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Asenapine maleate normalizes low frequency oscillatory deficits in a neurodevelopmental model of schizophrenia
Neuroscience Letters 711 (2019) 134404
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Neuroscience Letters journal homepage: www.elsevier.com/locate/neulet
Research article
Asenapine maleate normalizes low frequency oscillatory deficits in a neurodevelopmental model of schizophrenia Tapia Foute Nelong, Joshua D. Manduca, Paula M. Zonneveld, Melissa L. Perreault
T
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Department of Molecular and Cellular Biology, University of Guelph, Guelph, N1G 2W1 Ontario, Canada
A R T I C LE I N FO
A B S T R A C T
Keywords: Schizophrenia Cognition Neural oscillations Asenapine maleate Haloperidol Clozapine
Asenapine maleate (AM) is an atypical antipsychotic that, unlike many other antipsychotics, shows some efficacy in treating cognitive dysfunction in schizophrenia. Normal cognitive function has long since been associated with high frequency neuronal oscillations. However, recent research has highlighted the potential importance of low frequency oscillations. Here, the impact of AM on low frequency neural oscillatory activity was evaluated in the methylazoxymethanol acetate (MAM) rat model system used for the study schizophrenia, and the oscillatory signatures compared to those of haloperidol (HAL) and clozapine (CLZ). AM and CLZ normalized low frequency spectral power deficits in the prefrontal cortex, while HAL and AM reversed corticostriatal and corticocortical delta coherence deficits. However, only chronic AM administration normalized corticostriatal and corticocortical delta coherence deficits between 3–4 Hz. These findings support the idea that antipsychotic-induced amelioration of both delta coherence and power may be important for therapeutic efficacy in treating the cognitive deficits inherent in schizophrenia.
1. Introduction Cognitive dysfunction is a debilitating symptom of schizophrenia (SZ) that is inadequately treated by currently available antipsychotics, and while the introduction of novel drugs for SZ treatment is ongoing, drugs that are efficacious in treating this symptom of the disorder are as yet unavailable. Oscillatory activity in the gamma frequency band (˜32–100 Hz) has most commonly been associated with cognition due to their known relevance to processes such as working memory and perception [1,2]. More recently, however, research has highlighted the importance of low frequency oscillations, known for facilitating communication between remote brain regions, in cognition [3]. In individuals with SZ, alterations in low frequency oscillations within the frontal cortex have been reported, which likely underlie, at least in part, the cognitive deficits inherent in the disorder. Furthermore, low frequency oscillopathies are the most commonly reported resting-state abnormalities in SZ with aberrant patterns observed in both delta (1–4 Hz) and theta (4–7 Hz) frequency bands [4]. Additionally, disruptions to low frequency functional connectivity is evident in the cortex of patients with SZ [5]. In this regard, the normalization of aberrant low frequency oscillatory signatures within and between cortical regions may offer a strategy for delineating the potential efficacy of novel drugs on improving cognition. This idea is in ⁎
line with reports showing that antipsychotics can improve aberrant oscillatory patterns in SZ patients [6,7] as well as rodent models of SZ [8,9]. This effect is more pronounced with second-generation antipsychotics and is postulated to reflect the increased affinity of these drugs for serotonin receptors over dopamine receptors [9,10]. This may correlate to efficacy in treating cognitive deficits as first-generation antipsychotics such as haloperidol (HAL) have little reported effect on cognition [11,12]. Asenapine maleate (AM) is a promising, well-tolerated, secondgeneration antipsychotic approved for the treatment of bipolar mania and SZ. Apart from treating psychosis in SZ, clinical evidence indicates a therapeutic effect of AM in alleviating cognitive deficits [13]. This finding is supported by preclinical studies using rodent and non-human primate models of SZ which showed therapeutic effects of AM in specific aspects of cognitive function including visual recognition memory and reversal learning [14–16]. The impact of AM on normalizing neural oscillatory dysfunction in SZ, however, remains unknown. This study therefore aims to compare the effects of chronic AM administration on low frequency neural oscillations within the striatum and cortical regions to that of HAL and clozapine (CLZ) using the methylazoxymethanol acetate (MAM) model system of SZ.
Corresponding author. E-mail addresses: [email protected] (T. Foute Nelong), [email protected] (J.D. Manduca), [email protected] (P.M. Zonneveld), [email protected] (M.L. Perreault). https://doi.org/10.1016/j.neulet.2019.134404 Received 10 June 2019; Accepted 25 July 2019 Available online 26 July 2019 0304-3940/ © 2019 Elsevier B.V. All rights reserved.
Neuroscience Letters 711 (2019) 134404
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2. Materials and methods
2.5. Data analysis
2.1. Animals
MATLAB software in conjunction with routines from the Chronux software package was used to extract individual frequency bands from the LFP data and compare oscillatory synchrony between regions. All data analysis was performed on the last 5 min of the LFP recordings. Mean values from each frequency band for each electrode (6 per rat) were extracted and statically analyzed with IBM SPSS 24 software using a 95% confidence interval. Statistical outliers were removed prior to further analysis. Mean differences between MAM-VEH and SAL-VEH groups were analyzed using independent samples t-tests. Analysis of mean differences between MAM-VEH and drug treated MAM rats was performed using univariate ANOVAs. Group variance was assessed using Levene’s test of homogeneity to determine which post-hoc test, either Tukey’s or Games-Howell, was appropriate for each evaluated interaction.
