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. 2021 Jan 3;42(5):1341–1353. doi: 10.1007/s10571-020-01020-z

GSK-3β Disrupts Neuronal Oscillatory Function to Inhibit Learning and Memory in Male Rats

Abdalla M Albeely 1,2, Olivia O F Williams 1, Melissa L Perreault 1,2,✉
PMCID: PMC11421759  PMID: 33392916

Abstract

Alterations in glycogen synthase kinase-3β (GSK-3β) activity have been implicated in disorders of cognitive impairment, including Alzheimer’s disease and schizophrenia. Cognitive dysfunction is also characterized by the dysregulation of neuronal oscillatory activity, macroscopic electrical rhythms in brain that are critical to systems communication. A direct functional relationship between GSK-3β and neuronal oscillations has not been elucidated. Therefore, in the present study, using an adeno-associated viral vector containing a persistently active mutant form of GSK-3β, GSK-3β(S9A), the impact of elevated kinase activity in prefrontal cortex (PFC) or ventral hippocampus (vHIP) of rats on neuronal oscillatory activity was evaluated. GSK-3β(S9A)-induced changes in learning and memory were also assessed and the phosphorylation status of tau protein, a substrate of GSK-3β, examined. It was demonstrated that increasing GSK-3β(S9A) activity in either the PFC or vHIP had similar effects on neuronal oscillatory activity, enhancing theta and/or gamma spectral power in one or both regions. Increasing PFC GSK-3β(S9A) activity additionally suppressed high gamma PFC–vHIP coherence. These changes were accompanied by deficits in recognition memory, spatial learning, and/or reversal learning. Elevated pathogenic tau phosphorylation was also evident in regions where GSK-3β(S9A) activity was upregulated. The neurophysiological and learning and memory deficits induced by GSK-3β(S9A) suggest that aberrant GSK-3β signalling may not only play an early role in cognitive decline in Alzheimer’s disease but may also have a more central involvement in disorders of cognitive dysfunction through the regulation of neurophysiological network function.

Keywords: GSK-3β, Tau, Neuronal oscillations, Learning and memory, Prefrontal cortex, Hippocampus

Introduction

Glycogen synthase kinase-3β (GSK-3β) is a serine/threonine kinase with over 100 biological substrates (Sutherland 2011) that has been repeatedly shown to play a critical role in the pathology of various neuropsychiatric and neurodegenerative diseases, and in particular those that present with cognitive impairment (Lovestone et al. 2007; Caracci et al. 2016; Albeely et al. 2018; Jaworski et al. 2019). Whereas a decrease in GSK-3β activity has been implicated in autism (Onore C, Yang H, Van de Water J, Ashwood P 2017; Wu et al. 2017; Zhang et al. 2017), most other disorders associated with cognitive impairment are linked with elevated activation of the kinase, the most widely studied being Alzheimer’s disease (AD) (Takashima 2006; Medina and Avila 2014; Albeely et al. 2018; Manduca et al. 2020).

GSK-3β expression and/or activity levels are elevated in the ventral hippocampus (vHIP) and prefrontal cortex (PFC) of patients with AD (Blalock et al. 2003; Leroy et al. 2007; DaRocha-Souto et al. 2012), and this finding is mimicked in AD animal model systems (Terwel et al. 2008; Serenó et al. 2009). This elevation in GSK-3β activity results in the hyperphosphorylation of tau protein, the formation of soluble oligomeric tau species, and the eventual deposition of neurofibrillary tangles (NFTs), a major neuropathological hallmark of AD (Albeely et al. 2018). It is the soluble oligomeric species of tau that are believed to play a critical role in mediating the cognitive deficiencies observed in the disorder (Oddo et al. 2006; Koss et al. 2016). In other disorders of cognitive dysfunction, however, the presence of GSK-3β-induced tau hyperphosphorylation in brain and the impact on learning and memory processes has received much less attention. Further, in the absence of tau pathology, there is also the question as to whether elevated GSK-3β activity and cognitive decline may be linked through some additional mechanism. Indeed, GSK-3β has been shown to play a pivotal role in synaptic plasticity (Peineau et al. 2007, 2008; Bradley et al. 2012) suggesting a potential critical role for protein in the regulation of systems function.

