Faculty Bibliography

INTRODUCTION: The incidence of asthma may be increased in patients with obesity. However, recognition of airway disease is confounded by abnormal lung physiology seen in obesity per se. Healthy obese patients with normal spirometry have elevated resistance (oscillometry) similar to non-obese patients with obstructive spirometry. However, in obese patients elevated resistance is associated with decreased FRC (mass loading), whereas FRC is normal-high in non-obese patients with airway obstruction. We hypothesize that obese patients with obstructive dysfunction can be distinguished from obese patients without airway disease by relating oscillometry findings to resting lung volume (FRC). METHODS: 183 obese subjects (BMI 30-73 kg/m²) were divided into 3 groups. Group 1: healthy obese (non-smoker, no history of lung disease, normal FEV₁/FVC; n= 62) Group 2: obstructive airway disease (reduced FEV₁/FVC; n= 40) Group 3: reported diagnosis of asthma with normal airflow (normal FEV₁/FVC; n= 81). All subjects underwent spirometry and plethysmography. Oscillometry was performed at baseline and repeated during voluntary inflation to predicted FRC to minimize the confounding effect of reduced lung volume on airway resistance. Oscillometry parameters included resistance at 5 and 20Hx (R₅, R₂₀). RESULTS: VC, IC, and ERV were similar in Groups 1 and 2 (Table 1). FRC was reduced in all subjects of Group 1; in Group 2 higher values were seen extending into normal range despite obesity. R₅ and R₂₀ were elevated in all subjects to a similar degree in Groups 1 and 2; calculation of specific conductance for R₅ and R₂₀ (SGrs5, SGrs20) distinguished Group 1 from Group 2. Based on these observations, Group 3 was divided into normal vs. reduced FRC (Table 2). To minimize the effect of lung volume on resistance in Group 3, oscillometry data were analyzed at similar lung volumes (i.e. during voluntary inflation in subjects with reduced FRC vs. at baseline in remaining subjects with normal FRC). Subjects with normal FRC demonstrated higher values for R₅ and R₂₀ compared to subjects with reduced FRC. Response to bronchodilator was only noted in those subjects with normal FRC. CONCLUSIONS: Preservation of FRC occurred in obese patients with known airway disease and reduced FEV₁/FVC. In patients with normal airflow despite self reported asthma, increased airway resistance was associated with normal FRC. Therefore, whereas a reduction in FRC is expected in healthy obese subjects, a normal FRC may reflect pseudo-normalization as a manifestation of airway disease even when FEV₁/FVC is normal. (Table Presented)

Gamma rhythms are commonly observed in many brain regions during both waking and sleep states, yet their functions and mechanisms remain a matter of debate. Here we review the cellular and synaptic mechanisms underlying gamma oscillations and outline empirical questions and controversial conceptual issues. Our main points are as follows: First, gamma-band rhythmogenesis is inextricably tied to perisomatic inhibition. Second, gamma oscillations are short-lived and typically emerge from the coordinated interaction of excitation and inhibition, which can be detected as local field potentials. Third, gamma rhythm typically concurs with irregular firing of single neurons, and the network frequency of gamma oscillations varies extensively depending on the underlying mechanism. To document gamma oscillations, efforts should be made to distinguish them from mere increases of gamma-band power and/or increased spiking activity. Fourth, the magnitude of gamma oscillation is modulated by slower rhythms. Such cross-frequency coupling may serve to couple active patches of cortical circuits. Because of their ubiquitous nature and strong correlation with the "operational modes" of local circuits, gamma oscillations continue to provide important clues about neuronal population dynamics in health and disease.

Background: Tau pathology is involved in multiple neurodegenerative disorders, for example in Alzheimer's disease, Parkinson's disease, and Frontotemporal dementia (FTD). Tau is a neuronal protein that binds microtubules and is thought to be involved in the stabilization of microtubules. Over 50 different mutations within the MAPT gene, the gene encoding for Tau, have been associated with inherited FTD. FTD is thought to involve deficits in the communication between neurons and in the mechanisms neuronal adaptation to experience, synaptic plasticity. The role of Tau in mechanisms of synaptic plasticity is not well-understood. To address this gap in the field, we have investigated synaptic plasticity and behavior in P301L mice, a mouse model for tau pathology that over-expresses human Tau protein carrying an inherited human mutation. Methods: Long-lasting forms of plasticity, late-phase long term potentiation (L-LTP) were examined in P301L (JNPL3) mice and age-matched controls by measuring field excitatory postsynaptic potentiation (fEPSP) in the CA1 hippocampal region after high frequency electrophysiological stimulation. Two behaviors associated with GABAergic function were assayed, prepulse inhibition of startle response (PPI) and susceptibility to epileptic seizures. GABAergic interneurons were stained using two markers; paravalbumin and somatostatin. Results: By examining long-lasting forms of plasticity in aged (>18 months old) in hippocampal brain slices we found surprisingly enhanced L-LTP in P301L mice compared to age-matched controls. The enhanced L-LTP in P301L slices was rescued by treatment with a GABA agonist, Zolpidem. These results suggest a loss of GABAergic neurons in P301L mice. Next we examined PPI and susceptibility to epileptic seizures in P301L and control mice. We found an altered PPI response and differences in epileptic seizures grades. Finally, we stained GABAergic interneurons in the hippocampus using two markers that identify GABAergic cell types showing a decrease in GABAergic neurons in the hippocampal CA1 region. Conclusions: Our results suggest that GABAergic interneurons are more vulnerable to molecular lesions caused by pathological Tau, which may result in the selective loss of hippocampal GABAergic interneurons. The molecular mechanisms involved in this specific GABAergic loss remains to be resolved, but may help to explain the pathophysiological symptoms of diseases like FTD, which involve altered Tau function

