Faculty Bibliography

Acute seizures after a severe brain insult can often lead to epilepsy and cognitive impairment. Aberrant hippocampal neurogenesis follows the insult but the role of adult-generated neurons in the development of chronic seizures or associated cognitive deficits remains to be determined. Here we show that the ablation of adult neurogenesis before pilocarpine-induced acute seizures in mice leads to a reduction in chronic seizure frequency. We also show that ablation of neurogenesis normalizes epilepsy-associated cognitive deficits. Remarkably, the effect of ablating adult neurogenesis before acute seizures is long lasting as it suppresses chronic seizure frequency for nearly 1 year. These findings establish a key role of neurogenesis in chronic seizure development and associated memory impairment and suggest that targeting aberrant hippocampal neurogenesis may reduce recurrent seizures and restore cognitive function following a pro-epileptic brain insult.

KEY POINTS: Na(+) current (INa ) results from the integrated function of a molecular aggregate (the voltage-gated Na(+) channel complex) that includes the beta subunit family. Mutations or rare variants in Scn1b (encoding the beta1 and beta1B subunits) have been associated with various inherited arrhythmogenic syndromes, including Brugada syndrome and sudden unexpected death in patients with epilepsy. We used Scn1b null mice to understand better the relation between Scn1b expression, and cardiac electrical function. Loss of Scn1b caused, among other effects, increased amplitude of tetrodotoxin-sensitive INa , delayed after-depolarizations, triggered beats, delayed Ca(2+) transients, frequent spontaneous calcium release events and increased susceptibility to polymorphic ventricular arrhythmias. Most alterations in Ca(2+) homeostasis were prevented by 100 nm tetrodotoxin. We propose that life-threatening arrhythmias in patients with mutations in Scn1b, a gene classically defined as ancillary to the Na(+) channel alpha subunit, can be partly consequent to disrupted intracellular Ca(2+) homeostasis. ABSTRACT: Na(+) current (INa ) is determined not only by the properties of the pore-forming voltage-gated Na(+) channel (VGSC) alpha subunit, but also by the integrated function of a molecular aggregate (the VGSC complex) that includes the VGSC beta subunit family. Mutations or rare variants in Scn1b (encoding the beta1 and beta1B subunits) have been associated with various inherited arrhythmogenic syndromes, including cases of Brugada syndrome and sudden unexpected death in patients with epilepsy. Here, we have used Scn1b null mouse models to understand better the relation between Scn1b expression, and cardiac electrical function. Using a combination of macropatch and scanning ion conductance microscopy we show that loss of Scn1b in juvenile null animals resulted in increased tetrodotoxin-sensitive INa but only in the cell midsection, even before full T-tubule formation; the latter occurred concurrent with increased message abundance for the neuronal Scn3a mRNA, suggesting increased abundance of tetrodotoxin-sensitive NaV 1.3 protein and yet its exclusion from the region of the intercalated disc. Ventricular myocytes from cardiac-specific adult Scn1b null animals showed increased Scn3a message, prolonged action potential repolarization, presence of delayed after-depolarizations and triggered beats, delayed Ca(2+) transients and frequent spontaneous Ca(2+) release events and at the whole heart level, increased susceptibility to polymorphic ventricular arrhythmias. Most alterations in Ca(2+) homeostasis were prevented by 100 nm tetrodotoxin. Our results suggest that life-threatening arrhythmias in patients with mutations in Scn1b, a gene classically defined as ancillary to the Na(+) channel alpha subunit, can be partly consequent to disrupted intracellular Ca(2+) homeostasis in ventricular myocytes.

Endosomal-lysosomal and autophagic dysregulation occurs in the hippocampus in prodromal Alzheimer disease (AD), but its relationship with beta-amyloid (Abeta) and tau pathology remains unclear. To investigate this issue, we performed immunoblot analysis of hippocampal homogenates from cases with an antemortem clinical diagnosis of no cognitive impairment, mild cognitive impairment (MCI), and AD. Western blot analysis revealed significant increases in the acid hydrolase cathepsin D and early endosome marker rabaptin5 in the MCI group compared with AD, whereas levels of phosphorylated mammalian target of rapamycin proteins (pmTOR), total mammalian target of rapamycin (mTOR), p62, traf6, and LilrB2 were comparable across clinical groups. Hippocampal Abeta1-40 and Abeta1-42 concentrations and AT8-immunopositive neurofibrillary tangle density were not significantly different across the clinical groups. Greater cathepsin D expression was associated with global cognitive score and episodic memory score but not with mini mental state examination or advanced neuropathology criteria. These results indicate that alterations in hippocampal endosomal-lysosomal proteins in MCI are independent of tau or Abeta pathology.

Cancer pain sends a message. It is frightening to the patient. It heralds progression or recurrence to the oncologist. It is a biological readout of the cancer-nerve interaction for the scientist. Nerves have been considered bystanders within the cancer microenvironment. However, emerging information suggests that nerves are recruited and participate in the carcinogenic process. These newly formed fibers respond to mediators secreted by constituents of the cancer microenvironment. In this manner, these nerves serve as bellwethers and sensors embedded within the cancer. When we rigorously assess patients' cancer pain, we gain insight into the action of cancer. An enhanced understanding of cancer pain offers biological questions that if answered might not only provide relief from cancer pain but might also improve survival.