Another functional marker associated with cognitive impairment is the dysregulation of neuronal oscillatory activity. Neuronal oscillations are synchronous macroscopic electrical rhythms in the nervous system that are generated through summed neuronal population activity, and which play a critical role in brain systems communication (Fries 2005; Lisman and Jensen 2013). Specifically, whereas low-frequency oscillations are believed to be important in long-range communication between different brain regions, high-frequency activity is more restricted to short-range communication (Von Stein and Sarnthein 2000; Schnitzler and Gross, 2005). Both low-frequency theta oscillations and high-frequency gamma oscillations in vHIP and cortical regions have been repeatedly linked to learning and memory processes (Blalock et al. 2003; Canolty et al. 2006; Paz et al. 2008; O’Neill et al. 2013; Bosman et al. 2014; Kaplan et al. 2014; Backus et al. 2016). For example, in the vHIP, theta oscillations have been shown to play a significant role in the encoding of new memories possibly through facilitating interactions with other brain regions such as PFC (Colgin 2011; Backus et al. 2016), whereas gamma oscillations are key to memory encoding and retrieval (Colgin and Moser 2010). Gamma oscillations in the cortical regions have also been linked to higher executive functions including attention, visual processing, memory, and learning (Fries 2009; Bosman et al. 2014). Thus, it is not surprising that deficits in oscillatory activity in both the vHIP and PFC have been associated with cognitive decline both in ageing (Rondina et al. 2016, 2019) as well as in various disease states such as schizophrenia (Uhlhaas and Singer 2010; Gonzalez-Burgos et al. 2015; Senkowski and Gallinat 2015), autism (Kessler et al. 2016), as well as AD (Palop and Mucke 2016; Başar et al. 2017; Goodman et al. 2018; Mably and Colgin 2018).

The consistent demonstration of elevated GSK-3β activity in disorders of cognitive impairment, coincident with alterations in neuronal oscillatory function, suggests a potential coupling of the two mechanisms. Indeed, this idea is supported by our previous evidence showing that the systemic and short-term pharmacological inhibition of GSK-3β in rats altered neuronal oscillatory patterns within the PFC and vHIP that were associated with improved learning and memory (Nguyen et al. 2018). This study sought to expand on those findings to evaluate a direct role for GSK-3β within the PFC or vHIP in the regulation of neuronal oscillatory activity and learning and memory processes. Using a persistently active mutant of GSK-3β(S9A) we showed that elevated kinase activity in either region resulted in increased theta and high gamma frequency spectral power with discrete effects in high gamma coherence, changes associated with disruptions in memory and learning. Further, pathogenic tau phosphorylation was elevated in response to these manipulations.

Materials and Methods

Animals

Forty adult male Sprague Dawley rats (Charles River, Quebec, Canada) weighing approximately 350–400 g, and approximately 6 weeks of age on arrival, were randomly assigned to one of four experimental groups. Final numbers were 8–10 rats/group. Male rats were chosen as the goal of the study was to evaluate whether increasing GSK-3β activity could drive changes in systems function to impact behaviour, which could be accomplished in one sex. Rats were pair-housed in polypropylene cages until surgery after which they were housed singly. Both the housing room and experimental room were kept on a reverse 12-h light/dark cycle. As a result of the duration of the study, rats were food restricted, receiving 15 g of 18% chow per day to maintain weights. They were handled for five days, five minutes per day, before the beginning of the experiments. 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 Committee at the University of Guelph.

Constructs

AAV8-hSYN1-GSK-3β(S9A)-HA-WPRE and AAV8-hSYN1-HA-WPRE viruses were generated by Vector Biolabs (Malvern, PA). Construct size restrictions for the AAV required the use of an HA tag to evaluate expression levels. The GSK-3β(S9A) pcDNA3 construct was a gift from Jim Woodgett (Addgene plasmid #14,754; http://n2t.net/addgene:14754; RRID:Addgene_14754) (Stambolic and Woodget, 1994). The constitutively active GSK-3β(S9A) was generated by a point mutation in serine 9 converting it to adenine, thus preventing Akt-mediated phosphorylation and inhibition of GSK-3β.

