Neuronal death in the dorsal root ganglion after sciatic nerve injury does not depend on sortilin.

Injury to the sciatic nerve induces loss of sensory neurons in the affected dorsal root ganglia (DRGs). Previous studies have suggested the involvement of the neurotrophin receptors p75 neurotrophin receptor (p75(NTR)) and sortilin, proposing that sensory neuron subpopulations undergo proneurotrophin-induced apoptosis in a similar manner to what can be observed in the CNS following injury. To further investigate this hypothesis we induced sciatic nerve injury in sortilin-deficient mice, thereby preventing apoptotic signaling of proneurotrophins via the sortilin-p75(NTR) receptor complex. Using an unbiased stereological approach we found that loss of sortilin did not prevent the injury-induced loss of DRG neurons. This result demonstrates that previous findings linking p75(NTR) and proneurotrophins to loss of sensory neurons need to involve sortilin-independent pathways and suggests that proneurotrophins may elicit different functions in the CNS and PNS.

Distribution of serotonin receptor 5-HT6 mRNA in rat neuronal subpopulations: A double in situ hybridization study.

The 5-HT6 receptor (5-HT6R) is almost exclusively expressed in the brain and has emerged as a promising target for cognitive disorders, including Alzheimer's disease. In the present study, we have determined the cell types on which the 5-HT6R is expressed by colocalizing 5-HT6R mRNA with that of a range of neuronal and interneuronal markers in the rat brain. Here, we show that 5-HT6R mRNA was expressed at high levels in medium spiny neurons in caudate putamen and in nucleus accumbens, as well as in the olfactory tubercle. Striatal 5-HT6R mRNA was colocalized with both dopamine D1 and D2 receptor mRNA. 5-HT6R mRNA was moderately expressed in the hippocampus and throughout cortical regions in glutamatergic neurons coexpressing vGluT1. A subset of GAD67-positive GABAergic interneurons (approximately 15%) expressed 5-HT6R mRNA in the cortex and hippocampus, the majority of which belonged to the 5-HT3a receptor (5-HT3aR)-expressing subpopulation. In contrast, 5-HT6R mRNA was only expressed to a minor extent in the parvalbumin and somatostatin subpopulations. A subset of calbindin- and calretinin-positive GABAergic interneurons expressed 5-HT6R mRNA while only a very minor fraction of VIP or NPY interneurons in forebrain structures expressed 5-HT6R mRNA. Serotonergic, dopaminergic or cholinergic neurons did not express 5-HT6R mRNA. These data indicate that the 5-HT6R is located on GABAergic and glutamatergic principal neurons, and on a subset of interneurons mainly belonging to the 5-HT3aR subgroup suggesting that the 5-HT6R is positioned to regulate the balance between excitatory and inhibitory signaling in the brain. These data provide new insights into the mechanisms of 5-HT6R signaling.

Strain differences in the effects of adrenalectomy on the midbrain dopamine system: implication for behavioral sensitization to cocaine.

Adrenalectomy (ADX) abolishes behavioral sensitization to cocaine in DBA/2, but not C57BL/6 inbred mice. The present study tests the hypothesis that this ADX effect on behavioral sensitization in the DBA/2 strain involves changes in midbrain dopamine systems that do not occur in the C57BL/6 strain. For that purpose, we have measured tyrosine hydroxylase (TH) and dopamine transporter (DAT) mRNA and D1- and D2-like receptor binding in C57BL/6 and DBA/2 mice that were i) unoperated, ii) ADX or sham (SHAM) operated, or iii) ADX or SHAM operated and subjected to a cocaine sensitization regimen (15.0 mg/kg cocaine on nine consecutive days, followed by a 7.5 mg/kg challenge after a 5-day withdrawal). ADX prevented behavioral sensitization to cocaine in the DBA/2, but not the C57BL/6 strain [de Jong IEM, Oitzl MS, de Kloet ER (2007) Adrenalectomy prevents behavioural sensitisation of mice to cocaine in a genotype-dependent manner. Behav Brain Res 177:329-339]. Mice were killed under basal conditions, in the latter case 24 h after the cocaine challenge. ADX did not affect the dopaminergic markers in drug naïve mice. By contrast, strain-dependent neuroadaptations were found in the midbrain dopamine system of mice subjected to the sensitization regimen. In the DBA/2 strain, sensitization-resistant ADX mice were characterized by reduced D2 binding in the nucleus accumbens core and rostral caudate putamen. Furthermore, ADX prevented the increase in TH and DAT mRNA expression in the substantia nigra, and the decrease in D2 binding in the dorsomedial subdivision of the caudal caudate putamen associated with sensitization in SHAM mice. In the C57BL/6 strain ADX only marginally affected dopaminergic adaptations. These data suggest that adrenal hormones modulate behavioral sensitization to cocaine in a genotype-dependent fashion possibly through adaptations in pre- and post-synaptic components of the midbrain dopamine system. During cocaine sensitization, the DBA/2, but not the C57BL/6 strain, was susceptible to ADX in the dopamine system with respect to presynaptic TH and DAT and terminal D2 receptor expression.