Cup of Joe: a brain development "no"?

Treating pregnant mice with adenosine receptor antagonists including caffeine results in delayed migration of cortical γ-aminobutyric acid neurons and altered brain development in mouse offspring (Silva et al.).

Regional brain morphometry and impulsivity in adolescents following prenatal exposure to cocaine and tobacco.

IMPORTANCE: Animal studies have suggested that prenatal cocaine exposure (PCE) deleteriously influences the developing nervous system, in part attributable to its site of action in blocking the function of monoamine reuptake transporters, increasing synaptic levels of serotonin and dopamine. OBJECTIVE: To examine the brain morphologic features and associated impulsive behaviors in adolescents following prenatal exposure to cocaine and/or tobacco. DESIGN: Magnetic resonance imaging data and behavioral measures were collected from adolescents followed up longitudinally in the Maternal Lifestyle Study. SETTING: A hospital-based research center. PARTICIPANTS: A total of 40 adolescent participants aged 13 to 15 years were recruited, 20 without PCE and 20 with PCE; a subset of each group additionally had tobacco exposure. Participants were selected and matched based on head circumference at birth, gestational age, maternal alcohol use, age, sex, race/ethnicity, IQ, family poverty, and socioeconomic status. MAIN OUTCOME MEASURES: Subcortical volumetric measures of the thalamus, caudate, putamen, pallidum, hippocampus, amygdala, and nucleus accumbens; cortical thickness measures of the dorsolateral prefrontal cortex and ventral medial prefrontal cortex; and impulsivity assessed by Conners' Continuous Performance Test and the Sensation Seeking Scale for Children. RESULTS: After controlling for covariates, cortical thickness of the right dorsolateral prefrontal cortex was significantly thinner in adolescents following PCE (P = .03), whereas the pallidum volume was smaller in adolescents following prenatal tobacco exposure (P = .03). Impulsivity was correlated with thalamic volume following either PCE (P = .05) or prenatal tobacco exposure (P = .04). CONCLUSIONS AND RELEVANCE: Prenatal cocaine or tobacco exposure can differentially affect structural brain maturation during adolescence and underlie enhanced susceptibility to impulsivity. Additional studies with larger sample sizes are warranted.

Gene therapy for late infantile neuronal ceroid lipofuscinosis: neurosurgical considerations.

OBJECT: The authors conducted a phase I study of late infantile neuronal ceroid lipofuscinosis using an adenoassociated virus serotype 2 (AAV2) vector containing the deficient CLN2 gene (AAV2(CU)hCLN2). The operative technique, radiographic changes, and surgical complications are presented. METHODS: Ten patients with late infantile neuronal ceroid lipofuscinosis disease each underwent infusion of AAV2(CU)hCLN2 (3 x 10(12) particle units) into 12 distinct cerebral locations (2 depths/bur hole, 75 minutes/infusion, and 2 microl/minute). Innovative surgical techniques were developed to overcome several obstacles for which little or no established techniques were available. Successful infusion relied on preoperative stereotactic planning to optimize a parenchymal target and diffuse administration. Six entry sites, each having 2 depths of injections, were used to reduce operative time and enhance distribution. A low-profile rigid fixation system with 6 integrated holding arms was utilized to perform simultaneous infusions within a practical time frame. Dural sealant with generous irrigation was used to avoid CSF egress with possible subdural hemorrhage or altered stereotactic registration. RESULTS: Radiographically demonstrated changes were seen in 39 (65%) of 60 injection sites, confirming localization and infusion. There were no radiographically or clinically defined complications. CONCLUSIONS: The neurosurgical considerations and results of this study are presented to offer guidance and a basis for the design of future gene therapy or other clinical trials in children that utilize direct therapeutic delivery.

Newborn screening for Krabbe disease: the New York State model.

Krabbe disease is a rare inherited neurologic disorder affecting the central and peripheral nervous systems. The disease has four phenotypes: early infantile, later onset, adolescent, and adult. The only known treatment is hematopoietic stem cell transplantation, which is, in the early infantile form of the disease, most beneficial if performed before onset of clinical symptoms. In August 2006, New York State began screening all newborns for Krabbe disease. A rapid and accurate technique for assessing galactocerebrosidase activity and performing DNA mutation analysis had been developed. Interpreting these results was limited, however, because neither enzyme activity nor genetic mutation reliably predicts phenotype. A series of initiatives were therefore developed by a multidisciplinary group of neurologists, geneticists, metabolic pediatricians, neurodevelopmental pediatricians, and transplant physicians (the Krabbe Consortium of New York State) to enhance the effectiveness of the newborn screening program. A standardized clinical evaluation protocol was designed based on the available literature, criteria for transplantation for the early infantile phenotype were formulated, a clinical database and registry was developed, and a study of developmental and functional outcomes was instituted. This multidisciplinary standardized approach to evaluating infants who have positive results on newborn screening may serve as a model for other states as they begin the process of screening for Krabbe disease and other lysosomal storage disorders.

Enhanced CREB and DARPP-32 phosphorylation in the nucleus accumbens and CREB, ERK, and GluR1 phosphorylation in the dorsal hippocampus is associated with cocaine-conditioned place preference behavior.

