Faculty Bibliography

A group of central auditory neurons residing in the lateral superior olivary nucleus (LSO) responds selectively to interaural level differences and may contribute to sound localization. In this simple circuit, ipsilateral sound increases firing of LSO neurons, whereas contralateral sound inhibits the firing rate via activation of the medial nucleus of the trapezoid body (MNTB). During development, individual MNTB fibers arborize within the LSO, but they undergo a restriction of their boutons that ultimately leads to mature topography. A critical issue is whether a distinct form of inhibitory synaptic plasticity contributes to MNTB synapse elimination within LSO. Whole-cell recording from LSO neurons in brain slices from developing gerbils show robust long-term depression (LTD) of the MNTB-evoked IPSP/Cs when the MNTB was activated at a low frequency (1 Hz). These inhibitory synapses also display mixed GABA/glycinergic transmission during development, as assessed physiologically and immunohistochemically (Kotak et al. 1998). While either glycine or GABA(A) receptors could independently display inhibitory LTD, focal delivery of GABA, but not glycine, at the postsynaptic-locus induces depression. Furthermore, the GABA(B) receptor antagonist, SCH-50911, prevents GABA or synaptically induced depression. Preliminary evidence also indicated strengthening of inhibitory transmission (LTP) by a distinct pattern of inhibitory activity. These data support the idea that GABA is crucial for the expression inhibitory LTD and that this plasticity may underlie the early refinement of inhibitory synaptic connections in the LSO

Glycinergic transmission shapes the coding properties of the lateral superior olivary nucleus (LSO). We investigated intracellular pH responses in the LSO to glycine using BCECF-AM in brain slices. With extracellular bicarbonate, glycine produced an alkalinization followed by an acidification while, in the nominal absence of bicarbonate, glycine produced acidifications. Separately, in whole-cell recordings from LSO neurons, glycine caused hyperpolarization followed by long-lasting depolarization. While the bicarbonate-dependent intracellular alkalinization could be related to chloride/bicarbonate exchange, bicarbonate-independent acidification may be triggered by depolarization

Inhibitory transmission is critically involved in the functional maturation of neural circuits within the brain. However, the mechanisms involved in its plasticity and development remain poorly understood. At an inhibitory synapse of the developing auditory brain stem, we used whole cell recordings to determine the site of induction and expression of long-term depression (LTD), a robust activity-dependent phenomenon that decreases inhibitory synaptic gain and is postulated to underlie synapse elimination. Recordings were obtained from lateral superior olivary (LSO) neurons, and hyperpolarizing inhibitory potentials were evoked by stimulation of the medial nucleus of the trapezoid body (MNTB). Both postsynaptic glycine and GABAA receptors could independently display LTD when isolated pharmacologically. Focal application of GABA, but not glycine, on the postsynaptic LSO neuron was sufficient to induce depression of the amino acid-evoked response, or MNTB-evoked inhibitory postsynaptic potentials. This GABA-mediated depression, in the absence of MNTB stimulation, was blocked by a GABAB receptor antagonist. To assess whether a change in neurotransmitter release is associated with the LTD, the polyvalent cation, ruthenium red, was used to increase the frequency of miniature inhibitory synaptic events. Consistent with a postsynaptic locus of expression, we found that the mean amplitude of miniature events decreased after LTD with no change in their frequency of occurrence. Furthermore, there was no change in the paired-pulse ratio or release kinetics of evoked inhibitory responses. Together, these results provide direct evidence that activity-dependent LTD of inhibition has a postsynaptic locus of induction and alteration, and that GABA but not glycine plays a pivotal role

Loss of sensory function leads to atrophy or death within the developing CNS, yet little is known about the physiology of remaining synapses. After bilateral deafening, gramicidin-perforated-patch recordings were obtained from gerbil inferior colliculus neurons in a brain slice preparation. Afferent-evoked IPSPs had a diminished ability to block current-evoked action potentials in deafened neurons. This change could be attributed, in part, to a loss of potassium-dependent chloride transport function, with little change in K-Cl cotransporter expression. Treatments that suppressed chloride cotransport (bumetanide, cesium, and genistein) had little or no effect on neurons from deafened animals. These same treatments depolarized the E(IPSC) of control neurons. Semiquantitative RT-PCR and immunohistochemical staining indicated no change in the expression of chloride cotransporter mRNA or protein after deafness. Therefore, profound hearing loss leads rapidly to the disruption of chloride homeostasis, which is likely attributable to the dysfunction of the potassium-dependent chloride cotransport mechanism, rather than a downregulation of its expression. This results in inhibitory synapses that are less able to block excitatory events

The nasolabial flap is a straightforward and time-tested reconstructive option suitable for a variety of facial and oral defects. The superiorly and inferiorly based variants are well described in the literature and offer a rapid and reliable alternative to time-consuming microvascular free flaps and less esthetic skin grafts. Despite newer and more complex alternatives, the nasolabial flap maintains its prominent position in the reconstructive armamentarium of the oral and maxillofacial surgeon

We have previously shown that the integrin beta6 is neo-expressed in invasive oral squamous cell carcinoma (SCC) and is correlated with oral tumor progression. However, the mechanism by which the integrin beta6 promotes oral tumor progression is not well understood. The purpose of the present study was to determine whether integrin beta6 signaling activates Fyn and thus promotes oral squamous cell carcinoma progression. We analyzed the integrin beta6 signaling complex and investigated the function of these signaling molecules in oral SCC cells. We found that, upon ligation of the integrin beta6 with fibronectin, beta6 complexed with Fyn and activated it. The activation of Fyn recruited and activated focal adhesion kinase to this complex. This complex was necessary to activate Shc and to couple beta6 signaling to the Raf-ERK/MAPK pathway. This pathway transcriptionally activated the matrix metalloproteinase-3 gene and promoted oral SCC cell proliferation and experimental metastasis in vivo. These findings indicate that integrin beta6 signaling activates Fyn and thus promotes oral cancer progression

Massive sinonasal polyposis associated with skull base dehiscence and intracranial extension is a difficult disease to treat. Conventional transnasal or transfacial techniques can result in dural injury, cerebrospinal fluid (CSF) leak and infection. We describe our experience with a combined neurosurgical-endoscopic technique that protects the meninges. Five patients with massive sinonasal polyposis extending intracranially through skull base dehiscence were reviewed retrospectively. The minimum follow-up was 2 years. A frontal craniotomy was performed through a bicoronal approach. The dura was carefully separated from all infectious material at the floor of the anterior cranial fossa. The frontal lobe with the intact meninges was elevated off the anterior cranial floor. A sheet of blue plastic material was inserted under the frontal lobe from the craniotomy site to the planum sphenoidale. Next, a transnasal endoscopic ethmoidectomy, sphenoidectomy, and frontal sinusotomy were performed to remove the inflammatory processes. The blue plastic material was visible through any existing or potential skull base dehiscence, thus providing visual protection for the dura and brain. All gross disease was removed from the frontal, ethmoid, and sphenoid skull base regions in the 5 patients without dural injury. None of the patients developed a CSF leak or meningitis. Two patients developed recurrent polyposis limited to the sinuses without intracranial extension. The endoscopic craniofacial approach with the 'Blue-Sky' protective technique offers a safe method for completely removing massive sinonasal polyposis associated with an intracranial extension