Mossy fibre sprouting and re-organization in the inner molecular layer of the dentate gyrus is a characteristic of many models of temporal lobe epilepsy including that induced by perforant-path stimulation. However, neuroplastic changes on the dendrites of granule cells have been less-well studied. Basal dendrites are a transient morphological feature of rodent granule cells during development. The goal of the present study was to examine whether granule cell basal dendrites are generated in rats with epilepsy induced by perforant-path stimulation. Adult Wistar rats were stimulated for 24 h at 2 Hz and with intermittent (1/min) trains (10 s duration) of single stimuli at 20 Hz (20 V, 0.1 ms) delivered 1/min via an electrode placed in the angular bundle. The brains of these experimental rats and age- and litter-matched control animals were processed for the rapid Golgi method. All rats with perforant-path stimulation displayed basal dendrites on many Golgi-impregnated granule cells. These basal dendrites mainly originated from their somata at the hilar side and then extended into the hilus. Quantitative analysis of more than 800 granule cells in the experimental and matched control brains showed that 6-15% (mean=8.7%) of the impregnated granule cells have spiny basal dendrites on the stimulated side, as well as the contralateral side (mean=3.1%, range=2.9-3.9%) of experimental rats, whereas no basal dendrites were observed in the dentate gyrus from control animals. The formation of basal dendrites appears to be an adaptive morphological change for granule cells in addition to the previously described mossy fibre sprouting, as well as dendritic and somatic spine formation observed in the dentate gyrus of animal and human epileptic brains. The presence of these dendrites in the subgranular region of the hilus suggests that they may be postsynaptic targets of the mossy fibre collaterals.

Active caspase-3 immunoreactivity was detected in the rat forebrain proliferative regions at birth and remained high in these areas for about 2 weeks, during which period labeled cells were present centroperipherally across the olfactory bulb. By the end of the third postnatal week, only a small number of immunolabeled cells remained in these forebrain structures. Active caspase-3 immunolabeling was localized mostly to cell nuclei and co-localized partially with TuJ1 and NeuN immunoreactivity, but not with glial fibrially acidic protein, OX-42, gamma-aminobutyric acid, or terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL)-positive labeling. Active caspase-3 and 5-bromo-2'-deoxyuridine (BrdU) double-labeled nuclei were seen in the proliferative regions after 2 hours and in the periglomerular region of the bulb after 7 days following BrdU injections. Examination of the cells with electron microscopy confirmed that the active caspase-3-containing nuclei in the proliferative regions often had infoldings and appeared to be undergoing division. Some of the cells with active caspase-3-labeled nuclei in the bulb had synapses on their somata or dendrites. Labeled dendritic spines and a few axon terminals were also observed in the olfactory bulb. Taken together, it appears that a wave of active caspase-3-positive cells are dividing in the proliferative zones and then migrating to the bulb as they differentiate into neurons. Therefore, active caspase-3 may play a role in cellular processes such as neuronal differentiation, migration, and plasticity, in addition to its role in cell death.

Cerebral hypometabolism, mitochondrial dysfunction, and beta-amyloid peptide (Abeta) accumulation are well-characterized manifestations of Alzheimer's disease (AD). beta-Secretase (BACE) is a prerequisite for amyloidogenesis, and it is up-regulated in sporadic AD. To explore a potential in vivo mechanism by which Abeta production is modulated by neuronal activity and/or oxidative metabolism, we compared BACE expression with cytochrome c oxidase (CO) or succinic dehydrogenase (SDH) activity in normal and functionally deprived adult rat olfactory bulb. In normal bulb, BACE was expressed predominantly in the glomerular layer, but labeling intensity within individual glomeruli varied substantially. A strong negative correlation existed between BACE labeling intensity and CO or SDH activity among individual glomeruli. Unilateral naris occlusion resulted in elevated glomerular BACE labeling in the deprived bulbs relative to the nondeprived counterparts, which was correlated with decreased CO activity in the same anatomic location. Enhanced BACE labeling was confirmed by measurements of elevated protein levels, enzymatic activity, and beta-site cleavage products of amyloid precursor protein in bulb extracts. Our findings reveal a negative regulation of BACE expression by physiological neuronal activity and an intrinsic inverse correlation between BACE expression and oxidative metabolism at the first synapse on the olfactory pathway. The results point to a biological role of BACE in synapse function and plasticity as well as a potential mechanism whereby reduced neuronal activity or metabolism could lead to amyloid overproduction in synaptic terminals.

Corticotropin-releasing factor 1 (CRF 1 ) antagonists may be effective in the treatment of anxiety disorders with fewer side effects compared with classic benzodiazepines. The behavioral effects of DMP904 [4-(3-pentylamino)-2,7-dimethyl-8-(2-methyl-4-methoxyphenyl)-pyrazolo-[1,5-a]-pyrimidine] and its effects on the hypothalamic-pituitary-adrenal (HPA) axis were related to its levels in plasma and estimated occupancy of central CRF 1 receptors. DMP904 (10 -30 mg/kg, p.o.) and alprazolam (10 mg/kg, p.o.) increased time spent in open arms of an elevated-plus maze. In addition, acutely or chronically (14 days) administered DMP904 (1.0 -30 mg/kg, p.o.) and acute alprazolam (1.0 -3.0 mg/kg, p.o.) significantly reduced exit latency in the defensive withdrawal model of anxiety in rats, suggesting that tolerance may not develop to the anxiolytic-like effects of DMP904 in this model of anxiety. Acutely, DMP904 reversed the stress-induced increase in plasma corticosterone levels in defensive withdrawal at doses of 3.0 mg/kg and higher. These doses also resulted in levels of DMP904 in plasma similar to (for anxiolytic-like effects) or 4-fold higher (for effects on the HPA axis) than the in vitro IC 50 value for binding affinity at CRF 1 receptors and greater than 50% occupancy of CRF 1 receptors. Unlike alprazolam, DMP904 did not produce sedation, ataxia, or chlordiazepoxide-like subjective effects (as measured by locomotor activity, rotorod performance, and chlordiazepoxide discrimination assays, respectively) at doses at least 3-fold higher than anxiolytic-like doses. In conclusion, anxiolytic-like effects and effects on the stress-activated HPA axis of DMP904 in the defensive withdrawal model of anxiety required 50% or greater occupancy of central CRF 1 receptors. This level of CRF 1 receptor occupancy resulted in fewer motoric side effects compared with classic benzodiazepines.Corticotropin-releasing factor 1 (CRF 1 ) antagonists are a new class of compounds that may have anxiolytic-like effects in nonhuman animals without motoric side effects associated with classic anxiolytic agents (for review, see Takahashi, 2001). CP-154,526 reversed separation-induced increase in ultrasonic vocalization in rat pups (Kehne et al., 2000) and reduced expression of conditioned fear in rats (Hikichi et al., 2000). In addition, this compound also increased time spent in open arms of an elevated-plus maze in rats (Lundkvist et al., 1996), although this result was not repeated in another study (Griebel et al., 1998). Furthermore, SSR125543A inArticle, publication date, and citation information can be found at http://jpet.aspetjournals.org.DOI: 10.1124/jpet.103.058784.ABBREVIATIONS: CRF, corticotropin-releasing factor; 526,4,6,

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