Surgery

The current study targeted the vHIP because of its known involvement in working and social memory (Wilkerson and Levin 1999; Okuyama et al. 2016) and the reported importance of vHIP-PFC theta synchrony in spatial working memory (O’Neill et al. 2013). Rats underwent stereotaxic surgery to introduce the AAV8-hSYN1-GSK-3β(S9A)-HA-WPRE or control virus bilaterally into the prelimbic region of PFC or vHIP. Isoflurane was used to anesthetize the rats at 5% induction and 2.5% maintenance and body temperature maintained at 37οC using a thermostat-regulated heating pad. Animals were injected subcutaneously with 0.9% saline (3 mL) to ensure adequate hydration during surgeries, and 5 mg/ml carprofen (0.4 mL, s.c.) as well as a lidocaine/bupivacaine injection at the incision site. Injection coordinates for the PFC (AP + 3.24, ML ± 0.6, DV 3.5) or vHIP (AP -5.5, ML ± 5.1, DV 7.6 & 5.6) were obtained from Paxinos and Watson (2013). AAV was infused at a rate of 0.3 μl/min and syringes were removed 5 min post injection to avoid backflow of the virus to the surface of the skull. Four weeks following the AAV infusion surgery all rats underwent a second surgery to implant single unipolar electrodes bilaterally into both the PFC and vHIP. In the region where the AAV was infused, the electrodes were implanted at the same coordinates. Custom electrode microarrays were built using pre-fabricated Delrin templates and polyimide-insulated stainless-steel wires (A-M Systems: 791,600, 0.008″). All arrays used had an electrode impedance of less than 2MΩ. Local field potential (LFP) recordings were collected and placements verified at the end of the study. Following the second surgery final numbers for each group were intra-PFC GSK-3β(S9A) (n = 10), intra-PFC control (n = 9), intra-vHIP GSK-3β(S9A) (n = 8), and intra-vHIP control (n = 10).

Electrophysiology

Four days post electrode implantation surgery, animals began four days of habituation to the transparent plexiglass recording chambers (45 cm x 45 cm x 45 cm) as well as open-field arena (5 min per day). Following habituation, LFP recordings were taken from freely moving animals for 30 min using a wireless W2100 system (MultiChannel Systems), a sampling frequency of 1000 Hz. The spectral power of LFP oscillations in each region, coherence between regions, and cross-correlation analysis was performed using routines from the Chronux software package for MATLAB (MathWorks). Five-minute epochs were used, with epochs segmented, detrended, de-noised, and low-pass filtered to remove high frequencies greater than 100 Hz. Continuous multitaper spectral power (normalized to total power) and coherence (tapers = [5 9]) between regions were calculated for each segment in the following frequency bands: delta (1–4 Hz), theta (> 4–12 Hz), beta (> 12–32 Hz), slow gamma (> 32–60 Hz), and fast gamma (> 60–100 Hz). Electrode placements were verified post mortem.

Behavioural Tests

Animals underwent three different tests in the open-field arena (1 m2), one test daily over three consecutive days, that included the Novel Object Recognition task (NOR), Object Location (OL), and Object in Place test (OiP). The discrimination ratio was used as the output variable for these tests which was calculated as the difference between the time spent exploring the novel object/location and familiar object/location divided by the total object exploration time. Animals also underwent tests for spatial memory and reversal learning in the T-maze. To avoid any experimental bias, experimenters were blinded to the treatment groups. All tests were recorded using AnyMaze software (Stoelting Co.)

Novel Object Recognition

The NOR task was used to evaluate recognition memory, and comprised a 4-min acquisition phase and a 3-min test phase that were separated by a 2-h delay (Barker and Warburton 2011). Rats were allowed to explore two identical objects placed in two corners of the arena. During the delay period, two clean objects were placed in the same locales as used during the acquisition phase, however, one of the objects was switched with a novel object. Object types were randomized, and positions counterbalanced between rats. The time spent exploring each object was measured and the discrimination ratio was calculated.

Object Location

To evaluate spatial memory, the OL task was composed of an acquisition phase and a test phase, 3 min in length each, separated by 5-min delay (Barker and Warburton 2011). In the acquisition phase, rats explored two similar objects placed in two corners of the arena. Objects were cleaned during the delay period after which, for the testing phase, one object was relocated to opposite corner from which it was originally placed. The position of the objects was counterbalanced between animals. The time spent exploring each object was measured and the discrimination ratio was calculated.