Pregnant female Sprague-Dawley rats (Charles River, QC) were administered either MAM (20 mg/kg, i.p) or saline (SAL) on gestational day 17 as described previously by Sonnenschein et al. [17]. A 12 h reverse light-dark cycle was maintained in the colony room and rats had access to food and water ad libitum. Experimental procedures began once the male offspring weighed approximately 350 g (˜PND 70). The rats were then separated into 5 experimental groups: MAM-HAL (N = 8), MAM-AM (N = 7), MAM-CLZ (N = 7), MAM-VEH (N = 7) and SAL-VEH (N = 7). All procedures complied with the guidelines described in the Guide to the Care and Use of Experimental Animals (Canadian Council on Animal Care, 1993) and the Animal Care Ethics Committee of the University of Guelph.
3. Results 2.2. Drugs The effects of antipsychotics on low frequency neural oscillations in the MAM model of SZ were evaluated following 14 days of drug administration. A significant effect of treatment on MAM oscillatory power in both the delta and theta frequency bands was observed for each region (PFC-delta: F(348) = 9.397, P < 0.000; PFC-theta: F (347) = 8.220, P < 0.000; OFC-delta: F(346) = 10.595, P < 0.000; OFC-theta: F(348) = 8.549, P < 0.000; CPU-delta: F(349) = 6.098, P = 0.001; CPU-theta: F(348) = 7.757, P < 0.000). Similar effects were observed with CLZ and AM to increase delta and decrease theta power in all three regions (Fig. 1). In the PFC, MAM-VEH rats exhibited decreased delta (P = 0.003) and increased theta power (P = 0.001) compared to controls, an effect normalized by CLZ (P < 0.000) or AM (P = 0.012), but not HAL (Fig. 1C, D). Additionally, analysis of spectral power performed for OFC and CPU oscillations selectively in the theta 8–9 Hz range (Fig. 2) demonstrated a significant effect of treatment (OFC: F(348) = 5.640, P = 0.002; CPU: F(351) = 6.582, P = 0.001). In both the OFC and CPU, the MAM-VEH group exhibited significantly reduced theta oscillations at 8–9 Hz compared to SAL-VEH controls (OFC: P = 0.001, CPU: P = 0.009, Fig. 2). This effect was selectively worsened by chronic CLZ administration (OFC: P = 0.004; CPU: P = 0.017). Analysis of coherence showed that the MAM-VEH group exhibited significantly decreased low frequency delta and theta coherence compared to SAL-VEH rats between all brain regions (All P ≤ 0.002, Fig. 3). A significant effect of treatment on MAM rats in both the delta and theta frequency bands was also evident between the majority of regions (PFCCPU-delta: F(346) = 8.311, P < 0.000; PFC-CPU-theta: F (345) = 15.136, P < 0.000; PFC-OFC-delta: F(343) = 5.495, P = 0.003; PFC-OFC-theta: F(343) = 6.494, P = 0.001; OFC-CPU-delta: F(348) = 5.889, P = 0.002), the exception being OFC-CPU theta coherence (F(348) = 1.815, P = 0.157). Compared to MAM-VEH rats, both AM (P = 0.001) and HAL (P = 0.021) treatment normalized PFCCPU delta coherence deficits and additionally reversed aberrant PFCOFC delta coherence (AM: P = 0.020; HAL: P = 0.002, Fig. 3A–D). Only HAL treatment normalized decreased delta coherence between the OFC and CPU (P = 0.022, Fig. 3E, F). When analysis of coherence was performed for oscillations selectively in the delta 3–4 Hz range a significant effect of treatment was demonstrated (PFC-CPU: F (347) = 7.229, P < 0.000; PFC-OFC: F(345) = 5.325, P = 0.003; OFCCPU: F(349) = 4.891, P = 0.005). AM-treated MAM rats displayed normalized PFC-CPU (P = 0.001) and PFC-OFC (P = 0.015) delta coherence between 3–4 Hz following chronic administration (Fig. 4A, B). CLZ administration had no significant effect on delta coherence compared to MAM-VEH rats, however, was found to exacerbate the PFCCPU theta coherence deficit (Fig. 3A, B). A similar trend was observed with PFC-OFC theta coherence following CLZ administration (Fig. 3C, D).
MAM was purchased from MRI Global (Kansas City, MO). Haloperidol (HAL, Sigma-Aldrich, Oakville, ON) was dissolved in 0.8% glacial acetic acid and subsequently adjusted to pH 6 using 1 N NaOH. Clozapine (CLZ, Sigma-Aldrich, Oakville, ON) was dissolved in 0.5 N acetic acid, brought to the appropriate concentration with 0.5 M sodium acetate (pH 5.0), then adjusted to pH 5 with 1 N NaOH. Asenapine (AM, Sigma-Aldrich, Oakville, ON) was dissolved in 0.9% saline. The rats received doses of HAL, CLZ and AM at 1.0 mg/kg (i.p), 5.0 mg/kg (i.p) and 0.15 mg/kg (i.p) respectively for a total of 14 days. Doses are expressed as free bases. Injections were administered at a volume of 1.0 mL/kg. Dosing and duration of administration was based upon previous investigations evaluating the effects of antipsychotics in animal models of SZ [18–20].
