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To examine the function of Na+/H+ exchanger isoform 1 (NHE1) during embryogenesis, the Nhe1 gene was targeted by replacing the sequence encoding transmembrane domains 6 and 7 with the neomycin resistance gene. Results show that NHE1 activity is dispensable for normal embryogenesis. However, postnatal growth of homozygous mutants is affected and begin to exhibit ataxia and seizures at 2 weeks of age and histological analysis reveals an abnormal morphology of the grandular gastric mucosa.

Abstract Rationale Whether selective serotonin reuptake inhibitors (SSRIs) exposure during adolescent brain development causes lasting effects remains unresolved. Objective Assess the effects of fluoxetine and paroxetine 60 days after adolescent exposure compared with when on-drug. Methods Male Sprague-Dawley littermates (41 litters) were gavaged on postnatal days 33-53 with fluoxetine (3 or 10 mg/kg/day), paroxetine (3, 10 or, 17 mg/kg/day), or water; half were tested while on-drug (21 litters) and half after 60 days off-drug (20 litters). Results The highest dose of the drugs reduced body weight gain during treatment that rebounded 1 week post-treatment. On-drug, no significant group differences were found on elevated plus maze time-in-open, zone entries, or latency to first open entry; however, the high dose of paroxetine significantly reduced head-dips (N = 20/group). No significant effects were found on-drug for acoustic startle response/prepulse inhibition (ASR/PPI) although a trend (p < 0.10) was seen, which after combining dose levels, showed a significant increase in ASR amplitude for both fluoxetine and paroxetine (N = 20-21/group). No differences on immobility time were seen in the Porsolt forced swim test or in plasma corticosterone at the end of forced swim (N-19-21/group). Off-drug, no effects were seen in the elevated plus maze (N = 16/group), ASR/PPI (N = 20/group), forced swim (N = 19-20/group), or plasma corticosterone (N = 19/group). At the doses tested, fluoxetine and paroxetine induced minor effects with drug on-board but no residual, long-term adverse effects in rats 60 days after drug discontinuation. Conclusions The data provide no evidence that fluoxetine or paroxetine have long-term adverse effects on the behaviors measured here after adolescent to young adult exposure.

Abstract Background Prosaposin encodes, in tandem, four small acidic activator proteins (saposins) with specificities for glycosphingolipid (GSL) hydrolases in lysosomes. Extensive GSL storage occurs in various central nervous system regions in mammalian prosaposin deficiencies. Results Our hypomorphic prosaposin deficient mouse, PS-NA, exhibited 45% WT levels of brain saposins and showed neuropathology that included neuronal GSL storage and Purkinje cell loss. Impairment of neuronal function was observed as early as 6 wks as demonstrated by the narrow bridges tests. Temporal transcriptome microarray analyses of brain tissues were conducted with mRNA from three prosaposin deficient mouse models: PS-NA, prosaposin null (PS-/-) and a V394L/V394L glucocerebrosidase mutation combined with PS-NA (4L/PS-NA). Gene expression alterations in cerebrum and cerebellum were detectable at birth preceding the neuronal deficits. Differentially expressed genes encompassed a broad spectrum of cellular functions. The number of down-regulated genes was constant, but up-regulated gene numbers increased with age. CCAAT/enhancer-binding protein delta (CEBPD) was the only up-regulated transcription factor in these two brain regions of all three models. Network analyses revealed that CEBPD has functional relationships with genes in transcription, pro-inflammation, cell death, binding, myelin and transport. Conclusion These results show that: 1) Regionally specific gene expression abnormalities precede the brain histological and neuronal function changes, 2) Temporal gene expression profiles provide insights into the molecular mechanism during the GSL storage disease course, and 3) CEBPD is a candidate regulator of brain disease in prosaposin deficiency to participate in modulating disease acceleration or progression.

Abstract Background Methamphetamine (MA) use is a worldwide problem. Abusers can have cognitive deficits, monoamine reductions, and altered magnetic resonance spectroscopy findings. Animal models have been used to investigate some of these effects, however many of these experiments have not examined the impact of MA on the stress response. For example, numerous studies have demonstrated (+)-MA-induced neurotoxicity and monoamine reductions, however the effects of MA on other markers that may play a role in neurotoxicity or cell energetics such as glucose, corticosterone, and/or creatine have received less attention. In this experiment, the effects of a neurotoxic regimen of (+)-MA (4 doses at 2 h intervals) on brain monoamines, neostriatal GFAP, plasma corticosterone, creatinine, and glucose, and brain and muscle creatine were evaluated 1, 7, 24, and 72 h after the first dose. In order to compare MA's effects with stress, animals were subjected to a forced swim test in a temporal pattern similar to MA administration [i.e., (30 min/session) 4 times at 2 h intervals]. Results MA increased corticosterone from 1–72 h with a peak 1 h after the first treatment, whereas glucose was only increased 1 h post-treatment. Neostriatal and hippocampal monoamines were decreased at 7, 24, and 72 h, with a concurrent increase in GFAP at 72 h. There was no effect of MA on regional brain creatine, however plasma creatinine was increased during the first 24 h and decreased by 72 h. As with MA treatment, forced swim increased corticosterone more than MA initially. Unlike MA, forced swim reduced creatine in the cerebellum with no change in other brain regions while plasma creatinine was decreased at 1 and 7 h. Glucose in plasma was decreased at 7 h. Conclusion Both MA and forced swim increase demand on energy substrates but in different ways, and MA has persistent effects on corticosterone that are not attributable to stress alone.