Object in Place

The OiP task, used to test associative object recognition memory, requires coordinated PFC and vHIP communication (Barker and Warburton 2011), and was performed as previously described (Mitchnick et al. 2014, 2019). The task was composed of two phases, an acquisition phase as well as a test phase separated by a 20-min delay. During the acquisition phase, animals were placed in the open field and allowed to explore four different objects, one in each corner, for 5 min. In the test phase, the position of two of the objects were switched (right or left counterbalanced) such that a “novel” side was created. Rats were then allowed 2 min to investigate the objects. The time spent exploring the objects in the changed positions was compared to the time spent exploring the objects in the original positions. The time spent exploring objects on each of the two sides was measured and the discrimination ratio was calculated.

Reversal Learning

This test was composed of a 4-day training phase followed by a test to assess reversal learning on the fifth day. Prior to testing, animals were habituated to the T-maze for 4 days by raising all doors and baiting both food wells. The training phase lasted for four days during which the animals needed to learn the location of the food that was placed in one of the two maze arms. Animals received four trials daily with a minimum of 10 min between each trial. The time required to reach the food was recorded, and on the last day was used to calculate the cut-off time for the reversal testing phase (3 s). The reversal learning procedure was performed as described (Annett et al. 1989) with minor modifications. In the reversal learning test (day 5), the food was placed in the opposite maze arm from day 4 and the number of attempts required to reach the food within the cut-off time and in three consecutive attempts was recorded.

Immunohistochemistry

Following the behavioural tests, rats were perfused using 4% PFA and brain tissues were extracted, frozen, and stored in the -80 degrees Celsius. Fluorescence immunohistochemistry was performed as done previously (Perreault et al. 2016) on PFA-fixed free-floating brain Sections (30 µm). Free-floating sections were first washed in TBS (60.5 mM Tris, 87.6 mM NaCl ph 7.6), then blocked for 2 h (10% goat serum, 1% BSA, 0.2% Triton-X, 1X TBS), and incubated with rabbit anti-GSK3β (catalogue #12,456, 1:200, Cell Signalling), rabbit anti-HA (catalogue #ab9110, 1:200, Abcam), and mouse anti-phospho tau (AT8) (catalogue #MN1020, 1:200, Thermo Scientific) primary antibodies for 60 h at 4 ºC. For the anti-phospho tau incubation, an adjacent slice was used. Following the primary antibody incubation, sections were washed in TBS, blocked (5% goat serum, 0.5% BSA, 0.01% Triton-X, 1X TBS), and incubated in anti-mouse-Alexa 488 and/or anti-rabbit Alexa 594 secondary antibodies for 2 h. Brain slices were then washed three times in TBS and mounted on slides using Prolong Gold (Thermo Fisher Scientific). Fluorescence microscopy (Etaluma Lumascope) was used to evaluate construct expression in the PFC and vHIP.

Data Analysis

For LFP data, power and coherence curves are presented as normalized data with jackknife estimates of SEM. Data were log-transformed to better exhibit group differences as indicated. Quantification of the LFP power and coherence data at each frequency measure are reported as means ± SEM and may be expressed as percent change from baseline. LFP data analysis was performed using student’s t test. Data analyses for the IHC and behaviours were performed using student’s t test, with the exception of the T-maze training where a repeated measures ANOVA was used, followed by student’s t test for comparisons at each day of training. Prior to all analyses, normality was assessed using the Shapiro–Wilk test and Levene’s test for equality of variance. Outliers in the electrophysiological data were removed if they were greater than 2SD outside of the mean and are indicated by the t-values. No behavioural data were removed. Sample sizes were chosen using previously generated behavioural data in an online sample size calculator. Computations were performed using SPSS 24 software.

