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. 2020 Sep;27(9):346–354. doi: 10.1101/lm.051201.119

Evaluation of a TrkB agonist on spatial and motor learning in the Ube3a mouse model of Angelman syndrome

Maria N Schultz 1, Jacqueline N Crawley 1
PMCID: PMC7433657  PMID: 32817301

Abstract

Angelman syndrome is a rare neurodevelopmental disorder caused by a mutation in the maternal allele of the gene Ube3a. The primary symptoms of Angelman syndrome are severe cognitive deficits, impaired motor functions, and speech disabilities. Analogous phenotypes have been detected in young adult Ube3a mice. Here, we investigate cognitive phenotypes of Ube3a mice as compared to wild-type littermate controls at an older adult age. Water maze spatial learning, swim speed, and rotarod motor coordination and balance were impaired at 6 mo of age, as predicted. Based on previous findings of reduced brain-derived neurotrophic factor in Ube3a mice, a novel therapeutic target, the TrkB agonist 7,8-DHF, was interrogated. Semichronic daily treatment with 7,8-DHF, 5 mg/kg i.p., did not significantly improve the impairments in performance during the acquisition of the water maze hidden platform location in Ube3a mice, after training with either massed or spaced trials, and had no effect on the swim speed and rotarod deficits. Robust behavioral phenotypes in middle-aged Ube3a mice appear to result from continued motor decline. Our results suggest that motor deficits could offer useful outcome measures for preclinical testing of many pharmacological targets, with the goal of reducing symptoms in adults with Angelman syndrome.

Angelman syndrome is a rare genetic neurodevelopmental disorder with a prevalence of approximately 1:15,000 births (Wheeler et al. 2017). Symptoms include severe intellectual disabilities, impaired speech, developmental delays, microcephaly, seizures, anxiety, motor dysfunctions, ataxic gait, social communication deficits, and a happy demeanor with excessive laughter (Angelman 1965; Williams et al. 2010; Bird 2014; Wheeler et al. 2017; den Bakker et al. 2018; www.angelman.org). The genetic cause of Angelman syndrome resides in a deletion at chromosomal locus 15q11–q13 (Khatri and Man 2019). Imprinted loss of the gene UBE3A within the locus, leading to reduced expression of the UBE3A ubiquitin ligase protein, is central to the disorder. Maternal transmission of the deletion results in Angelman syndrome. Paternal transmission of the deletion results in another distinct neurodevelopmental disorder, Prader–Willi syndrome (Knoll et al. 1989; Nicholls 1993; Buiting et al. 2016). Currently, no medical treatments have been approved for treating the biological causes of Angelman syndrome.

Mouse models have been generated which incorporate the loss of maternal Ube3a and display behavioral features relevant to the symptoms of Angelman syndrome, including cognitive and motor deficits (Jiang et al. 1999, 2010; Heck et al. 2008; Mabb et al. 2011; Baudry et al. 2012; Jana 2012; Kaphzan et al. 2012; Huang et al. 2013; Santini et al. 2015; Leach and Crawley 2018; Sonzogni et al. 2018). Ube3a mutant mouse models provide preclinical research tools which are advancing therapeutic discovery (van Woerden et al. 2007; Huang et al. 2011; Egawa et al. 2012; Margolis et al. 2015; Beaudet and Meng 2016; Bi et al. 2016; Tan and Bird 2016; Ciarlone et al. 2017; Stoppel and Anderson 2017; Guzzetti et al. 2018; Lee et al. 2018; Rotaru et al. 2018; Liu et al. 2019; Rayi et al. 2019; Zylka 2020).

Angelman syndrome is a lifetime disorder. Symptoms persist across the adult lifespan (Smith 2001; Larson et al. 2015; Prasad et al. 2018). In contrast, most behavioral characterizations of Ube3a mutant mouse phenotypes have used young mice, in the 8–14 wk old range, paralleling the early stages of this neurodevelopmental disorder. Deficits have been consistently reported at younger ages on motor assays including rotarod (Miura et al. 2002; Heck et al. 2008; Jiang et al. 2010; Daily et al. 2011; Egawa et al. 2012; Huang et al. 2013; Ciarlone et al. 2017; Leach and Crawley 2018; Sonzogni et al. 2018) and open field exploratory locomotion (Allensworth et al. 2011; Huang et al. 2013; Ciarlone et al. 2017; Sonzogni et al. 2018). Additional phenotypes reported for Ube3a mice at younger ages include anxiety-related behaviors (Jiang et al. 2010; Ciarlone et al. 2017), impaired water maze spatial learning (Miura et al. 2002; Jiang et al. 2010; Huang et al. 2013; Leach and Crawley 2018) with slower swim speeds in some genetic backgrounds (Huang et al. 2013; Leach and Crawley 2018), and impaired fear-conditioned learning and memory (Miura et al. 2002; Jiang et al. 2010; Huang et al. 2013). To our knowledge, there is only one report describing behaviors in older ages of Ube3a mice (Huang et al. 2013). Here, we focus on 6-mo-old Ube3a mice and their wild-type (WT) controls.

