Deficits in GABAA receptor function and working memory in non-smokers with schizophrenia

https://doi.org/10.1016/j.schres.2016.01.008Get rights and content

Abstract

Background

Although altered gamma-aminobutyric acid (GABA) neurotransmission has been implicated in the pathophysiology of schizophrenia, it is unclear whether the influence of GABA on working memory processes is confounded by nicotine use in this population. It is therefore crucial to evaluate working memory and its underlying mechanisms in non-smokers with schizophrenia to eliminate the confounding effects of nicotine on behavior and neurophysiology.

Methods

In this cross-sectional study, working memory was assessed using the verbal N-back task, while GABAergic function was assessed through motor cortical inhibition using single and paired-pulse transcranial magnetic stimulation (TMS) to the left primary motor cortex in 11 non-smokers with schizophrenia and 13 non-smoker healthy subjects.

Results

Similar to previously published studies, working memory performance was significantly impaired in the 3-back condition in patients with schizophrenia compared to healthy subjects (p = 0.036). In addition, GABAA receptor function was significantly reduced in schizophrenia as assessed by short interval cortical inhibition (SICI) (p = 0.005). A positive correlation was found between GABAA inhibition and working memory performance on the 3-back task (r (23) = 0.55, p = 0.006), suggesting that greater GABAA inhibition is associated with better performance on tasks of working memory.

Conclusions

Our findings highlight the role of GABAA receptor dysfunction in working memory and the pathophysiology of schizophrenia, and may represent a selective characteristic of schizophrenia. Moreover, these findings suggest a potential therapeutic role for targeting GABA receptor activity to improve cognition and quality of life in patients with schizophrenia.

Introduction

Schizophrenia is a neuropsychiatric illness that affects nearly 1% of individuals worldwide (McGrath et al., 2008), and is characterized by cognitive deficits that significantly impair quality of life and functional outcomes (Green, 2006, Nuechterlein et al., 2011). Dysfunctional gamma-aminobutyric acid (GABA) neurotransmission is a replicated finding in schizophrenia (Daskalakis et al., 2002, Frankle et al., 2015, Salavati et al., 2015, Takahashi et al., 2013) that may underlie symptoms such as impairments in working memory or executive function (Chen et al., 2014, Tse et al., 2014, Volk and Lewis, 2002).

Working memory is a process that refers to the maintenance and active manipulation of incoming information (Baddeley et al., 1986), and is one of the most consistently reported cognitive deficits in schizophrenia (Forbes et al., 2009, Lee and Park, 2005). One study found that patients with schizophrenia performed significantly worse on the 3-back condition of the N-back task, a common task used to assess verbal working memory, compared to the 1-back condition (Barr et al., 2010). This study also found that patients displayed excessive GABA-mediated gamma oscillatory activity in the dorsolateral prefrontal cortex (DLPFC) which, unlike in healthy subjects, was not altered with task difficulty (Barr et al., 2010).

Transcranial magnetic stimulation (TMS) is a non-invasive brain stimulation technique that can be used to measure cortical inhibitory and excitatory networks in various brain regions (Kujirai et al., 1993, Levy, 1987, Valls-Sole et al., 1992). Cortical excitability represents a measure of membrane excitability in pyramidal neurons (Fitzgerald et al., 2002) that can be measured using TMS through evaluation of the resting motor threshold (RMT) and the motor evoked potential (MEP) amplitude from the target muscle (Boroojerdi et al., 1999, Cantello et al., 1992, Di Lazzaro et al., 2003). Cortical inhibition can be measured via the cortical silent period (CSP) (Cantello et al., 1992, Kimiskidis et al., 2006, Kukowski and Haug, 1992) and long-interval cortical inhibition (LICI) (Chu et al., 2008, Nakamura et al., 1997, Sanger et al., 2001, Valls-Sole et al., 1992), both measures of GABAB receptor function, and short interval cortical inhibition (SICI) (Kujirai et al., 1993, Ziemann et al., 1996), a measure of GABAA receptor function. TMS measures of GABAA and GABAB receptors have been validated using pharmacological adjuncts; notably, the ISIs (interstimulus interval) measured for GABAA and GABAB are selectively inhibited with respective GABAergic antagonists (Ziemann et al., 1998).