Results

To determine the effect of increased PFC GSK-3β(S9A) activity on neuronal oscillatory activity recorded from PFC and vHIP, LFP recordings from both regions were simultaneously acquired in awake, freely moving animals that received an AAV infusion incorporating a persistently active GSK-3β mutant, GSK-3β(S9A), or control vector. The experimental timeline is depicted in Fig. 1a. Analysis of PFC spectral power showed a significant elevation selectively in PFC theta power in the GSK-3β(S9A) rats compared to controls (t(33) = 2.57, p = 0.014) (Fig. 1b,c). No significant differences in PFC delta, beta, low gamma, or high gamma power were observed. In vHIP, the GSK-3β(S9A) animals exhibited elevated low (t(33) = 2.78, p = 0.009) and high gamma power (t(33) = 2.22, p = 0.034), with no effects in any of the other frequencies (Fig. 1d,e). Analysis of the coherence between the PFC and vHIP regions revealed changes selectively within the high gamma frequency, with reduced PFC–vHIP high gamma in the PFC GSK-3β(S9A) rats (t(33) = 2.66, p = 0.014) (Fig. 1f,g). There were no significant differences in PFC–vHIP coherence in any of the other frequencies. Cross-correlation analysis was next performed to determine the impact of PFC GSK-3β(S9A) administration on the temporal relationship between vHIP theta and PFC gamma cycles, a relationship known to be critical to normal cognitive functioning (Palop and Mucke, 2016). We found no significant time shifts in theta-gamma coupling, although increased PFC GSK-3β(S9A) activity enhanced the coupling strength (Fig. 1h).

Fig. 1.

Fig. 1

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Effect of elevated PFC GSK-3β(S9A) activity on neuronal oscillatory activity in rats. a The experimental timeline is shown. b Power spectrum showing changes in low and high-frequency oscillatory power in PFC in response to increased PFC GSK-3β(S9A) activity. c Quantification of PFC power spectrum showing increased theta power. d Power spectrum showing changes in low and high-frequency oscillatory power in vHIP in response to increased PFC GSK-3β(S9A) activity. e Quantification of vHIP power spectrum showing increased low and high gamma power. f, g Increased PFC GSK-3β(S9A) suppressed PFC–vHIP high gamma coherence. h Increased vHIP theta-PFC gamma coupling with no effect on the temporal relationship of the two frequency bands. Power and coherence curves are presented as normalized data with jackknife estimates of SEM shown as shaded areas. n = 9–10 rats/group, 1–2 electrodes/rat. *p < 0.05, **p < 0.01, student’s t test

The effects of GSK-3β(S9A) administration on cognition were next evaluated in a variety of behavioural tests for recognition memory, spatial memory, and reversal learning. In the NOR task, used to assess recognition memory, animals with elevated GSK-3β(S9A) activity in the PFC exhibited deficits, spending less time exploring a novel object than control animals (t(17) = 2.42, p = 0.027) (Fig. 2a). In the OL task for spatial memory, the GSK-3β(S9A) rats also showed impaired ability to discriminate between the moved object and stationary object (t(17) = 2.90, p = 0.010) (Fig. 2b). The OiP task requires the rats to make an association between an object and the place in which it was previously encountered. In this task, there were no significant group differences (Fig. 2c). For cognitive flexibility, we evaluated the animals during a reversal learning task. Over the course of four days, all of the rats were able to learn the location of the food reward (Fig. 2d, left panel). However, when the treat was shifted to the opposite arm of the T-maze, a deficit in the GSK-3β(S9A) rats was observed, with animals requiring significantly more trials to ascertain the location of the food reward (t(17) = 2.76, p = 0.013) (Fig. 2d, right panel). Following the study the brains were removed, and immunohistochemistry performed to visualize expression of GSK-3β(S9A), and determine whether increased GSK-3β(S9A) activity induced pathogenic tau phosphorylation (Fig. 2e,f). We determined that increased GSK-3β(S9A) activity resulted in a significant elevation in pathogenic tau phosphorylation in PFC (t(8) = 8.8, p < 0.001) (p < 0.001) (Fig. 2g).

Fig. 2.