Several pharmacological interventions have been reported to reverse Angelman-relevant phenotypes, using young Ube3a mice at 6–14 wks of age. Effective treatments included the ErbB inhibitor PD158780 (Kaphzan et al. 2012), ampakine CX929 (Baudry et al. 2012), serotonin transporter inhibitor fluoxetine (Godavarthi et al. 2014), GABA-A receptor modulator ganaxolone (Ciarlone et al. 2017), HDAC inhibitor sodium valproate (Jamal et al. 2017), mTOR inhibitor rapamycin (Sun et al. 2015), mTORC2 activation (Sun et al. 2016), mitochondrial CoQ10 antioxidant (Llewellyn et al. 2015), ketone ester dietary supplementation (Ciarlone et al. 2016), and the inhibitory amino acid taurine (Guzzetti et al. 2018). Preclinically effective genetic manipulations have been reported, including the introduction of a mutation at the inhibitory phosphorylation site of alphaCaMKII (van Woerden et al. 2007), reducing Arc expression (Mandel-Brehm et al. 2015), Cre-dependent induction of the maternal Ube3a allele (Silva-Santos et al. 2015), and a zinc finger artificial transcription factor which increased Ube3a expression (Bailus et al. 2016). Importantly, more direct genetic rescues have been discovered which unsilence the normal paternal Ube3a allele, including topoisomerase I inhibitors (Huang et al. 2011; Powell et al. 2013; Mabb et al. 2016; Lee et al. 2018), microRNA miRNA-708 (Vatsa et al. 2019), and the antisense ortholog Ube3a-ATS (Meng et al. 2012, 2015).

We posed a novel therapeutic hypothesis, based on the findings of abnormal synaptic dendritic spine morphology, decreased dendritic spine density, and reduced long-term potentiation (LTP)-induced actin polymerization within dendritic spines in Ube3a mutant mice (Dindot et al. 2008; Baudry et al. 2012; Kim et al. 2016; Sun et al. 2016; Khatri et al. 2018), consistent with the role of the ubiquitin pathway in synapse formation and dendritic spine architecture (Mabb and Ehlers 2010; Williams and Franco 2010; Lee et al. 2013; Park and Poo 2013; Kim et al. 2016). Brain-derived neurotrophic factor (BDNF) is a well-established regulator of synaptic plasticity and dendritic spine formation and maintenance (Thoenen 1995; Schuman 1999; Chao 2000; Lynch et al. 2008; Monteggia 2011; Leal et al. 2015; Park and Poo 2013). BDNF exerts its synaptic actions on promoting LTP through the TrkB receptor (Reichardt 2006; Kron et al. 2014; Lin et al. 2018). TrkB agonists, including 7,8-dihydroxyflavone (7,8-DHF) and LM22A-4, were reported to improve phenotypes in mouse models of neurodegenerative and neurodevelopmental disorders, including Alzheimer's, autism spectrum disorder, Fragile X, Huntington's, and Rett syndromes (Johnson et al. 1985; Devi and Ohno 2012; Jiang et al. 2013; Simmons et al. 2013; Castello et al. 2014; Tian et al. 2015; Aytan et al. 2018; García-Díaz Barriga et al. 2017; Li et al. 2017; Nguyen et al. 2019; Rhine et al. 2019). Importantly, BDNF and TrkB signaling were reported to be defective in Ube3a mice (Cao et al. 2013), and treatment with an ampakine which enhances BDNF effectively reversed deficits in LTP and in contextual and cued fear conditioning in 9- to 12-wk-old Ube3a mice (Baudry et al. 2012). Here, we investigate the therapeutic potential of a TrkB agonist as a pharmacological target for Angelman syndrome in older adult Ube3a mice, at age 6 mo, using Morris water maze spatial learning, a cognitive assay in which Ube3a mice have consistently displayed robust performance deficits (Miura et al. 2002; Huang et al. 2013; Leach and Crawley 2018). 7,8-DHF was administered before and during standard water maze training, using four consecutive trials each day. In a separate group of 6-mo-old WT and Ube3a mice, 7,8-DHF was administered before and during a distributed training procedure, in which the four daily training trials were separated by 1 h intervals. Our previous study using this spaced learning protocol discovered improved acquisition in 7- to 14-wk-old Ube3a mice, as compared to training with massed trials (Lauterborn et al. 2019). The combination of spaced training trials + 7,8-DHF treatment was designed to address the hypothesis that a behavioral intervention given together with a pharmacological intervention could produce additive or synergistic benefits in Ube3a mice at older ages.

Results

Figure 1 illustrates rotarod motor impairments in 6-mo-old Ube3a mice and the absence of effects of semi-chronic 7,8-DHF treatment. Three consecutive training trials per day were administered on three consecutive days. Genotype differences were highly significant overall (F(2,48) = 233.9, P < 0.001), confirming poor rotarod performance in 6-mo-old Ube3a mice. Longer latencies in Ube3a than WT appeared in the first training trial, indicating a phenotypic motor deficit rather than impaired motor learning. (A) WT in both the vehicle and 7,8-DHF groups improved across training days, displaying longer latencies to fall across days 1, 2, and 3 (F(2,46) = 97.07, P < 0.001). No significant difference was detected across training days between WT treated with vehicle versus WT treated with 7,8-DHF (F(2,46) = 1.08, NS). Interaction of training day × treatment was not significant (F(1,23) = 0.2354, NS). (B) Ube3a in both the vehicle and 7,8-DHF treatment groups improved across training days (F(2,46) = 87.31, P < 0.001), although latencies to fall were shorter than in WT, as predicted. No significant difference was detected across training days between Ube3a treated with vehicle versus Ube3a treated with 7,8-DHF (F(2,46) = 1.371, NS). Interaction of training day × treatment was not significant (F(1,23) = 3.838, P = 0.0623, NS). Note that only the first cohort of mice was used in rotarod testing, based on previous findings that rotarod performance did not differ between massed and spaced training conditions in either WT or Ube3a mice (Lauterborn et al. 2019).