2.3. Electrode implantation surgery Electrode microarrays were designed and constructed in-house using PFA-coated stainless steel wire and polyimide tubing. All arrays used had an electrode impedance of less than 2 Megaohms. Rats were anesthetized with isoflurane (5% induction, 2% maintenance) followed by bilateral electrode implantation into the medial prefrontal cortex (PFC, AP: +3.2, ML: ± 0.6, DV: −3.8), caudate putamen (CPU, AP: +1.9, ML: ± 2.6, DV: −4.4) and lateral orbitofrontal cortex (OFC, AP: +3.2, ML: ± 2.6, DV: −5.5). Thus, a total of 6 recording electrodes were implanted into each rat. Following surgery, rats were housed singly and allowed 10 days for recovery prior to commencing drug administration and electrophysiology recordings (Fig. 1A). Electrode placement was verified post-mortem (Fig. 1B).
2.4. Electrophysiology Local field potentials (LFP) were recorded using a Wireless 2100system (Multi-Channel Systems). 24 h after the final injection rats were placed in Plexiglas boxes (18″ × 18″ × 18″) while LFPs were recorded for 30 min at a sampling rate of 1000 samples/second. The spectral power of LFP oscillations in each region was analyzed using routines from the Chronux (version 2.12 v03) software package for MATLAB (MathWorks). Data analysis was conducted employing a fast Fourier transform with power and coherence analyzed using the powerspectrum.m and coherocyc.m chronux scripts respectively. Recordings were segmented, detrended and low-pass filtered to remove frequencies greater than 100 Hz. Continuous multitaper spectral power for the normalized data (to total spectral power) and coherence was calculated for the delta (1–4 Hz) and theta frequency bands (> 4–12 Hz). 2
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Fig. 1. Differential effects of 14 days of antipsychotic administration on low frequency spectral power in MAM rats. (A) Experimental timeline. (B) Electrode placements in the prefrontal cortex (PFC), orbitofrontal cortex (OFC) and caudate putamen (CPU). (C, D) Power spectrum and quantification of low frequency oscillatory power in the PFC showing normalization of aberrant delta and theta power following asenapine maleate (AM) and clozapine (CLZ) administration. (E–H) No significant changes were observed between MAM-VEH and SAL-VEH rats in the OFC and CPU. All three drugs showed similar effects to increase delta or decrease theta spectral power in these regions. Data presented is from a 5 min epoch, N = 5–7 rats, 1–2 electrodes/region/rat. Curves represent group means. Box plots display medians with whiskers representing highest and lowest values. *p < 0.05, **p < 0.01, ***p < 0.001 compared to MAM-VEH rats.
4. Discussion
between regions pertinent to the neuropathology of SZ. Our findings showing deficits in the delta frequency of MAM rats, a model that exhibits impairments in PFC-dependent cognitive tasks, are consistent with studies showing a relationship between delta wave activity and cognition. For example, it is well established that dopamine D1 receptor signaling plays a positive role in cognitive function [21] with blockade of D1 receptor signaling suppressing medial frontal delta rhythms to impair interval timing performance [22], a process critical to basic cognitive processes [23]. Reduced frontal cortical dopamine signaling is also a hallmark of SZ neuropathology, with reductions in delta oscillations also recently exhibited in SZ patients [24]. Chen and Yang [25] showed that CLZ-induced dopamine release heightens postsynaptic D1 receptor-dependent NMDA receptor function which may
The purpose of this study was to compare the low frequency electrophysiological profile of AM, a well-tolerated antipsychotic with the potential to improve cognitive deficits in SZ, with the antipsychotics HAL and CLZ in the MAM model of SZ. We showed that while CLZ normalized low frequency power in the PFC of MAM rats, and HAL normalized corticocortical and corticostriatal delta coherence, only AM was able to normalize both power and coherence deficits. Additionally, AM treatment improved both PFC-CPU and PFC-OFC delta coherence between 3–4 Hz, an effect not observed with administration of either HAL or CLZ. Thus, these findings indicate a unique effect of AM on low frequency coherence, principally in the delta 3–4 Hz frequency band, 3
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Fig. 2. Effects of antipsychotic administration on oscillatory power between 8–9 Hz. Power spectrum and quantification of low frequency oscillatory power in the (A) orbitofrontal cortex (OFC) and the (B) caudate putamen (CPU). MAM-VEH rats displayed decreased theta power in both regions, an effect exacerbated with clozapine (CLZ) administration. No significant changes were observed with haloperidol (HAL) and asenapine maleate (AM) although a similar trend was observed. Data presented is from a 5 min epoch, N = 5–7 rats, 1–2 electrodes/region/rat. Box plots display medians with whiskers representing highest and lowest values. *p < 0.05, **p < 0.01 compared to MAM-VEH rats.