Fig. 2

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Increased GSK-3β(S9A) activity in PFC induces deficits in learning and memory. a, b Elevated GSK-3β activation in PFC induced deficits in object recognition in the NOR test, but not in associative recognition memory when tested in the OiP. c Deficits in spatial memory in the OL test were also evident. d In the T-maze, both groups learned the location of the treat (left panel), with PFC GSK-3β(S9A) rats requiring more trials to learn the new location of the treat in a reversal learning test (right panel). e Representative immunohistochemistry images showing AAV-induced expression of the HA tag concomitant with increased expression of GSK-3β in the PFC. f Representative image showing tau hyperphosphorylation in response to increased GSK-3β(S9A) (left panel). Magnified area of the box is also shown (right panel). g Quantification of fluorescence showing increased tau AT8 phosphorylation in PFC by GSK-3β(S9A) n = 9 rats/group. *p < 0.05, **p < 0.01, ***p < 0.001 student’s t test

The effect of AAV-mediated vHIP GSK-3β(S9A) activity on neuronal oscillatory activity recorded from the PFC and vHIP was next evaluated. Increased activity of GSK-3β(S9A) in the vHIP region increased theta power in the PFC in comparison to the control group (t(27) = 3.43, p = 0.009) (Fig. 3a,b). These changes were accompanied by an increase in beta power (t(27) = 2.19, p = 0.037) and high gamma power (t(27) = 2.87, p = 0.008), with no significant changes observed in the delta or low gamma bands (Fig. 3a,b). In vHIP, increased GSK-3β(S9A) activity led to an increase in theta power (t(27) = 2.82, p = 0.030) and in high gamma power (t(27) = 2.49, p = 0.040) with no changes in the other frequency bands (Fig. 3c,d). No vHIP GSK-3β(S9A)-induced changes in PFC–vHIP coherence were evident (Fig. 3e,f). Cross-correlation analysis showed that increased vHIP GSK-3β(S9A) activity had no effect on the timing of theta-gamma coupling, however, in contrast to that observed when PFC GSK-3β(S9A) activity was increased, the coupling strength was reduced (Fig. 3g).

Fig. 3.

Fig. 3

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Effect of increased vHIP GSK-3β activity on neuronal oscillatory activity in rats. a Power spectrum showing changes in low and high-frequency oscillatory power in PFC in response to increased vHIP GSK-3β activity. b Quantification of PFC power spectrum showing increased theta power, beta power, and high gamma power. c Power spectrum from vHIP displaying alterations in low and high-frequency oscillatory power. d Quantification of vHIP power spectrum with increased theta power and high gamma power is shown. e, f There were no group differences in PFC–vHIP coherence. g There was a reduction in vHIP theta-PFC gamma coupling with no effect on the temporal relationship of the two frequency bands. Power and coherence curves are presented as normalized data with jackknife estimates of SEM shown as shaded areas. n = 8–10 rats/group, 1–2 electrodes/rat. *p < 0.05, **p < 0.01, student’s t test

In tests to evaluate cognition, increased GSK-3β(S9A) activity in the vHIP resulted in disruptions in recognition memory, whereby the GSK-3β(S9A) rats showed a lower discrimination ratio in the NOR task (t(16) = 2.52, p = 0.048) (Fig. 4a). In the OL task, there were no significant group differences (Fig. 4b). However, in the OiP task, there was a significant deficit in associative recognition memory in the GSK-3β(S9A) rats (t(16) = 3.43, p = 0.003) (Fig. 4c). In the T-maze, there was a significant effect of Treatment such that increased vHIP GSK-3β(S9A) activity reduced the animal’s ability to learn the location of the treat (F(1, 14) = 7.86, p = 0.014) (Fig. 4d, left panel). During reversal learning, when the treat was moved to the opposite arm of the maze, the GSK-3β(S9A) rats showed a deficit, requiring significantly more trials to learn the treat location (t(16) = 2.98, p = 0.009) (Fig. 4d, right panel). Following the behavioural tests, immunohistochemistry analysis showed increased vHIP GSK-3β(S9A) expression (Fig. 4e) that was concomitant with increased phosphorylation of tau protein (t(7) = 9.0, p < 0.001) (Fig. 4f,g).

Fig. 4.

