Biomedical subjects

Jehuda P Sepkuty

Publications and source records attributed to Jehuda P Sepkuty.

5 recordsLinked to original sources

PubMed2005

Secreted semaphorins modulate synaptic transmission in the adult hippocampus.

Modulation of synaptic activity is critical for neural circuit function and behavior. The semaphorins are a large, phylogenetically conserved protein family with important roles in neural development. However, semaphorin function in the adult brain has yet to be determined. Here, we show that the coreceptors for secreted semaphorins, the neuropilins, are found at synapses and localize to molecular layers of the adult mouse hippocampus and accessory olfactory cortex. Moreover, application of the secreted semaphorin Sema3F to acute hippocampal slices modulates both the frequency and amplitude of miniature EPSCs in granule cells of the dentate gyrus and pyramidal neurons of CA1. Finally, we show that mice lacking Sema3F are prone to seizures. These results suggest a novel role for semaphorins as synaptic modulators and illustrate the diverse repertoire of these guidance cues in both the formation and function of neural circuits.

Age Factors↗

PubMed2005

Spinal glutamate uptake is critical for maintaining normal sensory transmission in rat spinal cord.

Glutamate is a major excitatory neurotransmitter in primary afferent terminals and is critical for normal spinal excitatory synaptic transmission. However, little is known about the regulation of synaptically released glutamate in the spinal cord under physiologic conditions. The sodium-dependent, high-affinity glutamate transporters are the primary mechanism for the clearance of synaptically released glutamate. In the present study, we found that intrathecal injection of glutamate transporter blockers DL-threo-beta-benzyloxyaspartate (TBOA) and dihydrokainate produced significant and dose-dependent spontaneous nociceptive behaviors, such as licking, shaking, and caudally directed biting, phenomena similar to the behaviors caused by intrathecal glutamate receptor agonists. Intrathecal TBOA also led to remarkable hypersensitivity in response to thermal and mechanical stimuli. These behavioral responses could be significantly blocked by intrathecal injection of the NMDA receptor antagonists MK-801 and AP-5, the non-NMDA receptor antagonist CNQX or the nitric oxide synthase inhibitor L-NAME. In vivo microdialysis analysis showed short-term elevation of extracellular glutamate concentration in the spinal cord after intrathecal injection of TBOA. Furthermore, topical application of TBOA on the dorsal surface of the spinal cord resulted in a significant elevation of extracellular glutamate concentration demonstrated by in vivo glutamate voltametry. The present study indicates that defective spinal glutamate uptake caused by inhibition of glutamate transporters leads to excessive glutamate accumulation in the spinal cord. The latter results in persistent over-activation of synaptic glutamate receptors, producing spontaneous nociceptive behaviors and sensory hypersensitivity. Our results suggest that glutamate uptake through spinal glutamate transporters is critical for maintaining normal sensory transmission under physiologic conditions.

Animals↗

PubMed2004

Multimodal functional mapping of sensorimotor cortex prior to resection of an epileptogenic perirolandic lesion.

The effects of chronic epileptogenic lesions on functional anatomy are under debate. Our recent experience during mapping and resection of a lesion in sensorimotor cortex supports the idea that epileptogenic lesions may prompt development of alternate cortical motor representations. Multimodal mapping may uncover alternate areas of functionality that make surgery feasible even when conventional neuroanatomy suggests otherwise. Newer methods such as electrocorticographic spectral analysis may complement traditional electrical cortical stimulation mapping.

Adolescent↗

PubMed2002

A neuronal glutamate transporter contributes to neurotransmitter GABA synthesis and epilepsy.

The predominant neuronal glutamate transporter, EAAC1 (for excitatory amino acid carrier-1), is localized to the dendrites and somata of many neurons. Rare presynaptic localization is restricted to GABA terminals. Because glutamate is a precursor for GABA synthesis, we hypothesized that EAAC1 may play a role in regulating GABA synthesis and, thus, could cause epilepsy in rats when inactivated. Reduced expression of EAAC1 by antisense treatment led to behavioral abnormalities, including staring-freezing episodes and electrographic (EEG) seizures. Extracellular hippocampal and thalamocortical slice recordings showed excessive excitability in antisense-treated rats. Patch-clamp recordings of miniature IPSCs (mIPSCs) conducted in CA1 pyramidal neurons in slices from EAAC1 antisense-treated animals demonstrated a significant decrease in mIPSC amplitude, indicating decreased tonic inhibition. There was a 50% loss of hippocampal GABA levels associated with knockdown of EAAC1, and newly synthesized GABA from extracellular glutamate was significantly impaired by reduction of EAAC1 expression. EAAC1 may participate in normal GABA neurosynthesis and limbic hyperexcitability, whereas epilepsy can result from a disruption of the interaction between EAAC1 and GABA metabolism.

Action Potentials↗

PubMed2002

Optimizing parameters for terminating cortical afterdischarges with pulse stimulation.

PURPOSE: We previously reported that brief pulses of electrical stimulation (BPSs) can terminate afterdischarges (ADs) during cortical stimulation. We investigated conditions under which BPS is more likely to suppress ADs. METHODS: We analyzed parameters altering BPS effectiveness on 200 ADs in seven patients with implanted subdural electrodes. RESULTS: The odds of BPSs stopping ADs was 8.6 times greater at primary sites (directly stimulated electrodes) than at secondary sites (adjacent electrodes) (p = 0.016). BPS applied within 4.5 s after onset of AD had 2 times greater odds of stopping ADs (p = 0.014). BPS applied when AD voltage was negative was 1.9 times more likely to stop ADs (p = 0.012). ADs with rhythmic pattern responded best (p < 0.0001). BPS stopped 100% of ADs not starting immediately after localization stimulus (LS) versus 29% of those starting immediately (p < 0.0001). CONCLUSIONS: BPS is more likely to terminate ADs at primary electrodes, if given early, if applied to the negative peak of the AD waveform, if AD has a rhythmic pattern, and if AD did not start immediately after LS.

Adolescent↗