Environment-induced relapse is a major concern in drug addiction because of the strong associations formed between drug reward and environment. Cocaine-conditioned place preference is an ideal experimental tool to examine adaptations in the molecular pathways that are activated upon re-exposure to an environment previously paired with drug reward. To better understand the mechanism of cocaine-conditioned place preference we have used western blot analysis to examine changes in phosphorylation of cAMP-response element binding protein (CREB), dopamine- and cyclic AMP-regulated phosphoprotein 32 (DARPP-32), extracellular signal-regulated kinase (ERK) and GluR1, key molecular substrates altered by cocaine, in the nucleus accumbens (NAc) and dorsal hippocampus (DHC) of C57BL/6 mice. Our studies revealed that re-exposing mice to an environment in which they were previously given cocaine resulted in increased levels of Ser133 phospho-CREB and Thr34 phospho-DARPP-32 with a corresponding decrease in Thr75 phospho-DARPP-32 in the NAc. In DHC there were increased levels of phospho-CREB, Thr183/Tyr185 phospho-ERK, and Ser845 phospho-GluR1. These data suggest that the formation of contextual drug reward associations involves recruitment of the DHC-NAc circuit with activation of the DARPP-32/CREB pathway in the NAc and the ERK/CREB pathway in the DHC.

Augmented D1 dopamine receptor signaling and immediate-early gene induction in adult striatum after prenatal cocaine.

BACKGROUND: Prenatal exposure to cocaine can impede normal brain development, triggering a range of neuroanatomical and behavioral anomalies that are evident throughout life. Mouse models have been especially helpful in delineating neuro-teratogenic consequences after prenatal exposure to cocaine. The present study employed a mouse model to investigate alterations in D(1) dopamine receptor signaling and downstream immediate-early gene induction in the striatum of mice exposed to cocaine in utero. METHODS: Basal, forskolin-, and D(1) receptor agonist-induced cyclic adenosine monophosphate (cAMP) levels were measured ex vivo in the adult male striatum in mice exposed to cocaine in utero. Further studies assessed cocaine-induced zif 268 and homer 1 expression in the striatum of juvenile (P15), adolescent (P36), and adult (P60) male mice. RESULTS: The D(1) dopamine receptor agonist SKF82958 induced significantly higher levels of cAMP in adult male mice treated with cocaine in utero compared with saline control subjects. No effects of the prenatal treatment were found for cAMP formation induced by forskolin. After an acute cocaine challenge (15 mg/kg, IP), these mice showed greater induction of zif 268 and homer 1, an effect that was most robust in the medial part of the mid-level striatum and became more pronounced with increasing age. CONCLUSIONS: Together these findings indicate abnormally enhanced D(1) receptor signal transduction in adult mice after prenatal cocaine exposure. Such changes in dopamine receptor signaling might underlie aspects of long-lasting neuro-teratogenic effects evident in some humans after in utero exposure to cocaine and identify the striatum as one target potentially vulnerable to gestational cocaine exposure.

Lentiviral-mediated gene transfer of brain-derived neurotrophic factor is neuroprotective in a mouse model of neonatal excitotoxic challenge.

Excitotoxicity may be a critical factor in the formation of brain lesions associated with cerebral palsy. When injected into the murine neopallium at postnatal day 5, the glutamatergic analog N-methyl-D-aspartate (NMDA) produces transcortical neuronal death and periventricular white matter cysts, which mimic brain damage observed in human term and preterm neonates at risk for developing cerebral palsy. We previously showed that intracerebral injection of brain-derived neurotrophic factor (BDNF) was neuroprotective in this model. Because BDNF does not easily cross the blood-brain barrier, alternative strategies to avoid repeated intracerebral injections of BDNF should be tested, particularly when the goal of such translational research is ultimately to achieve clinical application. The goal of the present study was to assess the protective role of lentiviral-mediated gene transfer of BDNF against excitotoxic lesions induced by NMDA in newborn mice. We first assessed the biological activity of BDNF gene transfer in vitro and determined the efficiency of gene transfer in our in vivo model. We next administered the BDNF-expressing vector by intracerebral injection in neonatal mice, 3 days before inducing NMDA lesions. When compared with a control green fluorescent protein-expressing lentiviral vector, administration of BDNF-expressing vector induced a significant protection of the periventricular white matter and cortical plate against the NMDA-mediated insult. Intraventricular delivery of the BDNF-expressing lentiviral vector was more efficient in terms of neuroprotection than the intraparenchymal route. Altogether, the present study shows that viral-mediated gene transfer of BDNF to newborn mouse brain is feasible and affords significant neuroprotection against an excitotoxic insult.

BDNF-induced white matter neuroprotection and stage-dependent neuronal survival following a neonatal excitotoxic challenge.

Excitotoxicity may be critical in the formation of brain lesions associated with cerebral palsy. When injected into the murine neopallium at postnatal day (P) 5, ibotenate (activating NMDA and metabotropic glutamate receptors) produces neuronal death and white matter cysts. Such white matter cysts resemble those seen in periventricular leukomalacia, a lesion evident in numerous human premature newborns. The goal of this study was to assess BDNF neuroprotection against neonatal excitotoxic lesions. Cortical and white matter lesions induced by ibotenate at P5 were reduced by BDNF by up to 36 and 60%, respectively. BDNF neuroprotection involved TrkB receptors, MAPK pathway and reduced apoptosis. Although BDNF did not prevent the initial appearance of white matter lesions, it promoted secondary decrease of the lesion size. BDNF neuroprotection at P5 was maximal against lesions induced by NMDA or ibotenate but was moderate against lesions produced by an AMPA-kainate agonist. Finally, BDNF exacerbated neuronal death produced by ibotenate at P0 through increased apoptosis and p75(NTR) receptors, while BDNF had no detectable effect on lesions induced at P10. Altogether, these data showed that BDNF neuroprotection against neonatal excitotoxicity is dependent upon the type of activated glutamate receptors, the lesion localization and the developmental stage.