Figure 1.

Figure 1.

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Rotarod motor coordination and balance performance in 6-mo-old WT and Ube3a mice given three consecutive daily training trials for 3 d, and treated with either vehicle or the TrkB receptor agonist 7,8-dihydroxyflavanone (7,8-DHF, 5 mg/kg i.p.), showed no improvement with treatment. Consistent with previous reports for Ube3a mice at younger ages, middle-aged Ube3a mice displayed initial and continuing deficits on rotarod performance as compared to WT (for all figures, please see Results text for full statistical analyses). (A) WT in both the vehicle and 7,8-DHF groups improved across training days, displaying increasingly longer latencies to fall across training days 1, 2, and 3, indicating normal motor learning. No significant difference was detected between WT treated with vehicle versus 7,8-DHF. (B) Ube3a in both the vehicle and 7,8-DHF treatment groups improved across training days, although latencies to fall remained lower than in WT, as expected. No significant difference was detected in performance between Ube3a mice treated with vehicle versus 7,8-DHF.

Figure 2 illustrates Morris water maze spatial learning impairments in 6-mo-old Ube3a mice as compared to WT, when trained with the conventional four massed daily training trials. The performance was unaffected by semi-chronic treatment with daily intraperitoneal doses of the TrkB receptor agonist 7,8-dihydroxyflavanone (7,8-DHF, 5 mg/kg). (A) WT in both the vehicle and 7,8-DHF groups successfully reached the acquisition criterion of ≤15 sec to reach the hidden platform location. A significant effect of the training day was detected in WT (F(9,207) = 32.49, P < 0.001), indicating learning across days as expected. No significant difference was detected in the time course for acquisition across training days between WT treated with vehicle versus WT treated with 7,8-DHF (F(1,23) = 0.06, NS), indicating no faster learning in WT given 7,8-DHF. No significant interaction between vehicle versus 7,8-DHF × training day was detected in WT (F(9,207) = 0.67, NS). (B) Ube3a in both the vehicle and 7,8-DHF groups did not reach the acquisition criterion of ≤15 sec to reach the hidden platform location. A significant effect of the training day was detected (F(9,207) = 13.75, P < 0.001), indicating some learning across training days. No significant difference was detected in the time course across training days for acquisition by Ube3a mice treated with vehicle versus 7,8-DHF (F(1,23) = 2.89, NS), indicating no faster learning with 7,8-DHF. No significant interaction between vehicle versus 7,8-DHF × training day was detected in Ube3a (F(9,207) = 0.225, NS).

Figure 2.

Figure 2.

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Morris water maze spatial learning and memory in WT and Ube3a mice given four consecutive daily training trials and treated with either vehicle or with the TrkB receptor agonist 7,8-dihydroxyflavanone (7,8-DHF, 5 mg/kg i.p.). (A) WT in both the vehicle and 7,8-DHF groups successfully reached the acquisition criterion of under 15 sec to reach the hidden platform location. No significant difference was detected in the time course for acquisition across training days between WT mice treated with vehicle versus 7,8-DHF. (B) Ube3a in both the vehicle and 7,8-DHF groups did not successfully reach the acquisition criterion of under 15 sec to reach the hidden platform location, although improvement across training days was apparent in both groups. No significant difference was detected in the time course across training days for acquisition between Ube3a mice treated with vehicle versus 7,8-DHF.

Figure 3 illustrates that Morris water maze spatial learning was impaired in 6-mo-old Ube3a mice when trained with spaced trials, that is, four daily training trials spaced at 1 h intervals, but unaffected by treatment with daily intraperitoneal doses of the TrkB receptor agonist 7,8-dihydroxyflavanone (7,8-DHF, 5 mg/kg) as compared to vehicle, on latencies to reach the hidden platform. (A) WT in both the vehicle and 7,8-DHF groups successfully reached the acquisition criterion of ≤15 sec to reach the hidden platform location. A significant effect of the training day was detected in WT (F(9,108) = 9.8, P < 0.001), indicating learning across days as expected. No significant difference was detected in the time course for acquisition across training days between WT mice treated with vehicle versus 7,8-DHF (F(1,12) = 0.96, P = 0.346, NS), indicating no faster learning in WT given 7,8-DHF. No significant interaction between vehicle versus 7,8-DHF × training day was detected in WT (F(9,108) = 0.39, NS). (B) Ube3a in both the vehicle and 7,8-DHF groups did not reach the acquisition criterion of ≤ 5 sec to reach the hidden platform location. A significant effect of the training day was detected (F(9,171) = 14.74, P < 0.001), indicating some learning across training days. Latencies at day 10 were in the range of 20 sec in Ube3a mice trained with distributed learning trials, spaced at 1 h intervals, as compared with latencies at day 10 in the range of 30–35 sec, in Ube3a mice trained with massed learning trials (Fig. 2), consistent with previous findings (Lauterborn et al. 2019). No significant difference was detected in the time course across training days for acquisition by Ube3a mice treated with vehicle versus 7,8-DHF (F(1,19) = 0.07, NS), indicating no faster learning with 7,8-DHF. No significant interaction between vehicle versus 7,8-DHF × training day was detected in Ube3a (F(9,171) = 1.52, NS).