performance in a cognitive task. In the present study CLZ, an antipsychotic known to have some efficacy in improving cognition in SZ [27], elicited similar effects to AM on PFC power, although a change in delta coherence was not observed with CLZ administration. HAL, an antipsychotic known for having poor effects of cognitive symptoms [11], also elicited similar changes to AM on delta coherence, however only AM was able to normalize PFC-CPU and PFC-OFC delta coherence between 3–4 Hz. In a study by Nácher et al. [28] LFPs recorded from cortical regions in non-human primates performing a somatosensory discrimination task revealed a correlation between delta coherence and decision making, highlighting the potential importance of coherent cortical delta oscillations in executive functioning. Therefore, this unique effect of AM treatment on aberrant
elicit lasting changes to excitatory synaptic transmission in the PFC. Furthermore, in NMDA hypofunction models of SZ, the second generation antipsychotics AM and CLZ restore prefrontal activity and improve cognitive deficits, effects that are abolished when D1 receptor antagonists are introduced [16,26]. Thus, the normalization of prefrontal delta power observed following CLZ and AM in the current study may result, at least in part, through a D1 receptor-mediated mechanism. Additionally, the present findings provide support for the hypothesis that the normalization of aberrant delta function may represent a biomarker of therapeutic efficacy for cognitive symptoms in SZ. This idea is further supported by a study conducted by Parker et al. [24] which showed that delta frequency optogenetic stimulation of lateral cerebellar projection neurons normalized medial frontal activity and
Fig. 3. Differential effects of 14 days of antipsychotic administration on oscillatory coherence in MAM rats. MAM-VEH rats displayed consistently lower delta and theta coherence compared to SAL-VEH rats. (A, B) Asenapine maleate (AM) and haloperidol (HAL) treatment increased PFC-CPU delta coherence compared to MAM-VEH rats while clozapine (CLZ) further decreased MAM-induced theta deficits. (C, D) Normalization of PFC-OFC delta coherence by AM and HAL. (E, F) MAM-VEH rats exhibited suppressed OFC-CPU delta coherence which was normalized following HAL administration. Data presented is from a 5 min epoch, N = 5–7 rats, 1–2 electrodes/region/rat. Curves represent group means. Box plots display medians with whiskers representing highest and lowest values. *p < 0.05, **p < 0.01, ***p < 0.001 compared to MAM-VEH rats.
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Fig. 4. Effects of antipsychotic administration on oscillatory coherence between 3–4 Hz. MAM-VEH rats displayed consistently lower delta coherence compared to SAL-VEH rats. (A, B) Asenapine maleate treatment normalized PFC-CPU and PFC-OFC delta coherence. (C) No significant effects on coherence where observed between the OFC and CPU. Data presented is from a 5 min epoch, N = 5–7 rats, 1–2 electrodes/region/rat. Box plots display medians with whiskers representing highest and lowest values. *p < 0.05, **p < 0.01, ***p < 0.001 compared to MAM-VEH rats.
oscillatory patterns in SZ may reflect the heightened ability to improve cognitive deficits in comparison to currently used antipsychotics, although further studies will be required to confirm this. Although AM is FDA approved for the treatment of both SZ and bipolar disorder, to date it is more commonly used to treat bipolar mania. However, cognitive impairment is a symptom of both disorders and thus beneficial electrophysiological changes induced by AM may similarly affect patients with bipolar disorder. Although oscillatory normalization was observed after antipsychotic administration, chronically treated animals not only reversed MAMVEH deficits but often surpassed SAL-VEH power and coherence levels, the impact of which will need to be evaluated in future studies evaluating cognition. Additionally, CLZ significantly worsened OFC and CPU theta (8–9 Hz) power as well as PFC-CPU theta coherence. CLZ administration is associated with a significant adverse effect profile, including seizures, limiting its clinical utilization [29,30]. Interestingly, in a study conducted by Walker [31] patients with epilepsy displayed decreases in EEG theta coherence, however, other studies have reported overall hypersynchrony in relation to seizure [32]. Thus, once further characterized, preclinical electrophysiology studies may not only provide therapeutic indices in regards to improvement of cognitive symptoms, but also the amelioration of common adverse effects.
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5. Conclusion Cognitive symptoms of SZ often manifest before the first psychotic episode, thus providing an opportunity for early therapeutic intervention [33,34]. However, these symptoms are often not prioritized in the search for novel therapeutics despite evidence showing that they play an important role in patient quality of life [35]. With accumulating evidence implicating the role of delta oscillations in mediating the cognitive deficits that exist in SZ, research into the regulation of low frequency oscillations by AM and other antipsychotics is required to further the development of safe and efficacious treatments. Funding sources The funding of the study was supported by the Department of Molecular and Cellular Biology at the University of Guelph, Canada. The funding source had no influence on study design, data analysis, interpretation of results, writing of the manuscript, or the decision to submit the paper for publication. Acknowledgement No acknowledgements to declare. References [1] L. Melloni, C. Molina, M. Pena, D. Torres, W. Singer, E. Rodriguez, Synchronization of neural activity across cortical areas correlates with conscious perception, J. Neurosci. 27 (2007) 2858–2865, https://doi.org/10.1523/JNEUROSCI.4623-06. 2007.
