Visible Platform

To determine whether motor skills may have infl uenced results of the water maze tasks, another group of treatment and age-matched mice were tested using a cued- version of the task. No signifi cant difference was observed between groups in the latency to escape to a visible platform. This demonstrated that mice of all treatment groups were equally able to swim and escape to the visible platform. Therefore, a motor defi cit likely did not contribute to the poorer performance observed by MeHg-exposed mice.

8.7.4 SOCIAL DEVELOPMENT

The social behavior of adult mice treated as neonates was examined using the resident– intruder paradigm. The number of resident-to-intruder sniffi ng episodes and the number of attacks were recorded for two sessions run on consecutive days in treatment-matched pairs. Only mice pretreated with high-dose Trolox were assessed in this task.

8.7.4.1 Sniffi ng

There was a signifi cant effect of day on the number of times resident mice sniffed an intruder (F(1,26) = 5.9, p < 0.001). In addition, a signifi cant effect of treatment (F(1,26) = 6.68, p < 0.004) and a signifi cant treatment-by-day interaction were found (F(2,26) = 9.0, p < 0.001). As shown in Figure 8.3a, MeHg-exposed resident mice made signifi cantly fewer sniffs of the intruder on day 1 compared to control mice. Pretreatment with Trolox resulted in complete reversal of the defi cit in sniffi ng observed in MeHg-treated mice. Furthermore, both control and Trolox-pretreated mice engaged in a greater number of sniffi ng episodes on day one than on day 2. MeHg-exposed mice

engaged in a similar level of sniffi ng on both test days that was reduced compared to the control and Trolox-pretreated mice.

8.7.4.2 Attacks

A signifi cant effect of treatment on the number of attacks was also observed in the resident–intruder paradigm (F(1,26) = 6.68, p < 0.004). MeHg-exposed resident mice made many more attacks than controls. This increased aggression was completely absent in Trolox-pretreated mice, such that none of the resident mice pretreated with Trolox attacked the intruder (see Figure 8.3b). All three groups maintained a similar level of attack behavior on the fi rst and second day of testing. Results of the resident–intruder paradigm indicate that less social investigation and greatly enhanced aggressive behavior occur in adult mice that were exposed to MeHg during postnatal development. This behavioral pattern was completely protected by high-dose Trolox pretreatment.

8.8 CONCLUSIONS

Methylmercury is a developmental neurotoxicant that causes damage, in part, through the generation of ROS. A number of studies have reported that MeHg exposure dur- ing development leads to impaired cognitive and motor behavior. The postnatal MeHg exposure regimen used here resulted in behavioral impairments consistent with those reported by others including impaired refl ex development and defi cits in a spatial learning task. In addition, the present study also revealed that early MeHg exposure results in abnormal social and aggressive interactions behavior much later in life. Pretreatment with Trolox, a water-soluble vitamin E derivative, resulted in a robust protective effect against these MeHg-induced behavioral defi cits. Trolox was particularly effective at abolishing the MeHg-induced defi cits in midair righting and

FIGURE 8.3 (a) The number of times a pair of mice sniffed one another and (b) the number of attacks resident mice made to the intruder in the resident–intruder paradigm on two consecu- tive days is illustrated. * Indicates signifi cantly different than control. + Indicates signifi cantly different than on day one of testing. Error bars indicate SEM.

PBS MeHg 4 mg/kg MeHg 4 mg/kg + Trolox 2.5 mg/kg Resident-intruder paradigm 35 30 25 20 15 10 10 8 6 4 2 0 5 0 Day 1 (a) (b) Sniffing e p is o d es N umb er of a tt ac k s

Day 2 Day 1 Day 2

*

*

*

+ +

the increased aggressive behaviors of the adults. These data suggest that free-radical scavenging antioxidants might be an effective means of reducing the potential health risks of early MeHg exposure.

Dramatically increased aggressive behavior together with reduced social investiga- tion was observed in MeHg-treated mice compared to controls. When control mice are paired in a small chamber with a target intruder mouse for the fi rst time, they quickly develop a “social” memory (File and Seth, 2003). That is, they frequently approach and investigate the intruder on the fi rst test day but this approach behavior decreases when they are exposed to the same intruder on subsequent days. MeHg-treated mice, how- ever, approached the intruder signifi cantly fewer times on the fi rst test day, but main- tained a similar level of investigation upon the second exposure to the same intruder. Moreover, MeHg-exposed mice attacked the intruder much more frequently than con- trols on both test days. This indicates that developmental MeHg exposure altered the social behavior expressed in adulthood, leading to increased aggression with reduced social investigation. We recently reported that mice treated with the same MeHg regi- men exhibited signifi cant increases in amphetamine-induced self-injurious behaviors as adults (Wagner et al., 2007). In the present study, Trolox pretreatment protected mice against the MeHg-induced alterations in social behavior observed in the resident– intruder paradigm, completely preventing increase in intrusive attack behavior.