Fig. 4

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Increased vHIP GSK-3β activity induces deficits in learning and memory. a, b Increased vHIP GSK-3β activity induced deficits in object recognition and associative recognition in the OiP test. c No effects were observed in spatial memory in the OL test. d In the T-maze, increased vHIP GSK-3β activity inhibited spatial learning, with those rats taking longer to learn the location of the treat on days 1 and 2 of training (F(1, 14) = 7.86, p = 0.014, repeated measures ANOVA) (left panel). vHIP GSK-3β rats showed also exhibit a deficit in reversal learning, requiring more trials to learn the treat location (right panel). e Representative immunohistochemistry images showing AAV-induced expression of the HA tag concomitant with increased expression of GSK-3β in the vHIP. f Representative image showing tau hyperphosphorylation in response to increased GSK-3β (left panel). Magnified area of the box is also shown (right panel). g Quantification of fluorescence showing increased tau AT8 phosphorylation in vHIP by GSK-3β(S9A) n = 8 rats/group. *p < 0.05, **p < 0.01, ***p < 0.001 student’s t test

Discussion

In the present study, the impact of an AAV-induced increase in GSK-3β(S9A) activity within the PFC or vHIP on neuronal oscillatory activity, learning and memory, and pathogenic AT8 tau phosphorylation was evaluated. It was demonstrated that increasing GSK-3β activity, through the use of a persistently active mutant, GSK-3β(S9A), in either region altered neuronal oscillations particularly in the theta and gamma frequencies and was sufficient to induce pathogenic tau phosphorylation. These oscillatory changes were accompanied by deficits in recognition memory, spatial memory, and reversal learning.

The present findings showed that increasing GSK-3β(S9A) selectively in PFC or in vHIP elevated theta and gamma spectral power in one or both of the regions. Both frequencies have been linked with working memory as well as episodic memory, encoding and retrieval, by facilitating the interaction between the HIP and frontal cortex (Nyhus and Curran 2010; Tamura et al. 2017). Moreover, alterations in theta and gamma frequencies have been associated with deficits in working memory in neuropsychiatric disorders including AD, schizophrenia, and autism (Basar-Eroglu et al. 2007; Barr et al. 2010; Larrain-Valenzuela et al. 2017; Goodman et al. 2018). Our findings are consistent with previous reports examining oscillatory dysfunction in AD and schizophrenia, two disorders that also present with increased expression and activity of vHIP and/or cortical GSK-3β (Lovestone et al. 2007; Albeely et al. 2018; Jaworski et al. 2019). For example, enhanced resting state and evoked gamma power has also been reported for both AD and schizophrenia (Van Deursen et al. 2008; Díez et al. 2014; Wang et al. 2017; Grent-’t-jong T 2018), with increased high gamma activity in schizophrenia inversely associated with cognitive performance both in patients and their first-degree relatives (Díez et al. 2014). Electroencephalogram (EEG) studies have also demonstrated that persons with AD or schizophrenia exhibited heightened global theta power (Musaeus et al. 2018; Newson and Thiagarajan 2018). Of importance, elevated theta power in the HIP of 3xTg AD mice correlated with tau hyperphosphorylation (Móndragon-Rodríguez et al. 2018) and a transgenic murine AD model overexpressing the A152T variant of human tau showed heightened cortical delta and theta oscillatory power (Das et al. 2018), findings that together implicate a direct role for tau phosphorylation in the regulation of oscillatory function. In a murine model of fragile X syndrome, a disorder also characterized by elevated GSK-3β activity and cognitive impairment (Mines and Jope 2011; Franklin et al. 2014), elevated vHIP theta was also evident (Arbab et al. 2018) and in autistic youth, there is a higher relative EEG theta power (Chan and Leung 2006; Coben et al. 2008). These clinical findings are supported by magnetoencephalography, which demonstrated region-specific elevations in theta and gamma power in children with autism (Cornew et al. 2012), results which reflect a similar trend to that observed in AD (Wang et al. 2017; Musaeus et al. 2018). It is noteworthy that although GSK-3β has recently emerged as a potential signalling hub in autism (Caracci et al. 2016), evidence indicates kinase activity, unlike in AD, may actually be downregulated (Onore C, Yang H, Van de Water J, Ashwood P 2017; Wu et al. 2017; Zhang et al. 2017). This raises the possibility that GSK-3β may play a more homeostatic role in brain systems function, with aberrant up or downregulation in activity having consequent negative effects on cognitive performance. This would also suggest, however, that GSK-3β would have additional regulatory control over oscillatory function that is independent of its actions at tau protein.