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Research article
Asenapine maleate normalizes low frequency oscillatory deficits in a neurodevelopmental model of schizophrenia Tapia Foute Nelong, Joshua D. Manduca, Paula M. Zonneveld, Melissa L. Perreault
T
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Department of Molecular and Cellular Biology, University of Guelph, Guelph, N1G 2W1 Ontario, Canada
A R T I C LE I N FO
A B S T R A C T
Keywords: Schizophrenia Cognition Neural oscillations Asenapine maleate Haloperidol Clozapine
Asenapine maleate (AM) is an atypical antipsychotic that, unlike many other antipsychotics, shows some efficacy in treating cognitive dysfunction in schizophrenia. Normal cognitive function has long since been associated with high frequency neuronal oscillations. However, recent research has highlighted the potential importance of low frequency oscillations. Here, the impact of AM on low frequency neural oscillatory activity was evaluated in the methylazoxymethanol acetate (MAM) rat model system used for the study schizophrenia, and the oscillatory signatures compared to those of haloperidol (HAL) and clozapine (CLZ). AM and CLZ normalized low frequency spectral power deficits in the prefrontal cortex, while HAL and AM reversed corticostriatal and corticocortical delta coherence deficits. However, only chronic AM administration normalized corticostriatal and corticocortical delta coherence deficits between 3–4 Hz. These findings support the idea that antipsychotic-induced amelioration of both delta coherence and power may be important for therapeutic efficacy in treating the cognitive deficits inherent in schizophrenia.
1. Introduction Cognitive dysfunction is a debilitating symptom of schizophrenia (SZ) that is inadequately treated by currently available antipsychotics, and while the introduction of novel drugs for SZ treatment is ongoing, drugs that are efficacious in treating this symptom of the disorder are as yet unavailable. Oscillatory activity in the gamma frequency band (˜32–100 Hz) has most commonly been associated with cognition due to their known relevance to processes such as working memory and perception [1,2]. More recently, however, research has highlighted the importance of low frequency oscillations, known for facilitating communication between remote brain regions, in cognition [3]. In individuals with SZ, alterations in low frequency oscillations within the frontal cortex have been reported, which likely underlie, at least in part, the cognitive deficits inherent in the disorder. Furthermore, low frequency oscillopathies are the most commonly reported resting-state abnormalities in SZ with aberrant patterns observed in both delta (1–4 Hz) and theta (4–7 Hz) frequency bands [4]. Additionally, disruptions to low frequency functional connectivity is evident in the cortex of patients with SZ [5]. In this regard, the normalization of aberrant low frequency oscillatory signatures within and between cortical regions may offer a strategy for delineating the potential efficacy of novel drugs on improving cognition. This idea is in ⁎
line with reports showing that antipsychotics can improve aberrant oscillatory patterns in SZ patients [6,7] as well as rodent models of SZ [8,9]. This effect is more pronounced with second-generation antipsychotics and is postulated to reflect the increased affinity of these drugs for serotonin receptors over dopamine receptors [9,10]. This may correlate to efficacy in treating cognitive deficits as first-generation antipsychotics such as haloperidol (HAL) have little reported effect on cognition [11,12]. Asenapine maleate (AM) is a promising, well-tolerated, secondgeneration antipsychotic approved for the treatment of bipolar mania and SZ. Apart from treating psychosis in SZ, clinical evidence indicates a therapeutic effect of AM in alleviating cognitive deficits [13]. This finding is supported by preclinical studies using rodent and non-human primate models of SZ which showed therapeutic effects of AM in specific aspects of cognitive function including visual recognition memory and reversal learning [14–16]. The impact of AM on normalizing neural oscillatory dysfunction in SZ, however, remains unknown. This study therefore aims to compare the effects of chronic AM administration on low frequency neural oscillations within the striatum and cortical regions to that of HAL and clozapine (CLZ) using the methylazoxymethanol acetate (MAM) model system of SZ.
Corresponding author. E-mail addresses: [email protected] (T. Foute Nelong), [email protected] (J.D. Manduca), [email protected] (P.M. Zonneveld), [email protected] (M.L. Perreault). https://doi.org/10.1016/j.neulet.2019.134404 Received 10 June 2019; Accepted 25 July 2019 Available online 26 July 2019 0304-3940/ © 2019 Elsevier B.V. All rights reserved.
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2. Materials and methods
2.5. Data analysis
2.1. Animals
MATLAB software in conjunction with routines from the Chronux software package was used to extract individual frequency bands from the LFP data and compare oscillatory synchrony between regions. All data analysis was performed on the last 5 min of the LFP recordings. Mean values from each frequency band for each electrode (6 per rat) were extracted and statically analyzed with IBM SPSS 24 software using a 95% confidence interval. Statistical outliers were removed prior to further analysis. Mean differences between MAM-VEH and SAL-VEH groups were analyzed using independent samples t-tests. Analysis of mean differences between MAM-VEH and drug treated MAM rats was performed using univariate ANOVAs. Group variance was assessed using Levene’s test of homogeneity to determine which post-hoc test, either Tukey’s or Games-Howell, was appropriate for each evaluated interaction.