Figure 3.

Figure 3.

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Latencies to reach the hidden platform during Morris water maze spatial learning and memory in WT and Ube3a mice given four daily training trials spaced at 1 h intervals, and treated with either vehicle or the TrkB receptor agonist 7,8-dihydroxyflavanone (7,8-DHF, 5 mg/kg i.p.). (A) WT in both the vehicle and 7,8-DHF groups successfully reached the acquisition criterion of under 15 sec to reach the hidden platform location. No significant difference was detected in the time course for acquisition across training days in WT mice treated with vehicle and 7,8-DHF. (B) Ube3a in both the vehicle and 7,8-DHF groups did not successfully reach the acquisition criterion of under 15 sec to reach the hidden platform location, although acquisition latencies at day 10 were generally lower after spaced training trials than latencies at day 10 after the massed training trials shown in Figure 2. This observation extends previous findings of better learning with spaced versus massed training in 2- to 3-mo-old Ube3a mice (Lauterborn et al. 2019). No significant difference was detected in the time course across training days for acquisition by Ube3a mice treated with vehicle versus 7,8-DHF.

Figure 4 shows that the speed of swimming during water maze acquisition was unaffected by 7,8-DHF treatment. In mice trained with four massed trials, the velocity of swimming did not differ between WT mice treated with vehicle versus 7,8-DHF (F(1,23) = 1.182, NS), nor between Ube3a mice treated with vehicle versus 7,8-DHF (F(1,23) = 2.751, NS). However, swim speed was lower in Ube3a overall as compared to WT overall (F(1,49) = 37.9, P < 0.001). Similarly, in mice trained with four trials separated by 1 h intervals, the velocity of swimming did not differ between WT mice treated with vehicle versus 7,8-DHF (F(1,12) = 1.151, NS), nor between Ube3a mice treated with vehicle versus 7,8-DHF (F(1,19) = 0.393, P = 0.538, NS). However, swim speed was significantly lower in Ube3a overall as compared to WT overall (F(1,39) = 25.5, P < 0.001). A parsimonious explanation for the apparent acquisition deficit, in which Ube3a displayed longer latencies to reach the hidden platform, is, therefore, slower swimming. Because swim speeds were somewhat lower in Ube3a than WT in both the massed and spaced training groups, slower latencies to reach the hidden platform could be responsible for the apparent learning deficits. Results from these experiments may be more correctly interpreted as a performance deficit in Ube3a, rather than a cognitive deficit. 7,8-DHF treatment had no effect on the performance deficit.

Figure 4.

Figure 4.

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Speed of swimming during Morris water maze spatial learning in WT and Ube3a mice given four consecutive daily training trials (A,B), or four daily training trials spaced by 1 h intervals (C,D), and treated with either vehicle or the TrkB receptor agonist 7,8-dihydroxyflavanone (7,8-DHF, 5 mg/kg i.p.). Ube3a swam more slowly than WT overall in both training conditions (P < 0.001). (A) The velocity of swimming did not differ between WT mice treated with vehicle versus 7,8-DHF. A significant effect of the training day was detected in WT (P < 0.001), indicating slightly faster swimming during the latter training days. No significant interaction between vehicle versus 7,8-DHF × training day was detected in WT. (B) The velocity of swimming did not differ between Ube3a mice treated with vehicle versus 7,8-DHF. A significant effect of the training day was detected (P < 0.001), indicating somewhat faster swimming across training days. No significant interaction between vehicle versus 7,8-DHF × training day was detected in Ube3a. (C) The velocity of swimming did not differ between WT mice given spaced training trials and treated with vehicle versus 7,8-DHF. No effect of the training day was detected in WT. A significant interaction between vehicle versus 7,8-DHF × training day was detected in WT (P < 0.001). (D) The velocity of swimming did not differ between Ube3a mice given spaced training trials and treated with vehicle versus 7,8-DHF. No significant effect of the training day was detected in Ube3a. No significant interaction between vehicle versus 7,8-DHF × training day was detected in Ube3a.