PURPOSE: Delivering the recommended care is an important quality measure that has been insufficiently studied in urology. Obstructive pyelonephritis is a suitable case study for this focus because many patients do not receive such care, although guidelines advocate decompression. We determined the influence of hospital factors, particularly familiarity with urolithiasis, on the likelihood of decompression in such patients. MATERIALS AND METHODS: We used the NIS from 2002 to 2011 to retrospectively identify patients admitted to community hospitals with severe infection and ureteral calculi. Hospital familiarity with nephrolithiasis was estimated by calculating hospital stone volume (divided into quartiles) and hospital treatment intensity (the decompression rate in patients with ureteral calculi and no infection). After calculating national estimates we performed logistic regression to determine the association between the receipt of decompression and hospital stone volume, controlling for treatment intensity and other covariates thought to be associated with receiving recommended care. RESULTS: Of an estimated 107,848 patients with obstructive pyelonephritis 27.4% failed to undergo decompression. Discrepancies were greatest between hospitals with the highest and lowest stone volumes (76% vs 25%, OR 2.77, 95% CI 1.94-3.96, p <0.01) as well as high and low treatment intensity (78% vs 37%, p <0.01). CONCLUSIONS: High hospital stone volume and treatment intensity were associated with an increased likelihood of receiving decompression. Such findings might be useful to identify hospitals and regions where access to quality urological care should be augmented.

INTRODUCTION: Our aim was to assess differences in movement measures in attention-deficit/hyperactivity disorder (ADHD) vs. typically developing (TD) controls. METHODS: We performed meta-analyses of published studies on motion measures contrasting ADHD with controls. We also conducted a case-control study with children/adolescents (n=61 TD, n=62 ADHD) and adults (n=30 TD, n=19 ADHD) using the McLean motion activity test, semi-structured diagnostic interviews and the behavior rating inventory of executive function and Conners (parent, teacher; self) rating scales. RESULTS: Meta-analyses revealed medium-to-large effect sizes for actigraph (standardized mean difference [SMD]: 0.64, 95% confidence interval (CI): 0.43, 0.85) and motion tracking systems (SDM: 0.92, 95% CI: 0.65, 1.20) measures in differentiating individuals with ADHD from controls. Effects sizes were similar in studies of children/adolescents ([SMD]: 0.75, 95% CI: 0.50, 1.01) and of adults ([SMD]: 0.73, 95% CI: 0.46, 1.00). In our sample, ADHD groups differed significantly in number of head movements (p=0.02 in children; p=0.002 in adults), displacement (p=0.009/p<0.001), head area (p=0.03/p<0.001), spatial complexity (p=0.06/p=0.02) and temporal scaling (p=0.05/p=0.04). Mean effect sizes were non-significantly larger (d=0.83, 95% CI: 0.20, 1.45) in adults vs. children/adolescents with ADHD (d=0.45, 95% CI: 0.08, 0.82). In the concurrent go/no-go task, reaction time variability was significantly greater in ADHD (p<0.05 in both age groups) than controls. CONCLUSIONS: Locomotor hyperactivity remains core to the construct of ADHD even in adults. Our results suggest that objective locomotion measures may be particularly useful in evaluating adults with possible ADHD.

Differential thermal nociception across inbred mouse strains has genetic determinants. Thermal nociception is largely attributed to the heat/capsaicin receptor TRPV1; however, the contribution of this channel to the genetics of thermal nociception has not been revealed. In this study we compared TRPV1 expression levels and electrophysiological properties in primary sensory neurons and thermal nociceptive behaviors between two (C57BL/6 and BALB/c) inbred mouse strains. Using immunofluorescence and patch-clamp physiology methods, we demonstrated that TRPV1 expression was significantly higher in isolectin B4 (IB4) -positive trigeminal sensory neurons of C57BL/6 relative to BALB/c; the expression in IB4-negative neurons was similar between the strains. Furthermore, using electrophysiological cell classification (current signature method), we showed differences between the two strains in capsaicin sensitivity in IB4-positive neuronal cell types 2 and 13, that were previously reported as skin nociceptors. Otherwise electrophysiological membrane properties of the classified cell types were similar in the two mouse strains. In publicly available nocifensive behavior data and our own behavior data from the using the two mouse strains, C57BL/6 exhibited higher sensitivity to heat stimulation than BALB/c, independent of sex and anatomical location of thermal testing (the tail, hind paw and whisker pad). The TRPV1 selective antagonist JNJ-17203212 inhibited thermal nociception in both strains; however, removing IB4-positive trigeminal sensory neurons with IB4-conjugated saporin inhibited thermal nociception on the whisker pad in C57BL/6, but not in BALB/c. These results suggest that TRPV1 expression levels in IB4-positive type 2 and 13 neurons contributed to differential thermal nociception in skin of C57BL/6 compared to BALB/c.

In June 2014 Dr. Joseph D. Fenstermacher celebrated his 80th birthday, which was honored by the symposium held in New London, NH, USA. This review discusses Fenstermacher's contribution to the field of fluids and barriers of the CNS. Specifically, his fundamental work on diffusion of molecules within the brain extracellular space and the research on properties of the blood-brain barrier in health and disease are described. Fenstermacher's early research on cerebrospinal fluid dynamics and the regulation of cerebral blood flow is also reviewed, followed by the discussion of his more recent work involving the use of magnetic resonance imaging.