Pregnant female Sprague-Dawley rats (Charles River, QC) were administered either MAM (20 mg/kg, i.p) or saline (SAL) on gestational day 17 as described previously by Sonnenschein et al. [17]. A 12 h reverse light-dark cycle was maintained in the colony room and rats had access to food and water ad libitum. Experimental procedures began once the male offspring weighed approximately 350 g (˜PND 70). The rats were then separated into 5 experimental groups: MAM-HAL (N = 8), MAM-AM (N = 7), MAM-CLZ (N = 7), MAM-VEH (N = 7) and SAL-VEH (N = 7). All procedures complied with the guidelines described in the Guide to the Care and Use of Experimental Animals (Canadian Council on Animal Care, 1993) and the Animal Care Ethics Committee of the University of Guelph.
3. Results 2.2. Drugs The effects of antipsychotics on low frequency neural oscillations in the MAM model of SZ were evaluated following 14 days of drug administration. A significant effect of treatment on MAM oscillatory power in both the delta and theta frequency bands was observed for each region (PFC-delta: F(348) = 9.397, P < 0.000; PFC-theta: F (347) = 8.220, P < 0.000; OFC-delta: F(346) = 10.595, P < 0.000; OFC-theta: F(348) = 8.549, P < 0.000; CPU-delta: F(349) = 6.098, P = 0.001; CPU-theta: F(348) = 7.757, P < 0.000). Similar effects were observed with CLZ and AM to increase delta and decrease theta power in all three regions (Fig. 1). In the PFC, MAM-VEH rats exhibited decreased delta (P = 0.003) and increased theta power (P = 0.001) compared to controls, an effect normalized by CLZ (P < 0.000) or AM (P = 0.012), but not HAL (Fig. 1C, D). Additionally, analysis of spectral power performed for OFC and CPU oscillations selectively in the theta 8–9 Hz range (Fig. 2) demonstrated a significant effect of treatment (OFC: F(348) = 5.640, P = 0.002; CPU: F(351) = 6.582, P = 0.001). In both the OFC and CPU, the MAM-VEH group exhibited significantly reduced theta oscillations at 8–9 Hz compared to SAL-VEH controls (OFC: P = 0.001, CPU: P = 0.009, Fig. 2). This effect was selectively worsened by chronic CLZ administration (OFC: P = 0.004; CPU: P = 0.017). Analysis of coherence showed that the MAM-VEH group exhibited significantly decreased low frequency delta and theta coherence compared to SAL-VEH rats between all brain regions (All P ≤ 0.002, Fig. 3). A significant effect of treatment on MAM rats in both the delta and theta frequency bands was also evident between the majority of regions (PFCCPU-delta: F(346) = 8.311, P < 0.000; PFC-CPU-theta: F (345) = 15.136, P < 0.000; PFC-OFC-delta: F(343) = 5.495, P = 0.003; PFC-OFC-theta: F(343) = 6.494, P = 0.001; OFC-CPU-delta: F(348) = 5.889, P = 0.002), the exception being OFC-CPU theta coherence (F(348) = 1.815, P = 0.157). Compared to MAM-VEH rats, both AM (P = 0.001) and HAL (P = 0.021) treatment normalized PFCCPU delta coherence deficits and additionally reversed aberrant PFCOFC delta coherence (AM: P = 0.020; HAL: P = 0.002, Fig. 3A–D). Only HAL treatment normalized decreased delta coherence between the OFC and CPU (P = 0.022, Fig. 3E, F). When analysis of coherence was performed for oscillations selectively in the delta 3–4 Hz range a significant effect of treatment was demonstrated (PFC-CPU: F (347) = 7.229, P < 0.000; PFC-OFC: F(345) = 5.325, P = 0.003; OFCCPU: F(349) = 4.891, P = 0.005). AM-treated MAM rats displayed normalized PFC-CPU (P = 0.001) and PFC-OFC (P = 0.015) delta coherence between 3–4 Hz following chronic administration (Fig. 4A, B). CLZ administration had no significant effect on delta coherence compared to MAM-VEH rats, however, was found to exacerbate the PFCCPU theta coherence deficit (Fig. 3A, B). A similar trend was observed with PFC-OFC theta coherence following CLZ administration (Fig. 3C, D).
MAM was purchased from MRI Global (Kansas City, MO). Haloperidol (HAL, Sigma-Aldrich, Oakville, ON) was dissolved in 0.8% glacial acetic acid and subsequently adjusted to pH 6 using 1 N NaOH. Clozapine (CLZ, Sigma-Aldrich, Oakville, ON) was dissolved in 0.5 N acetic acid, brought to the appropriate concentration with 0.5 M sodium acetate (pH 5.0), then adjusted to pH 5 with 1 N NaOH. Asenapine (AM, Sigma-Aldrich, Oakville, ON) was dissolved in 0.9% saline. The rats received doses of HAL, CLZ and AM at 1.0 mg/kg (i.p), 5.0 mg/kg (i.p) and 0.15 mg/kg (i.p) respectively for a total of 14 days. Doses are expressed as free bases. Injections were administered at a volume of 1.0 mL/kg. Dosing and duration of administration was based upon previous investigations evaluating the effects of antipsychotics in animal models of SZ [18–20].