Probe trial performance at 3 h after the last training trial indicated that 6-mo-old Ube3a mice used distal spatial cues to achieve their moderate level of learning of the water maze platform locations, with no improvement in probe trial scores by 7,8-DHF treatment, as shown in Supplemental Figure S1. Both WT and Ube3a trained with four massed daily trials displayed significantly more time spent in the previously trained quadrant than in the other four quadrants, independent of treatment group (WT + vehicle F(3,48) = 7.79, P < 0.001; WT + 7,8-DHF F(3,44) = 9.018, P < 0.001; Ube3a + vehicle F(3,48) = 4.044, P < 0.05; Ube3a + 7,8-DHF F(3,44) = 3.66, P < 0.05). Similarly, crossings over the previously trained platform location were higher than crossings over the other three analogous imaginary platform locations for both WT and Ube3a trained with four massed daily training trials (WT + vehicle F(3,44) = 14.91, P < 0.001; WT + 7,8-DHF F(3,48) = 15.32, P < 0.001; Ube3a + vehicle (F(3,48) = 8.026, P < 0.001; Ube3a + 7,8-DHF F(3,46) = 9.851, P < 0.001).

Analogous 3 h probe trial results were obtained for the 6-mo-old WT and Ube3a mice trained with four daily training trials that were spaced at 1 h intervals, as shown in Supplemental Figure S2 (Quadrant time: WT + vehicle F(3,42) = 9.026, P < 0.001; WT + 7,8-DHF F(3,44) = 7.29, P < 0.001; Ube3a + vehicle F(3,40) = 9.432, P < 0.001; Ube3a + 7,8-DHF F(3,36) = 0.348, NS; Platform crossings: WT + vehicle F(3,24) = 28.83, P < 0.001; WT + 7,8-DHF F(3,24) = 24.54, P < 0.001; Ube3a + vehicle F(3,40) = 31.66, P < 0.001; Ube3a + 7,8-DHF), indicating that some spatial learning based on distal environmental cues had occurred in the Ube3a mice.

Probe trial performance at 24 h after the last training trial indicated that 6-mo-old Ube3a mice retained partial memory of the water maze platform locations in some cases, following their impaired performance on acquisition, although 7,8-DHF treatment did not improve probe trial scores. WT trained with either four massed training trials (Supplemental Fig. S3) or four spaced training trials (Supplemental Fig. S4) displayed selective quadrant search and more crossings over the previously trained quadrant location at the 24 h time point, in both the vehicle and 7,8-DHF treatment groups (Massed quadrant time: WT + vehicle F(3,44) = 7.253, P < 0.001; WT + 7,8-DHF F(3,48) = 5.797, P < 0.01; Massed platform crossings: WT + vehicle F(3,44) = 9.58, P < 0.001; WT + 7,8-DHF F(3,48) = 7.4, P < 0.001; Spaced quadrant time: WT + vehicle F(3,24) = 4.212, P < 0.05; WT + 7,8-DHF F(3,24) = 3.313, P < 0.05; Spaced platform crossings: WT + vehicle F(3,24) = 19.96, P < 0.001; WT + 7,8-DHF F(3,24) = 9.137, P < 0.001). Ube3a trained with either four massed or four spaced training trials displayed selective quadrant search and more crossings over the previously trained quadrant location in the 24 h probe trial on some, but not all, parameters (Massed quadrant time: Ube3a + vehicle F(3,48) = 5.797, P < 0.01; Ube3a + 7,8-DHF F(3,44) = 1.25, NS; Massed platform crossings: Ube3a + vehicle F(3,48) = 10.16, P < 0.001; Ube3a + 7,8-DHF F(3,44) = 4.95, P < 0.01; Spaced quadrant time: Ube3a + vehicle F(3,40) = 7.416, P < 0.001; Ube3a + 7,8-DHF F(3,36) = 2.015, NS; Spaced platform crossings: Ube3a + vehicle F(3,24) = 9.137, P < 0.001; Ube3a + 7,8-DHF F(3,36) = 2.861, P = 0.052, NS). Further investigation will be required to understand the observed impairments in groups treated with 7,8-DHF on 24 h probe trial performance on some parameters. In addition, the observation from probe trial results that the spatial location of the hidden platform was acquired by the Ube3a groups to some extent will be interesting to investigate further.

Discussion

Adults with Angelman syndrome continue to display most of the symptoms characterized at younger ages, including impaired locomotion and mobility, continuing severe cognitive impairments, limited speech, anxiety, sleep dysfunction, seizures, obesity, and gastrointestinal disruption (Smith 2001; Larson et al. 2015; Prasad et al. 2018). The present studies used older adult male and female Ube3a mutant mice to model spatial and motor learning deficits relevant to cognitive deficits in Angelman syndrome, and to evaluate a hypothesis-driven pharmacological intervention.

Extending previous reports of motor behavioral phenotypes in younger Ube3a mice, (Miura et al. 2002; Heck et al. 2008; Jiang et al. 2010; Daily et al. 2011; Egawa et al. 2012; Huang et al. 2013; Ciarlone et al. 2017; Leach and Crawley 2018; Sonzogni et al. 2018), rotarod motor coordination and balance was significantly impaired in 6-mo-old Ube3a as compared to WT in the present study. Swim speeds were lower in Ube3a as compared to WT at age 6 mo, as discussed below. Similarly, lower open field locomotor activity has been extensively documented in Ube3a mice at younger ages (Allensworth et al. 2011; Huang et al. 2013; Ciarlone et al. 2017; Sonzogni et al. 2018), and in our recent report of Ube3a mice at 12 mo of age (Dutta and Crawley 2019). Further, number of total arm entries into the elevated plus-maze, the internal measure of general exploratory locomotion, and number of entries into the side chambers of the 3-chambered social approach apparatus, was significantly lower in 12-mo-old Ube3a mice as compared to WT controls, consistent with the open field results (Dutta and Crawley 2019).