Homeostatic scaling of synaptic strengths is essential for maintenance of network "gain", but also poses a risk of losing the distinctions among relative synaptic weights, which are possibly cellular correlates of memory storage. Multiplicative scaling of all synapses has been proposed as a mechanism that would preserve the relative weights among them, because they would all be proportionately adjusted. It is crucial for this hypothesis that all synapses be affected identically, but whether or not this actually occurs is difficult to determine directly. Mathematical tests for multiplicative synaptic scaling are presently carried out on distributions of miniature synaptic current amplitudes, but the accuracy of the test procedure has not been fully validated. We now show that the existence of an amplitude threshold for empirical detection of miniature synaptic currents limits the use of the most common method for detecting multiplicative changes. Our new method circumvents the problem by discarding the potentially distorting subthreshold values after computational scaling. This new method should be useful in assessing the underlying neurophysiological nature of a homeostatic synaptic scaling transformation, and therefore in evaluating its functional significance.

Background: Immunotherapy targeting hyperphosphorylated tau is a promising prospect to mitigate the neurodegenerative effects of tauopathies. Assessing the effectiveness of such immunotherapies often involves sacrifice of the animal. However, Manganese-Enhanced Magnetic Resonance Imaging (MEMRI) permits the longitudinal study of neuronal function with minimal risk to the animal. We hypothesize that tract-tracing MEMRI in a mouse model of tau pathology should enable non-invasive monitoring of various tau targeting therapies aimed at improving neuronal integrity. Methods: Twenty-five homozygous JNPL3 tangle transgenic mice underwent MEMRI at 6 months of age. Thirteen of the mice received tau immunotherapy with Tau379-408[P-Ser396,404] in alum adjuvant from 3 months of age, and twelve controls received an adjuvant alone. Imaging studies were performed on a 7-T micro-MRI. Mice were imaged pre-injection, then injected in one nostril with a solution of 2.5 M MnCl 2, under isoflurane anesthesia. Image sets were acquired at 1, 4, 8, 12, 24, 36 and 48 hours, and finally at 7 days (Fig 1). The datasets were processed using ImageJ. Normalized measurements for each mouse were plotted and fitted to a tract tracing bolus model using MATLAB. Fitting enabled the estimation of the timing (Pt) and intensity (Pv) of the bolus peak of Mn, and maximal slope of uptake (Sv). Results: A significant increase in maximal slope of manganese uptake, Sv, was observed in the mitral cell layer (35%, P <.005) and glomerular layer (36%, P <0.02) in treated JNPL3 mice compared to identical controls. There was also a significant increase in bolus peak value, Pv, in the mitral layer in the treated group (7%, P = 0.02). Furthermore, in the immunized mice, there was a strong trend for a decrease in the time to peak value, Pt (-9%P = 0.10), in the mitral cell layer, compared to the controls. Conclusions: Utilizing MEMRI's non-invasive, longitudinal measurements from 1 hour to 7 days, allowed us to detect substantial improvements in neuronal transport following tau immunotherapy. We are analyzing tau pathology in olfactory sections from these mice to assess the correlation of these benefits with clearance of tau lesions, which we have shown previously to occur with this treatment

Functional neuronal homeostasis has been studied in a variety of model systems and contexts. Many studies have shown that there are a number of changes that can be activated within individual cells or networks in order to compensate for perturbations or changes in levels of activity. Dissociating the cell autonomous from the network-mediated events has been complicated due to the difficulty of sparsely targeting specific populations of neurons in vivo. Here, we make use of a recent in vivo approach we developed that allows for the sparse labeling and manipulation of activity within superficial caudal ganglionic eminence (CGE)-derived GABAergic interneurons. Expression of the inward rectifying potassium channel Kir2.1 cell-autonomously reduced neuronal activity and lead to specific developmental changes in their intrinsic electrophysiological properties and the synaptic input they received. In contrast to previous studies on homeostatic scaling of pyramidal cells, we did not detect any of the typically observed compensatory mechanisms in these interneurons. Rather, we instead saw a specific alteration of the kinetics of excitatory synaptic events within the reelin-expressing subpopulation of interneurons. These results provide the first in vivo observations for the capacity of interneurons to cell-autonomously regulate their excitability.