2.3. Electrode implantation surgery Electrode microarrays were designed and constructed in-house using PFA-coated stainless steel wire and polyimide tubing. All arrays used had an electrode impedance of less than 2 Megaohms. Rats were anesthetized with isoflurane (5% induction, 2% maintenance) followed by bilateral electrode implantation into the medial prefrontal cortex (PFC, AP: +3.2, ML: ± 0.6, DV: −3.8), caudate putamen (CPU, AP: +1.9, ML: ± 2.6, DV: −4.4) and lateral orbitofrontal cortex (OFC, AP: +3.2, ML: ± 2.6, DV: −5.5). Thus, a total of 6 recording electrodes were implanted into each rat. Following surgery, rats were housed singly and allowed 10 days for recovery prior to commencing drug administration and electrophysiology recordings (Fig. 1A). Electrode placement was verified post-mortem (Fig. 1B).
2.4. Electrophysiology Local field potentials (LFP) were recorded using a Wireless 2100system (Multi-Channel Systems). 24 h after the final injection rats were placed in Plexiglas boxes (18″ × 18″ × 18″) while LFPs were recorded for 30 min at a sampling rate of 1000 samples/second. The spectral power of LFP oscillations in each region was analyzed using routines from the Chronux (version 2.12 v03) software package for MATLAB (MathWorks). Data analysis was conducted employing a fast Fourier transform with power and coherence analyzed using the powerspectrum.m and coherocyc.m chronux scripts respectively. Recordings were segmented, detrended and low-pass filtered to remove frequencies greater than 100 Hz. Continuous multitaper spectral power for the normalized data (to total spectral power) and coherence was calculated for the delta (1–4 Hz) and theta frequency bands (> 4–12 Hz). 2
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Fig. 1. Differential effects of 14 days of antipsychotic administration on low frequency spectral power in MAM rats. (A) Experimental timeline. (B) Electrode placements in the prefrontal cortex (PFC), orbitofrontal cortex (OFC) and caudate putamen (CPU). (C, D) Power spectrum and quantification of low frequency oscillatory power in the PFC showing normalization of aberrant delta and theta power following asenapine maleate (AM) and clozapine (CLZ) administration. (E–H) No significant changes were observed between MAM-VEH and SAL-VEH rats in the OFC and CPU. All three drugs showed similar effects to increase delta or decrease theta spectral power in these regions. Data presented is from a 5 min epoch, N = 5–7 rats, 1–2 electrodes/region/rat. Curves represent group means. Box plots display medians with whiskers representing highest and lowest values. *p < 0.05, **p < 0.01, ***p < 0.001 compared to MAM-VEH rats.
4. Discussion
between regions pertinent to the neuropathology of SZ. Our findings showing deficits in the delta frequency of MAM rats, a model that exhibits impairments in PFC-dependent cognitive tasks, are consistent with studies showing a relationship between delta wave activity and cognition. For example, it is well established that dopamine D1 receptor signaling plays a positive role in cognitive function [21] with blockade of D1 receptor signaling suppressing medial frontal delta rhythms to impair interval timing performance [22], a process critical to basic cognitive processes [23]. Reduced frontal cortical dopamine signaling is also a hallmark of SZ neuropathology, with reductions in delta oscillations also recently exhibited in SZ patients [24]. Chen and Yang [25] showed that CLZ-induced dopamine release heightens postsynaptic D1 receptor-dependent NMDA receptor function which may
The purpose of this study was to compare the low frequency electrophysiological profile of AM, a well-tolerated antipsychotic with the potential to improve cognitive deficits in SZ, with the antipsychotics HAL and CLZ in the MAM model of SZ. We showed that while CLZ normalized low frequency power in the PFC of MAM rats, and HAL normalized corticocortical and corticostriatal delta coherence, only AM was able to normalize both power and coherence deficits. Additionally, AM treatment improved both PFC-CPU and PFC-OFC delta coherence between 3–4 Hz, an effect not observed with administration of either HAL or CLZ. Thus, these findings indicate a unique effect of AM on low frequency coherence, principally in the delta 3–4 Hz frequency band, 3
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Fig. 2. Effects of antipsychotic administration on oscillatory power between 8–9 Hz. Power spectrum and quantification of low frequency oscillatory power in the (A) orbitofrontal cortex (OFC) and the (B) caudate putamen (CPU). MAM-VEH rats displayed decreased theta power in both regions, an effect exacerbated with clozapine (CLZ) administration. No significant changes were observed with haloperidol (HAL) and asenapine maleate (AM) although a similar trend was observed. Data presented is from a 5 min epoch, N = 5–7 rats, 1–2 electrodes/region/rat. Box plots display medians with whiskers representing highest and lowest values. *p < 0.05, **p < 0.01 compared to MAM-VEH rats.