Intellectual impairment is a primary symptom of Angelman syndrome. Therapeutics that improve cognitive abilities could provide an important benefit to adults with Angelman syndrome. Previous studies reported reduced BDNF and TrkB signaling in Ube3a mice (Cao et al. 2013), and that treatment with an ampakine which elevates BDNF was effective in reversing a deficit in contextual and cued fear conditioning in young Ube3a mice (Baudry et al. 2012). Following our previous confirmation of deficits in water maze performance in young Ube3a mice (Leach and Crawley 2018), older adult Ube3a and WT mice were used in the present studies to evaluate water maze performance and the effects of semi-chronic treatment with the TrkB agonist 7,8-DHF. Based on our previous findings of compromised motor functions in 12-mo-old Ube3a mice (Dutta and Crawley 2019), which could introduce direct artifacts into many cognitive assays for mice, we focused on the 6 mo age for the evaluation of a novel pharmacological strategy in learning tasks in the present studies. Apparent acquisition deficits in water maze spatial learning were again detected in vehicle-treated Ube3a mice at this age. Specifically, WT reached the acquisition criterion of 15 sec latency to reach the hidden platform by 10 d of training, whereas Ube3a did not reach the acquisition criterion, averaging ∼30–35 sec to reach the hidden platform after 10 d of massed training trials. At 5 mg/kg i.p., the semichronic dose used, 7,8-DHF did not improve acquisition in Ube3a mice. We then repeated this experiment in a separate cohort of 6-mo-old Ube3a and WT mice using spaced training trials. Previously we had discovered that spacing the training trials by 1 h intervals improved acquisition in young Ube3a mice (Lauterborn et al. 2019). To test the hypothesis that the combination of spaced training plus TrkB receptor activation could additively or synergistically improve water maze performance in Ube3a mice, the second independent cohort of 6-mo-old Ube3a and WT was trained with four daily spaced trials and 5 mg/kg 7,8-DHF. WT again reached the acquisition criterion of 15 sec latency to reach the hidden platform by 10 d of training. Ube3a did not reach the acquisition criterion, but averaged ∼20 sec to reach the hidden platform after 10 d of training, considerably better than the group trained with massed trials, replicating and extending our previous findings (Lauterborn et al. 2019). The 7,8-DHF treatment did not further improve acquisition in Ube3a mice.

It is important to recognize that reduced swim speeds were apparent in both groups of 6-mo-old Ube3a mice as compared to WT. In addition, probe trial performance was almost as good in Ube3a as in WT, consistent with our previous findings in younger WT and Ube3a mice (Lauterborn et al. 2019), indicating that the location of the hidden platform was acquired to some extent in all Ube3a groups. However, given that 6-mo-old Ube3a mice displayed selective quadrant and platform location search in some of the probe trials, and based on the slower swim speeds in Ube3a than WT shown in Figure 4, results from the Ube3a water maze experiments may be most parsimoniously interpreted as motor rather than cognitive deficits.

The interpretation of partial acquisition and memory of this spatial learning task using distal environmental cues in middle-aged adult Ube3a mice suggests that improvement in learning and memory may be possible in adult Ube3a mice. Learning and memory tasks that do not rely heavily on motor performance, such as fear conditioning and operant tasks, will be needed to more fully evaluate cognitive phenotypes in older Ube3a mice, which could serve as outcome measures for future therapeutic discovery.

It is interesting to note that similar but not identical results were obtained from WT and Ube3a mice purchased from JAX (Cohort 1) versus bred in-house (Cohort 2). Another difference between the two cohorts was that Cohort 1 consisted of males only, while Cohort 2 consisted of both males and females. No obvious sex differences were seen within Cohort 2, although Ns were insufficient for proper statistical comparison. It remains possible that the small differences in absolute values of water maze latencies between Cohorts 1 and 2 could be related to different breeding colony conditions or to a potential sex difference.

The present negative findings indicate that a TrkB agonist strategy may not be directly useful for Angelman syndrome. However, other dose regimens of 7,8-DHF and other more selective TrkB agonists remain to be tested and could yield more positive results. The 5 mg/kg i.p. dose and semi-chronic administration used in the present studies are consistent with an extensive literature in which this dose produced behavioral actions, and significantly activated TrkB receptors as assayed with Western immunoblots for levels of phosphorylated TrkB, in several brain regions in various mouse models on diverse genetic backgrounds (Andero et al. 2011; Devi and Ohno 2012; Jiang et al. 2013; Sconce et al. 2015; Tan and Bird 2016; García-Díaz Barriga et al. 2017; Stagni et al. 2017; Giacomini et al. 2019; Seese et al. 2020). Future experiments with pTrkB assays will be necessary to fully confirm target engagement in 6-mo-old Ube3a mice.

