ResultsA total of 70% of patients improved in at least one cognitive domain and over 50% obtained a normalized score. Among the clinical and neurocognitive factors examined, the only significant predictor of quality of life's improvement was the proportion of cognitive functions that reached an equivalent score of “normal”. ConclusionsThis study suggests that improvements in daily functioning depend on the achievement of a cognitive profile as much as possible “normal”, harmonious and balanced, supporting the idea that a qualitative leap in cognition is needed in order to gain an advantage in real life activities.

L-Proline, GABA Synthesis and Gamma Oscillations in Schizophrenia

Altered inhibition from parvalbumin-containing GABA neurons is thought to contribute to impaired gamma frequency oscillations and cognitive deficits in schizophrenia. Crabtree and colleagues report that proline dehydrogenase deficits produce excessive cytosolic levels of the GABA-mimetic l-proline which impairs GABA synthesis and gamma oscillations in a manner that mimics schizophrenia.

Cognitive impairments in patients with first episode psychosis: The relationship between neurophysiological and neuropsychological assessments

Cognitive deficits in schizophrenia have been widely reported. Neurophysiological and neuropsychological assessments have been conducted to study these impairments. Event-related potentials (ERPs) are relevant markers of cognitive deficits in schizophrenia, and reductions in specific ERP components have been found. The MATRICS Consensus Cognitive Battery (MCCB) was developed to obtain a consensus battery for the assessment of cognitive deficits in schizophrenia. Here, we aimed to study modulations of several ERP components in first episode psychosis (FEP). We also examined neuropsychological deficits using the MCCB, and correlations between ERP and MCCB impairments. Thirty-eight FEP patients were compared to thirty-eight healthy controls. The following ERP components were examined: P1, N1, MMN, P2, early-P3 and late-P3. We used an auditory three-stimulus oddball paradigm, with standard (60%), target (20%) and distractor (20%) stimuli. FEP patients showed significantly lower amplitudes of P2, early-P3 and late-P3 components. FEP patients also showed significant deficits in all the MCCB cognitive domains. Finally, correlational analyses found strong associations between amplitudes of P2, early-P3 and late-P3 components and MCCB tests for attention and speed of processing. These findings indicate that deficits in late auditory ERP components are present in FEP, whereas early components are preserved. These reductions in late ERP components were related to attentional deficits in FEP as assessed by MCCB. These findings indicate that MCCB is a valid battery for studying cognitive impairments in the initial stages of schizophrenia, and highlight the utility of converging neurophysiological and neuropsychological measures to examine attentional impairments in schizophrenia.

Neural Correlates of Belief and Emotion Attribution in Schizophrenia.

Impaired mental state attribution is a core social cognitive deficit in schizophrenia. With functional magnetic resonance imaging (fMRI), this study examined the extent to which the core neural system of mental state attribution is involved in mental state attribution, focusing on belief attribution and emotion attribution. Fifteen schizophrenia outpatients and 14 healthy controls performed two mental state attribution tasks in the scanner. In a Belief Attribution Task, after reading a short vignette, participants were asked infer either the belief of a character (a false belief condition) or a physical state of an affair (a false photograph condition). In an Emotion Attribution Task, participants were asked either to judge whether character(s) in pictures felt unpleasant, pleasant, or neutral emotion (other condition) or to look at pictures that did not have any human characters (view condition). fMRI data were analyzing focusing on a priori regions of interest (ROIs) of the core neural systems of mental state attribution: the medial prefrontal cortex (mPFC), temporoparietal junction (TPJ) and precuneus. An exploratory whole brain analysis was also performed. Both patients and controls showed greater activation in all four ROIs during the Belief Attribution Task than the Emotion Attribution Task. Patients also showed less activation in the precuneus and left TPJ compared to controls during the Belief Attribution Task. No significant group difference was found during the Emotion Attribution Task in any of ROIs. An exploratory whole brain analysis showed a similar pattern of neural activations. These findings suggest that while schizophrenia patients rely on the same neural network as controls do when attributing beliefs of others, patients did not show reduced activation in the key regions such as the TPJ. Further, this study did not find evidence for aberrant neural activation during emotion attribution or recruitment of compensatory brain regions in schizophrenia.