Many studies have shown deficits in GABA neurotransmission in schizophrenia using measures of cortical inhibition (Chen et al., 2014, Daskalakis et al., 2002, Takahashi et al., 2013, Wobrock et al., 2008, Wobrock et al., 2009). In line with these results, a meta-analysis conducted in 2013 on cortical inhibition and facilitation in patients with schizophrenia only revealed a deficit in SICI, which is a measure of GABAA receptor function (Radhu et al., 2013). As such, an important consensus paper recently posited that TMS is one of several neurophysiological techniques that are suitable for identifying proposed biomarkers in schizophrenia (Thibaut et al., 2015). Differences in cortical GABA receptor expression have also been shown in patients with schizophrenia, suggesting a central role of dysfunctional GABA activity in these patients (Volk and Lewis, 2002).

The aim of this study was to build upon previous findings that show altered cortical inhibition and working memory performance in schizophrenia. To our knowledge, there have not yet been any studies that have exclusively studied cortical inhibition and working memory in non-smokers with schizophrenia, which is a necessary control in order to eliminate confounds associated with tobacco smoking. In particular, smokers in general may display altered GABAergic signaling (Lang et al., 2008), since nicotine has been shown to directly and indirectly impact cholinergic, glutamatergic, and GABAergic synapses (Albuquerque et al., 1997). Therefore, we studied working memory and cortical inhibition in biochemically verified non-smokers with schizophrenia compared to healthy subjects, as well as the relationship between potential deficits in cortical inhibition and working memory performance.

Section snippets

Subjects

Written informed consent was given from 11 (mean age: 38.5, SD: 9.0 years) non-smokers with a diagnosis of schizophrenia or schizoaffective disorder and 13 (mean age: 35.5, SD: 10.5 years) non-smoker healthy subjects who completed this study. Inclusion criteria for this study were: 1) 18–55 years, 2) current/abstinent non-smoker for at least one year verified by a carbon monoxide reading, and 3) right handed. Exclusion criteria for this study were: 1) illicit drug use in the past month, 2) current

Demographics

Demographic information is presented in Table 1. The groups did not differ on measures of sex (χ2 = 0.509), race (χ2 = 4.178), age, and years of education. However, subjects with schizophrenia had a lower IQ than healthy subjects.

Working memory

One schizophrenia patient did not understand the task and was removed from the working memory analysis due to a response rate of more than 3 standard deviations above the mean. A repeated measures ANOVA found increased N-back performance in the 1-back (91.0% ± 8.32) compared

Discussion

The aim of the current study was to assess GABA receptor function and working memory performance in patients with schizophrenia to establish whether these deficits are present as part of the pathophysiology of schizophrenia in non-smokers. Our results suggest a selective GABAA receptor deficit in schizophrenia that is in line with previous research showing decreased GABAA function without controlling for smoking status (Daskalakis et al., 2002, Radhu et al., 2013). We did not find any

Role of the funding source

This work was supported by Canadian Institutes of Health Research grant MOP#115145 to TPG.

Contributors

ACB collected and analyzed the data, and prepared the manuscript. TPG, MSB, TKR, and ZJD designed and wrote the study protocol. All authors contributed to and have approved the final manuscript.

Conflict of interest

MSB receives research support from Brain and Behavior Research Foundation (Formerly NARSAD) (#20501).

TKR receives research support from Brain Canada, Brain and Behavior Research Foundation (#17826) and CIHR (MP 244041). TKR reports no competing interests.

In the last 5 years, ZJD received research and equipment in-kind support for an investigator-initiated study through Brainsway Inc. ZJD has also served on the advisory board for Hoffmann-La Roche Limited, Merck and Sunovion and received speaker

Acknowledgments

We would like to thank Reza Zomorrodi for his help in analyzing the N-Back data. We would also like to thank Emily Simpkin, Matthew Tracey, Marya Morozova, and Maryam Sharif-Razi for assisting in the initial assessment of participants.

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