Learning and memory defi cits were observed in MeHg-treated mice tested in the water maze during adolescence. We found an increase in their escape latency in the hidden platform water maze, as well as in the reversal-learning task. Sensorimotor problems did not appear to contribute signifi cantly to the MeHg-induced defi cits, since no difference in escape latency was observed between groups in the visible platform version of the task. Trolox elicited a partial, dose-related protective effect on hidden-platform and reversal-learning performance.

The proportion of time that mice spent in the previous escape quadrant was recorded during the reversal-learning task. This measure functioned as a probe trial to assess memory for the former escape quadrant. The control mice spent more time in the former escape location on early trials. This decreased after just a few trials and the controls were able to quickly adapt their strategy to learn the new plat- form location. In contrast, mice exposed to MeHg showed a decreased proportion of time spent in the former escape location, refl ecting their overall poor performance at fi nding the hidden-platform. However, Trolox pretreatment did not improve this measure. The lack of protection on this measure suggests that subtle abnormalities of MeHg exposure may still be present. Future studies determining the effect of Trolox in other learning and memory tasks may lead to a clearer understanding of the degree of protection conferred on MeHg-induced learning defi cits.

Finally, the maturation of the mid-air righting refl ex over the fi rst 3 weeks of post- natal life is mediated, in part, by continuing cerebellar maturation. MeHg exposure resulted in a signifi cant disruption in the maturation of the midair righting refl ex and, as above, Trolox pretreatment effectively attenuated this defi cit.

It appears likely that pretreatment with the free radical scavenging antioxidant, Trolox, protected mice against the behavioral defi cits by decreasing the amount of oxidative damage to neurons induced by the MeHg. Gutierrez et al. (2006) recently reported that rats exposed to mercuric chloride displayed reduced levels of total

radical trapping antioxidant potential following MeHg, suggesting that oxidative stress may be induced as intracellular stores of glutathione and other antioxidants become depleted. Shanker et al. (2005) showed that intracellular glutathione and antioxidants play an important role in protecting against MeHg-induced oxidative stress in the brain. Usuki et al. (2001) reported that high-dose Trolox resulted in signifi cant protection against MeHg-induced toxicity in adult rats, reducing the num- ber of apoptotic cells in the cerebellum as well as the degree of hind-limb crossing (a behavioral manifestation of MeHg toxicity in the adult). Likewise, Shanker and Aschner (2003) reported that Trolox was able to completely block the increase in ROS following MeHg exposure in isolated PND1 cerebral astrocytes. Thus, it is con- cluded that early exposure to MeHg leads to motor, cognitive, and social defi ciencies that resemble human developmental disorders such as autism and that pretreatment with the antioxidant, Trolox, affords protection against the neurobehavioral defi cits.

In summary, it appears that autism may be the result of early toxicant exposure acting upon individuals sensitive to their damaging effects because of a constellation of gene polymorphisms. While no single toxicant has been identifi ed, a number of compounds have been associated indirectly with autism and these appear to share a common mech- anism of generating ROS. Likewise, no single gene has been identifi ed but a number of the polymorphisms that have been associated with autism directly or indirectly affect the response to ROS. We (and others) have previously linked the occurrence of autism to the proximity of toxic landfi lls (Ming et al., 2008a) and have demonstrated increased excretion of biomarkers of ROS in a cohort of autism cases compared to age-matched controls (Ming et al., 2005). Finally, using our animal model, we have shown that dele- tion of genes in mice that have been associated with human autism polymorphisms results in neurobehavioral defi cits during development (Cheh et al., 2006), that early administration of toxicants that have been linked to human autism produces a spectrum of behavioral defi cits quite similar to the gene deletions (Wagner et al., 2006, 2007; Yochum et al., 2008), and most recently, that pretreatment with antioxidants protects mice against the deleterious effects of these toxicants (Ming et al., 2008b; present chap- ter). The protective effects afforded by antioxidant pretreatment against the neurobehav- ioral defi cits induced by VPA and MeHg are consistent with the interpretation that these compounds exert their damaging effects, at least in part, through the generation of ROS. The clinical ramifi cations of these observations await further study.

ACKNOWLEDGMENTS

Supported by: NIEHS grants ES05022, ES07148, ES11256, as well as the NJ Governor’s Council on Autism (GCW) and Autism Speaks (GCW).

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