performance in a cognitive task. In the present study CLZ, an antipsychotic known to have some efficacy in improving cognition in SZ [27], elicited similar effects to AM on PFC power, although a change in delta coherence was not observed with CLZ administration. HAL, an antipsychotic known for having poor effects of cognitive symptoms [11], also elicited similar changes to AM on delta coherence, however only AM was able to normalize PFC-CPU and PFC-OFC delta coherence between 3–4 Hz. In a study by Nácher et al. [28] LFPs recorded from cortical regions in non-human primates performing a somatosensory discrimination task revealed a correlation between delta coherence and decision making, highlighting the potential importance of coherent cortical delta oscillations in executive functioning. Therefore, this unique effect of AM treatment on aberrant
elicit lasting changes to excitatory synaptic transmission in the PFC. Furthermore, in NMDA hypofunction models of SZ, the second generation antipsychotics AM and CLZ restore prefrontal activity and improve cognitive deficits, effects that are abolished when D1 receptor antagonists are introduced [16,26]. Thus, the normalization of prefrontal delta power observed following CLZ and AM in the current study may result, at least in part, through a D1 receptor-mediated mechanism. Additionally, the present findings provide support for the hypothesis that the normalization of aberrant delta function may represent a biomarker of therapeutic efficacy for cognitive symptoms in SZ. This idea is further supported by a study conducted by Parker et al. [24] which showed that delta frequency optogenetic stimulation of lateral cerebellar projection neurons normalized medial frontal activity and
Fig. 3. Differential effects of 14 days of antipsychotic administration on oscillatory coherence in MAM rats. MAM-VEH rats displayed consistently lower delta and theta coherence compared to SAL-VEH rats. (A, B) Asenapine maleate (AM) and haloperidol (HAL) treatment increased PFC-CPU delta coherence compared to MAM-VEH rats while clozapine (CLZ) further decreased MAM-induced theta deficits. (C, D) Normalization of PFC-OFC delta coherence by AM and HAL. (E, F) MAM-VEH rats exhibited suppressed OFC-CPU delta coherence which was normalized following HAL administration. Data presented is from a 5 min epoch, N = 5–7 rats, 1–2 electrodes/region/rat. Curves represent group means. Box plots display medians with whiskers representing highest and lowest values. *p < 0.05, **p < 0.01, ***p < 0.001 compared to MAM-VEH rats.
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Fig. 4. Effects of antipsychotic administration on oscillatory coherence between 3–4 Hz. MAM-VEH rats displayed consistently lower delta coherence compared to SAL-VEH rats. (A, B) Asenapine maleate treatment normalized PFC-CPU and PFC-OFC delta coherence. (C) No significant effects on coherence where observed between the OFC and CPU. Data presented is from a 5 min epoch, N = 5–7 rats, 1–2 electrodes/region/rat. Box plots display medians with whiskers representing highest and lowest values. *p < 0.05, **p < 0.01, ***p < 0.001 compared to MAM-VEH rats.
oscillatory patterns in SZ may reflect the heightened ability to improve cognitive deficits in comparison to currently used antipsychotics, although further studies will be required to confirm this. Although AM is FDA approved for the treatment of both SZ and bipolar disorder, to date it is more commonly used to treat bipolar mania. However, cognitive impairment is a symptom of both disorders and thus beneficial electrophysiological changes induced by AM may similarly affect patients with bipolar disorder. Although oscillatory normalization was observed after antipsychotic administration, chronically treated animals not only reversed MAMVEH deficits but often surpassed SAL-VEH power and coherence levels, the impact of which will need to be evaluated in future studies evaluating cognition. Additionally, CLZ significantly worsened OFC and CPU theta (8–9 Hz) power as well as PFC-CPU theta coherence. CLZ administration is associated with a significant adverse effect profile, including seizures, limiting its clinical utilization [29,30]. Interestingly, in a study conducted by Walker [31] patients with epilepsy displayed decreases in EEG theta coherence, however, other studies have reported overall hypersynchrony in relation to seizure [32]. Thus, once further characterized, preclinical electrophysiology studies may not only provide therapeutic indices in regards to improvement of cognitive symptoms, but also the amelioration of common adverse effects.
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5. Conclusion Cognitive symptoms of SZ often manifest before the first psychotic episode, thus providing an opportunity for early therapeutic intervention [33,34]. However, these symptoms are often not prioritized in the search for novel therapeutics despite evidence showing that they play an important role in patient quality of life [35]. With accumulating evidence implicating the role of delta oscillations in mediating the cognitive deficits that exist in SZ, research into the regulation of low frequency oscillations by AM and other antipsychotics is required to further the development of safe and efficacious treatments. Funding sources The funding of the study was supported by the Department of Molecular and Cellular Biology at the University of Guelph, Canada. The funding source had no influence on study design, data analysis, interpretation of results, writing of the manuscript, or the decision to submit the paper for publication. Acknowledgement No acknowledgements to declare. References [1] L. Melloni, C. Molina, M. Pena, D. Torres, W. Singer, E. Rodriguez, Synchronization of neural activity across cortical areas correlates with conscious perception, J. Neurosci. 27 (2007) 2858–2865, https://doi.org/10.1523/JNEUROSCI.4623-06. 2007.
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