It is important to consider the possibility that treatments beginning at adult ages may reduce the likelihood of therapeutic improvements. Beginning a neurotrophic drug intervention early in life, during a critical period of brain development, may be essential for neurodevelopmental disorders such as Angelman syndrome (Sonzogni et al. 2019). Although TrkB agonists have been shown to improve components of social and motor behaviors in adult mice (Simmons et al. 2013; Kang et al. 2017; Li et al. 2017; Nasrallah et al. 2019; Rhine et al. 2019), brain disorders with structural neuroanatomical abnormalities established during early development, such as reductions in myelination which have been reported for Angelman syndrome (Harting et al. 2009; Peters et al. 2011; Tiwari et al. 2012; Grier et al. 2015), may require that neurotrophic interventions begin at a very young age (Silva-Santos et al. 2015; Sonzogni et al. 2019).

Reporting negative as well as positive results is especially important at the preclinical phase of evaluating therapeutics for neurodevelopmental disorders. Although negative results were obtained with the present 7,8-DHF treatment regimen, our findings support the feasibility of using older adult Ube3a mice to test a wide range of therapeutic targets. The present results, along with our recent report (Dutta and Crawley 2019), demonstrate the presence of robust motor deficits in 6- and 12-mo-old Ube3a mice. Therefore, impaired performance on parameters of rotarod motor coordination and balance, open field exploratory locomotion, number of chamber entries during the 3-chambered social approach, and swim speeds during water maze learning, could provide strong outcome measures for evaluating improvements in behavioral phenotypes of adult Ube3a mice after pharmacological interventions.

Efficacious interventions for adults with Angelman syndrome could significantly improve the quality of life. Impressively diverse strategies have been used in the preclinical evaluation of pharmacological and genetic interventions, using prenatal, juvenile and young adult ages of Ube3a mice, as appropriate for the discovery of cures early in life (van Woerden et al. 2007; Huang et al. 2011; Baudry et al. 2012; Kaphzan et al. 2012; Meng et al. 2012, 2015; Powell et al. 2013; Godavarthi et al. 2014; Llewellyn et al. 2015; Mandel-Brehm et al. 2015; Silva-Santos et al. 2015; Sun et al. 2015, 2016; Bailus et al. 2016; Ciarlone et al. 2016, 2017; Mabb et al. 2016; Jamal et al. 2017; Guzzetti et al. 2018; Lee et al. 2018; Zylka 2020). Our results indicate that behavioral phenotypes in Ube3a mice are similarly robust at older adult ages. In particular, motor deficits in older Ube3a mice may provide optimal preclinical opportunities to identify pharmacological interventions which may significantly improve components of the symptomatology which persist in adults with Angelman syndrome.

Materials and Methods

Mice

Conventional Ube3a knockout mice, derived from maternal transmission and generated on a C57BL/6J background, were purchased from The Jackson Laboratory (JAX) in Bar Harbor, Maine (JAX catalog #016590), along with their WT littermates (Cohort 1, males). Breeding pairs of female Ube3a and male WT were subsequently purchased from JAX, and breeding of Cohort 2 was conducted at the University of California Davis in Sacramento, CA, USA. Female Ube3a were bred with male WT to maintain maternal transmission of the heterozygous mutation. Offspring were housed in cages containing same-sex littermates, 2–4 mice per cage (Cohort 2, males and females). Mice were housed in ventilated Tecniplast cages in an AAALAC approved temperature-controlled vivarium on a 12:12 circadian cycle with lights on at 7 a.m. All husbandry, breeding, behavioral testing, and drug treatment procedures were approved by the University of California Davis Institutional Animal Care and Use Committee, and were conducted in compliance with the NIH Guide for the Care and Use of Laboratory Animals.

Methodological considerations

Behavioral testing was conducted during the light phase of the circadian cycle, between 8.30 a.m. and 5.30 p.m. On the day of each behavioral experiment, mice in their home cages were habituated to the testing room for 1 h before the start of the assay. To evaluate phenotypes in older adult Ube3a and WT mice, behavioral assays were conducted at ages 6 mo of age. To investigate treatment effects on a task that directly addresses motor coordination and balance, rotarod motor learning was tested in Cohort 1 one week before the start of water maze testing. Cohort 1, including a total of 25 WT and 25 Ube3a, males only, was tested on Morris water maze with massed training trials and drug or vehicle treatment. A separate set of female Ube3a and male WT breeders was ordered from JAX and bred in-house, to generate males and females for an initial partial evaluation of sex differences. Cohort 2, bred in-house, including a total of 14 WT and 21 Ube3a, approximately equal numbers of males and females, was tested on Morris water maze spatial learning with spaced training trials. Purchases and breeding were designed to yield Ns of sufficient power to detect drug effects, as confirmed in previous studies (Silverman et al. 2011, 2012; Brielmaier et al. 2012; Kazdoba et al. 2016; Leach and Crawley 2018; Stoppel et al. 2018). Comparison of massed versus spaced training in vehicle-treated Ube3a and WT was designed as a replication and extension study, to evaluate the beneficial effects of spaced training that we previously detected in Ube3a mice at a younger age (Lauterborn et al. 2019).