With the exception of AD, few studies have examined a role for tau hyperphosphorylation in disorders of cognitive dysfunction. A link between GSK-3β, tau, and disrupted reelin signalling in schizophrenia has been proposed (Deutsch et al. 2006) and, more recently, GSK-3β-mediated tau phosphorylation was shown to underlie cognitive deficits in an animal model system of type 2 diabetes (Dey et al. 2017). Another preclinical study showed enhanced GSK-3β activation and tau phosphorylation-mediated early-onset cognitive dysfunction after traumatic brain injury in mice (Zhao et al. 2017). Clearly more research is required to discern a role for tau protein phosphorylation in oscillatory systems processes, however, other potential mechanisms by which GSK-3β may influence neuronal oscillations should also be considered (Manduca et al. 2020). For instance, GSK-3β regulates the activity of voltage-gated ion channels such as sodium (James et al. 2015; Scala et al. 2018), potassium (Borsotto et al. 2007; Scala et al. 2015), and calcium channels (Zhu et al. 2010) and irregular expression and/or function of various channels have been linked to schizophrenia (Georgiev et al. 2014; Nanou and Catterall 2018; Rees et al. 2019), AD (Coon et al. 1999; Kim et al. 2007; Verret et al. 2012; Frazzini et al. 2016), as well as with aberrant gamma oscillations (Llinás et al. 2007; Kezunovic et al. 2011; Verret et al. 2012). Ligand-gated ion channels, critical to neuronal plasticity and long-term potentiation, and functionally relevant to cognitive disorders including AD (Jurado 2018; Liu et al. 2019) and schizophrenia (Barkus et al. 2014; Hardingham and Do 2016), are also regulated by GSK-3β. GSK-3β forms a complex with the GluA1 and GluA2 subunits of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor in rat vHIP (Peineau et al. 2007), and phosphorylates accessory proteins associated with AMPA receptor mobilization and removal from the plasma membrane (Wei et al. 2010; Yagishita et al. 2015; Beurel et al. 2016). Similarly, GSK-3β plays a critical role in N-methyl-D-aspartate (NMDA) receptor-dependent plasticity, with its activity determining whether NMDA receptor activation induces, or inhibits, long-term depression (Peineau et al. 2007). β-catenin, perhaps the most a well-known substrate of GSK-3β, has also been implicated in both AD (Boonen et al. 2009) and schizophrenia (Hoseth et al. 2018). Some evidence also suggests that GSK-3β can also inhibit brain-derived neurotrophic factor signalling (Mai et al. 2002; Yasuda et al. 2009), a protein widely known to play a pivotal role in cognition (Kowiański et al. 2018).

The overall purpose of this study was to demonstrate whether changes in GSK-3β activity in select regions could drive changes in systems function, and we showed that these two processes are intimately connected. That increased GSK-3β(S9A) activity in PFC or vHIP could dysregulate neuronal oscillatory patterns and induce learning and memory deficits suggests that this protein may not only play a more prominent role in the early cognitive deficits associated with AD, but may also have a more widespread and functionally relevant involvement in regulating systems activity in disorders of cognitive dysfunction. It is important to highlight, however, that sex differences were not assessed and therefore it is possible that the neuronal oscillatory changes observed herein may differ in female subjects. More research into the mechanisms by which GSK-3β regulates oscillatory systems function in both male and female subjects, via tau-dependent and independent processes, will provide fundamental information on its role in cognition.

Author Contributions

AA performed the experiments, analysed the data, and assisted writing the manuscript. OW assisted performing experiments. MP designed the study, assisted with the data analysis, and contributed to writing the manuscript. All authors read and approved the final manuscript.

Funding

This work was supported by grants from the Natural Sciences and Engineering Research Council of Canada (#401359) and the Weston Family Foundation (to MLP).

Data Availability

The datasets used and/or analysed during the current study are available from the corresponding author upon reasonable request.

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no competing interests.

Ethical Approval

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 Committee at the University of Guelph.

Footnotes

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The datasets used and/or analysed during the current study are available from the corresponding author upon reasonable request.

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