Faculty Bibliography

Thalamocortical dysrhythmias (TCD) may underlie a variety of neurological and neuropsychiatric symptoms. In TCD, pathological theta-range (4-8 Hz) activity from thalamic deafferentation or disfacilitation has been hypothesized to trigger thalamocortical (TC) domains to function at low frequency, surrounded by areas of gamma-band activity. This intersection has been viewed as creating an 'edge effect' which underlies some positive symptoms. TC properties could also maintain and distribute TCD. Spontaneous neuromagnetic activity was recorded from patients suffering from refractory obsessive-compulsive disorder (OCD) and/or major depression (MD) and from healthy controls. Recordings were performed with a whole-head magnetoencephalogram (MEG) (4-D Neuroimaging) in a shielded room. Activity was recorded for 5-10 min while subjects rested with eyes closed. Spectral analysis using a multitaper technique and cross-correlations between spectral amplitudes were calculated using Matlab (Mathworks, Inc.) and in-house software on a Linux cluster computer system. Power spectra from control recordings demonstrated typical alpha-rhythms, while spectra from OCD and MD subjects showed robust activity in the theta range and increased total power compared to controls. Coherence patterns from controls displayed activation of discrete frequency ranges, while patterns from OCD and MD subjects showed high coherence over a wide range of frequencies. This may reflect theta-range recursive corticothalamic activation

The interaction between cortical input frequency and intrinsic thalamic neuron (TN) properties were investigated using intracellular recordings from mice TNs in thalamocortical (TC) slices. Excitatory postsynaptic potentials (EPSPs) of corticothalamic (CT) origin were recorded at TN membrane potentials (V-m) held, by current clamp means, between -59 and -55 mV to avoid low-threshold calcium currents (I-T) activation. EPSPs elicited in ventrobasal neurons (n = 25) by stimulation in the internal capsule showed constant latency, relatively fast rise time (2.9 +/- 0.56 ms) and short duration (26.6 +/- 9.11 ms). EPSPs evoked by threshold stimulation (n = 10) showed similar characteristics (mean rise time, 2.74 +/- 0.42 ms; mean duration, 30 +/- 8.00 ms). The time course of CT synaptic facilitation was determined using pairs of stimuli. Paired-pulse facilitation (PPF) of CT EPSPs peaked at 25-30 ms stimulus intervals and decayed exponentially with an average time constant of 130 ms (n = 50). Application of the NMDA receptor blocker APV (25 mu M, n = 4) did not modify PPF for any interstimulus interval studied but suppressed frequency facilitation evoked by trains of CT stimuli. We compared the number of spikes per stimulus (F-s) evoked in TNs by repetitive CT stimulation over a range of frequencies at different V-m. At hyperpolarized V-m (below -65 mV) and frequencies of stimulation >= 10 Hz, F-s decreased along the train while at depolarized V-m (above -59 mV) F-s increased along the train. Decremental patterns resulted from the activation of I-T while facilitatory patterns emerged from superposition of synaptic and intrinsic mechanisms. At hyperpolarized V-m steady-state F-s was maximal for frequencies <= 2 Hz, intermediate for frequencies between 2 and 10 Hz and zero at >= 10 Hz. At depolarized V-m, steady-state F-s increased with increasing frequencies (from 1 to 40 Hz).We conclude that the CT-TN junctions are tuned to establish stable thalamocortical resonant dynamics

Synaptotagmin (Syt) I, an abundant synaptic vesicle protein, consists of one transmembrane region, two C2 domains, and a short C terminus. This protein is essential for both synaptic vesicle exocytosis and endocytosis via its C2 domains. Although the short C terminus is highly conserved among the Syt family and across species, little is known about the exact role of the conserved C terminus of Syt I. In this paper, we report a function of the Syt I C terminus in synaptic vesicle docking at the active zones. Presynaptic injection of a peptide corresponding to the C-terminal 21 amino acids of Syt I (named Syt-C) into the squid giant synapse blocked synaptic transmission without affecting the presynaptic action potential or the presynaptic Ca(2+) currents. The same procedure repeated with a mutant C-terminal peptide (Syt-CM) had no effect on synaptic transmission. Repetitive presynaptic stimulation with Syt-C produced a rapid decrease in the amplitude of the postsynaptic potentials as the synaptic block progressed, indicating that the peptide interferes with the docking step rather than the fusion step of synaptic vesicles. Electron microscopy of the synapses injected with the Syt-C peptide showed a marked decrease in the number of docked synaptic vesicles at the active zones, as compared with controls. These results indicate that Syt I is a multifunctional protein that is involved in at least three steps of synaptic vesicle cycle: docking, fusion, and reuptake of synaptic vesicles

BACKGROUND AND PURPOSE: Several issues regarding ethnic-cultural factors, sex-related variation, and risk factors for stroke have been described in the literature. However, there have been no prospective studies comparing ethnic differences and stroke subtypes between populations from South America and North America. It has been suggested that natives from Buenos Aires, Argentina, may have higher frequency of hemorrhagic strokes and penetrating artery disease than North American subjects. The aim of this study was to validate this hypothesis. METHODS: We studied the database of all consecutive acute stroke patients admitted to the Ramos Mejia Hospital (RMH) in Buenos Aires and to the Beth Israel Deaconess Medical Center (BIMC) in Boston, Massachusetts, from July 1997 to March 1999. Stroke subtypes were classified according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria. All information on patients (demographic, clinical, and radiographic) was recorded prospective to the assessment of the stroke subtype. RESULTS: Three hundred sixty-one and 479 stroke patients were included at RMH and BIMC stroke data banks, respectively. Coronary artery disease was significantly more frequent in BIMC (P:<0.001), whereas tobacco and alcohol intake were significantly more frequent in RMH (P:<0.001). Intracerebral hemorrhage (P:<0.001) and penetrating artery disease (P:<0.001) were significantly more frequent in the RMH registry, whereas large-artery disease (P:<0.02) and cardioembolism (P:<0.001) were more common in the BIMC data bank. CONCLUSIONS: Penetrating artery disease and intracerebral hemorrhage were the most frequent stroke subtypes in natives from Buenos Aires. Lacunar strokes and intracerebral hemorrhage were more frequent among Caucasians from Buenos Aires than Caucasians from Boston. Poor risk factor control and dietary habits could explain these differences

The GTPase dynamin I is required for synaptic vesicle (SV) endocytosis. Our observation that dynamin binds to the SV protein synaptophysin in a Ca(2+)-dependent fashion suggested the possibility that a dynamin/synaptophysin complex functions in SV recycling. In this paper we show that disruption of the dynamin/synaptophysin interaction by peptide injection into the squid giant synapse preterminal results in a decrease in transmitter release during high-frequency stimulation, indicating an inhibition of SV recycling. Electron microscopy of these synapses reveals a depletion of SVs, demonstrating a block of vesicle retrieval after fusion. In addition, we observed an increase in clathrin-coated vesicles, indicating that the peptide does not block clathrin-dependent endocytosis. We conclude that the dynamin/synaptophysin complex functions in a clathrin-independent mechanism of SV endocytosis that is required for efficient synaptic transmission