Mice were coded by ear notch pattern to ensure that investigators remained uninformed of genotype. Automated videotracking equipment was used for the water maze assay. Observers scored rotarod latencies. Investigators remained blind to treatment condition through coding of drug and vehicle vials by another investigator. Each subject mouse was weighed on the morning of each drug treatment, for calculations of dose by body weight. The 7,8-DHF dose was chosen from previous publications on behavioral actions of 7,8-DHF in mice, in which no adverse health effects were reported (Devi and Ohno 2012; Castello et al. 2014; Ren et al. 2014; Stagni et al. 2017; Rhine et al. 2019). For all assays, surfaces of the testing chamber were cleaned with 70% ethanol after each subject mouse was tested, with sufficient time for the ethanol odor to dissipate before the start of the next test session.

Behavioral testing methods

Rotarod

Rotarod motor coordination and balance was tested using an Ugo-Basile accelerating mouse rotarod, (Stoelting Co., Wood Dale, IL) as previously described (Silverman et al. 2011; Leach and Crawley 2018; Lauterborn et al. 2019). Rotations increased from 5 to 40 rpm across the 5 min test session. Three trials per day were administered across three consecutive days. Latency to fall was automatically detected by the equipment and recorded for each trial.

Water maze

Morris water maze spatial learning and memory was tested using methods previously described (Brielmaier et al. 2012; Leach et al. 2016; Leach and Crawley 2018; Lauterborn et al. 2019). The 120 cm circular pool was filled with water maintained at 24°C–25°C, mixed with dilute Crayola nontoxic liquid white paint for opacity, to prevent proximal visual detection of the hidden platform. Room lighting was ∼25 lux. External cues for distal spatial navigation included a prominent sink, computer, water temperature regulator with hose, a large colorful poster, and a yellow paper lantern hung from the ceiling. Platform locations and start locations were pseudorandomized. Trials were videorecorded and scored by automated software (Noldus Ethovision). Hidden platform acquisition was quantified for latency to find the hidden platform and swim speed. For the conventional massed training trials experiment, each subject mouse was given four consecutive trials per day for 10 d. The WT control group reached the criterion of 15 sec or less latency to reach the hidden platform by day 10.

Our previous study with young Ube3a mice revealed improved learning when training trials were temporally spaced instead of massed (Lauterborn et al. 2019). We therefore conducted spaced training trials in a separate group of 6 mo old WT and Ube3a mice (Cohort 2). Each subject mouse was given four trials per day separated by 1 h between each trial, for 10 d. The WT control group reached the latency criterion of 15 sec or less to reach the hidden platform by day 10. In both groups, mice were allowed to remain on the platform for ∼15 sec after each trial. Each mouse was placed under an infrared heating lamp to help restore body temperature, at the end of the fourth daily trial in the massed training of Cohort 1, and between trials in the spaced training of Cohort 2.

Probe trial analysis was conducted at 3 h after the last training trial, to confirm that the acquisition strategy used distal spatial cues. A second probe trial was conducted at 24 h after the last training trial, to evaluate long-term memory of the location of the hidden platform. The duration of each probe trial was 60 sec. Time spent in each of the four quadrants of the pool, and number of crossings over the former platform location versus the three analogous imaginary platform locations in the other three quadrants, were automatically scored by the Noldus videotracking software.

Drug administration

7,8-dihydroxyflavanone (7,8-DHF, catalog #D5446, Sigma–Aldrich) stock was dissolved in dimethyl sulfoxide (DMSO, Sigma–Aldrich) and diluted fresh on the day of injections with phosphate-buffered saline (0.1 M, Thermo Fisher Scientific), to reach the treatment preparation of 0.5 mg/mL 7,8-DHF in 17% DMSO. The vehicle solution was similarly prepared fresh on the day of injections and consisted of 17% DMSO in 0.1 M phosphate-buffered saline. Intraperitoneal injection volume was 10 mL/kg, yielding a 7,8-DHF dose of 5 mg/kg. Subject mice were injected with either 7,8-DHF or vehicle daily for 5 d before the start of treatment. Starting on day 6 and continuing through the last day of each testing sequence, each mouse was injected 1 h before the start of behavioral testing.

Statistics

GraphPad Prism version 7 was used to conduct statistical analyses of the data and to generate graphs. Rotarod motor learning was analyzed by two-way repeated measures ANOVA for factors of training day and treatment. Water maze acquisition and swim speed were analyzed with a two-way repeated measures ANOVA for factors of training day and treatment, followed by Bonferroni post-hoc analyses in cases of significant ANOVA F-values. Overall genotype differences in rotarod performance and in swim speed were analyzed with a two-way analysis of variance. Water maze probe trial data were analyzed with one-way ANOVA followed by post-hoc Dunnett's test comparing the target location to the three other locations, within genotype and within treatment condition.

Supplementary Material

Supplemental Material
supp_27_9_346__index.html (682B, html)

Acknowledgments

We are grateful to Dr. Gary Lynch, Dr. Christine Gall, and Dr. Julie Lauterborn, University of California Irvine, for discussions of the concepts underlying these studies, in particular the TrkB agonist pharmacological strategy. We thank Prescott Leach, Tatiana Kazdoba, and Jennifer Parrott for their pilot studies and published findings, which informed our choice of the 7,8-DHF dose and treatment regimen. This work was supported by the National Institutes fof Health grants R01 NS085709 (J.N.C.) and U54 HD079125 (J.N.C.).

Footnotes

[Supplemental material is available for this article.]

Freely available online through the Learning & Memory Open Access option.

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