Fronto-temporal connectivity predicts cognitive empathy deficits and experiential negative symptoms in schizophrenia.

Impaired cognitive empathy is a core social cognitive deficit in schizophrenia associated with negative symptoms and social functioning. Cognitive empathy and negative symptoms have also been linked to medial prefrontal and temporal brain networks. While shared behavioral and neural underpinnings are suspected for cognitive empathy and negative symptoms, research is needed to test these hypotheses. In two studies, we evaluated whether resting-state functional connectivity between data-driven networks, or components (referred to as, inter-component connectivity), predicted cognitive empathy and experiential and expressive negative symptoms in schizophrenia subjects. Study 1: We examined associations between cognitive empathy and medial prefrontal and temporal inter-component connectivity at rest using a group-matched schizophrenia and control sample. We then assessed whether inter-component connectivity metrics associated with cognitive empathy were also related to negative symptoms. Study 2: We sought to replicate the connectivity-symptom associations observed in Study 1 using an independent schizophrenia sample. Study 1 results revealed that while the groups did not differ in average inter-component connectivity, a medial-fronto-temporal metric and an orbito-fronto-temporal metric were related to cognitive empathy. Moreover, the medial-fronto-temporal metric was associated with experiential negative symptoms in both schizophrenia samples. These findings support recent models that link social cognition and negative symptoms in schizophrenia. Hum Brain Mapp 38:1111-1124, 2017. © 2016 Wiley Periodicals, Inc.

Association between DBH 19 bp insertion/deletion polymorphism and cognition in schizophrenia with and without tardive dyskinesia

Long-term antipsychotic treatment for schizophrenia is associated with the development of tardive dyskinesia (TD), which is involved in increased cognitive impairment. Dopamine beta-hydroxylase (DBH) gene associated with dopamine and norepinephrine systems influences cognition. Schizophrenia with TD have higher DBH activity than those without TD. This study examined whether DBH5′-insertion/deletion (-Ins/Del) polymorphism could influence cognitive function in schizophrenia with and without TD. The presence of DBH5′-Ins/Del polymorphism was determined in 345 schizophrenia with TD and 397 schizophrenia without TD. The Abnormal Involuntary Movement Scale and Repeatable Battery for Assessment of Neuropsychological Status (RBANS) were used to assess TD severity and cognition. The allele and genotype frequencies of DBH5′-Ins/Del polymorphism did not differ between patients with and without TD (both p>0.05). RBANS total score and subscales did not differ by DBH5′-Ins/Del genotype groups in patients with TD (all p>0.05). However, attention score significantly differed by DBH5′-Ins/Del genotype groups in those without TD (p<0.05). Patients without TD who were Del homozygous had significantly lower attention score than those without TD who were Ins alleles (p<0.05). Immediate memory and attention scores were lower in patients with TD than without TD (both p<0.05). This study indicated that DBH5′-Ins/Del polymorphism may not play a role in the susceptibility to TD and cognitive deficits in schizophrenia with TD, but it may influence cognitive function in schizophrenia with non-TD. Moreover, schizophrenia with TD experienced greater cognitive deficits than those with non-TD, especially in immediate memory and attention.

Increased plasma asymmetric dimethylarginine is associated with cognitive deficits in patients with schizophrenia.

Cognitive deficits are a core feature of schizophrenia. Previous studies have shown that plasma asymmetric dimethylarginine (ADMA), an endogenous inhibitor of the nitric oxide synthase, was increased in patients with schizophrenia. This study aimed to investigate the association of ADMA with cognitive deficits in schizophrenia. Forty-seven patients with schizophrenia and 45 healthy control subjects were recruited in present study. Cognitive function was assessed with a neuropsychological battery including 7 neurocognitive tests. Schizophrenic symptoms were assessed using the Positive and Negative Syndrome Scale and plasma ADMA concentration was measured by HPLC. We found that patients with schizophrenia exhibited poorer performances in nearly all of the cognitive tests except for the visual memory index compared with healthy controls. Plasma ADMA levels were significantly increased in patients with schizophrenia when compared to normal controls, and the mean ADMA concentration in patients with multiple episode schizophrenia was much higher than that of patients with first episode schizophrenia. For the patients, ADMA was negatively associated with attention, working memory and executive function in schizophrenia. These results suggest that ADMA may be involved in the pathophysiology of schizophrenia-associated cognitive impairments, and plasma ADMA could be a peripheral biomarker for evaluation of cognitive function in schizophrenia.

