The room. Subjects were released from the same compass point (N) on all trials, and latency to reach the platform was recorded for each trial (SmartTrack, San Diego, CA). All other testing parameters were similar to the spatial version of the MWM (number of trials, testing days, and length of time subject was left on platform). Histology At P100, subjects were weighed, anesthetized with ketamine/xylazine (100/15 mg/kg), and transcardially perfused with saline followed by 10 phosphate buffered formalin. Brains were extracted, placed in formalin, and shipped to GDR at Beth Israel Deaconess Medical Center for anatomical analysis. Brains were embedded in celloidin, and serially sectioned in the coronal plane at 30 m. A series of every tenth section was stained with cresyl violet for Nissl substance. A screener identified the distribution and relative severity of the malformations without knowledge of treatment group or litter of origin. The most common anatomical anomalies consisted of disrupted cortical lamination, periventricular nodular heterotopia (PNH), and hippocampal dysplasia. PNH were ranked by severity (mild (n=8), moderate (n=16), and severe (n=12)), and this categorization was used for post hoc analyses of acoustic testing results. Hippocampal dysplasia was also ranked by severity (mild n=6, moderate n=11, severe n=19). However, hippocampal malformations were identified in all MAM treated subjects, and were typically more severe (with less variability) as compared to the overall PNH profile. In addition, volumes of the cerebral cortex, hippocampus, and corpus callosum were assessed using Pyridine, 2-amino-5-methoxy- a Fisher Micromaster II digital microscope. Structural volumes were measured by overlaying serial images with a grid (ImageJ), and were computed using Cavalieri’s estimator of volume [43, 44]. Statistics For initial acoustic processing analyses, MAM subjects were analyzed as one group. When main effects of Treatment were observed, post hoc analyses were conducted using severity of PNH (three levels: mild, moderate, severe) as a between-subjects variable.Results Histology Histological analyses were performed on the 36 MAM treated and 23 control brains. A blind screener documented the severity of neurological dysplasia and identified three categories of PNH; mild (n=8); moderate (n=16); and severe (n=12; see Fig. 1). All MAM treated subjects showed hippocampal dysplasia, as well as some degree of disrupted cortical lamination. There were no malformations in any of the control brains. MAM treated rats showed a significant difference in volume of the cerebral cortex [F(1, 57)=181.5, p<0.001] as compared to controls, with smaller cortical volume in the MAM group. MAM animals also differed significantly in the volume of corpus callosum [F(1, 57)=225.2, p<0.001] and hippocampus [F(1,57)= 91.1, p<0.001] as compared to controls, again with both structures smaller in the MAM group (see Fig. 2). Interestingly, overall volume reductions in MAM subjects were not related to severity of PNH, or to severity of hippocampal heterotopia. Juvenile testing: normal single tone (NST) Results from paired samples t-tests of absolute response scores (cued versus uncued) showed that both MAM [t= 6.99, p<0.001] and control [t=8.905, p<0.001] rats were able to significantly detect the normal single tone cue (NST). However, a one-way ANOVA also showed a significant difference between MAM and control animals on the juvenile single tone detection task [F(1, 57)=7.653, p<0.01.