Molecular signatures associated with cognitive deficits in schizophrenia: a study of biopsied olfactory neural epithelium.

Cognitive impairment is a key feature of schizophrenia (SZ) and determines functional outcome. Nonetheless, molecular signatures in neuronal tissues that associate with deficits are not well understood. We conducted nasal biopsy to obtain olfactory epithelium from patients with SZ and control subjects. The neural layers from the biopsied epithelium were enriched by laser-captured microdissection. We then performed an unbiased microarray expression study and implemented a systematic neuropsychological assessment on the same participants. The differentially regulated genes in SZ were further filtered based on correlation with neuropsychological traits. This strategy identified the SMAD 5 gene, and real-time quantitative PCR analysis also supports downregulation of the SMAD pathway in SZ. The SMAD pathway has been important in multiple tissues, including the role for neurodevelopment and bone formation. Here the involvement of the pathway in adult brain function is suggested. This exploratory study establishes a strategy to better identify neuronal molecular signatures that are potentially associated with mental illness and cognitive deficits. We propose that the SMAD pathway may be a novel target in addressing cognitive deficit of SZ in future studies.

Conscious and unconscious performance monitoring: Evidence from patients with schizophrenia

The ability to detect our own errors is an essential component of action monitoring. Using a masking paradigm in normal adults, we recently discovered that some error-detection processes can proceed without awareness, while other markers of performance monitoring such as the Error-Related Negativity (ERN) are tightly linked to conscious perception. Interestingly, research on cognitive deficit in schizophrenia has shown that the ERN is altered in these patients. In the present study, we therefore tested if the error detection impairment in schizophrenia is specific to conscious perception or is also found under non-conscious conditions, probing whether these performance monitoring processes are truly distinct. Thirteen patients with schizophrenia and thirteen age-matched healthy control subjects performed a speeded number comparison task on masked stimuli while EEG and MEG signals were recorded. Conscious perception and error-detection were assessed on a trial-by-trial basis using subjective reports of visibility and confidence. We found that patients with schizophrenia presented altered cingulate error-detection responses in conscious trials, as reflected by a decreased ERN. By contrast, on unconscious trials, both controls and schizophrenia patients performed above chance in evaluating the likelihood of having made an error. This dissociation confirms the existence of two distinct performance monitoring systems, and suggests that conscious metacognition in schizophrenia is specifically altered while non-conscious performance monitoring remains preserved.

Acute and chronic effects of clozapine on cholinergic transmission in cultured mouse superior cervical ganglion neurons

Cholinergic dysfunction contributes to cognitive deficits in schizophrenia. The atypical antipsychotic clozapine improves cognition in patients with schizophrenia, possibly through modulation of the cholinergic system. However, little is known about specific underlying mechanisms. We investigated the acute and chronic effects of clozapine on cholinergic synaptic transmission in cultured superior cervical ganglion (SCG) neurons. Spontaneous excitatory postsynaptic currents (sEPSCs) were detected and were reversibly inhibited by the nicotinic receptor antagonist d-tubocurarine, confirming that the synaptic responses were primarily mediated by nicotinic receptors. Bath application of clozapine at therapeutic concentrations rapidly and reversely inhibited both the amplitude and frequency of sEPSCs in a concentration-dependent manner, without changing either rise or decay time, suggesting that clozapine effects have both presynaptic and postsynaptic origins. The acute effects of clozapine on sEPSCs were recapitulated by chronic treatment of SCG cultures with similar concentrations of clozapine, as clozapine treatment for 4 d reduced the frequency and amplitude of sEPSCs without affecting their kinetics. Cell survival analysis indicated that SCG neuron cell counts after chronic clozapine treatment were comparable to the control group. These results demonstrate that therapeutic concentrations of clozapine suppress nicotinic synaptic transmission in SCG cholinergic synapses, a simple in vitro preparation of cholinergic transmission.