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J L Feldman

Publications and source records attributed to J L Feldman.

At least 19 recordsLinked to original sources
PubMed1998

AMPA receptor activation and phosphatase inhibition affect neonatal rat respiratory rhythm generation.

1. We investigated the role of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors and their regulation in affecting respiratory-related neurones in a neonatal rat medullary slice that spontaneously generates respiratory-related rhythm and motor output in the hypoglossal (XII) nerve. 2. Bath application of the AMPA receptor antagonist 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2, 3-benzodiazepine (GYKI) completely blocked XII nerve activity, as well as respiratory-related synaptic drives in neurones within the preBötzinger Complex (preBotC), site of rhythm generation in the slice. 3. Local application of GYKI to the preBötC blocked respiratory rhythm. Local application of AMPA to the preBötC increased rhythm frequency and depolarized respiratory-related neurones. 4. In the presence of tetrodotoxin (TTX), GYKI completely blocked the inward current induced by local application of AMPA, but not that induced by kainate. 5. Local application of okadaic acid, a membrane-permeable inhibitor of phosphatase 1 and 2A, to the preBotC increased the frequency of respiratory motor discharge. 6. Intracellular application of microcystin, a membrane-impermeable inhibitor of phosphatase 1 and 2A, enhanced endogenous inspiratory drive and exogenous AMPA-induced current (in the presence of TTX) in preBotC inspiratory neurones. Both the enhanced inspiratory drive and the increased AMPA-induced current were completely blocked by GYKI. 7. We suggest that AMPA receptor activation and AMPA receptor modulation by phosphorylation are crucial for the rhythm generation within the preBötC.

Animals↗
PubMed1998

PreBötzinger complex and pacemaker neurons: hypothesized site and kernel for respiratory rhythm generation.

Identification of the sites and mechanisms underlying the generation of respiratory rhythm is of longstanding interest to physiologists and neurobiologists. Recently, with the development of novel experimental preparations, especially in vitro en bloc and slice preparations of rodent brainstem, progress has been made In particular, a site in the ventrolateral medulla, the preBötzinger Complex, is hypothesized to contain neuronal circuits generating respiratory rhythm. Lesions or disruption of synaptic transmission within the preBötzinger Complex, either in vivo or in vitro, can abolish respiratory activity. Furthermore, the persistence of respiratory rhythm following interference with postsynaptic inhibition and the subsequent discovery of neurons with endogenous bursting properties within the preBötzinger Complex have led to the hypothesis that rhythmogenesis results from synchronized activity of pacemaker or group-pacemaker neurons.

Animals↗
PubMed1997

Intrinsic and extrinsic factors affecting phrenic motoneuronal excitability in neonatal rats.

We examined intrinsic and extrinsic factors affecting phrenic motoneuron (PMN) excitability in neonatal rats. Using an in vitro brainstem-spinal cord en bloc, 127 PMNs were recorded under whole-cell patch-clamp conditions. Inspiratory synaptic drives and passive membrane properties, including whole-cell membrane capacitance (Cm), input resistance (Rn), and time constant (tau), were measured with either voltage- or current-clamp techniques. On the basis of firing behavior during inspiration, two types of PMNs could be distinguished: active (107/127 = 84%) and silent PMNs (20/127 = 16%). Active PMNs always produced multiple spikes during inspiration, while silent PMNs remained silent for most inspiratory cycles. Compared to silent PMNs, active PMNs had significantly higher Rn, inspiratory drive potential, and more depolarized resting membrane potential (RMP). With respect to inspiratory drive current, no significant difference was observed between the two types of PMN. Analysis of action potential waveforms did not show a significant difference between their threshold levels. Our results suggest that in addition to size-related properties, RMP determines the recruitment of PMNs and consequently, of motor units in the diaphragm.

Action Potentials↗
PubMed1997

Vagal stimulation induces expiratory lengthening in the in vitro neonate rat.

Respiration is modulated by lung mechanoreceptor feedback in vivo on a cycle-to-cycle basis. We replicated this modulation in vitro and tested four stimulus protocols to identify which of these most closely replicated in vivo responses to lung mechanoreceptor activation in mammals. We activated pulmonary vagal afferent pathways by electrical stimulation or by lung inflation, applied during expiration, which produces expiratory lengthening in vivo. In each modality, transient and tonic stimuli were applied. Stimuli were applied over a range of delays following inspiratory termination. Tonic stimuli were maintained until subsequent inspiratory onset. All stimulus modalities prolonged expiration (P < 0.05). These results indicate that the neural circuitry mediating pulmonary afferent modulation of expiratory duration is retained in vitro.

Animals↗
PubMed1997

Respiratory rhythm generation and synaptic inhibition of expiratory neurons in pre-Bötzinger complex: differential roles of glycinergic and GABAergic neural transmission.

A key distinction between neural pacemaker and conventional network models for the generation of breathing rhythm in mammals is whether phasic reciprocal inhibitory interactions between inspiratory and expiratory neurons are required. In medullary slices from neonatal rats generating respiratory-related rhythm, we measured the phasic inhibitory inputs to expiratory neurons with the use of whole cell patch clamp in the hypothesized rhythm generation site, the pre-Bötzinger complex (pre-BötC). Expiratory neurons, which generate tonic impulse activity during the expiratory period, exhibited inhibitory postsynaptic potentials (IPSPs) synchronized to the periodic inspiratory bursts of the hypoglossal nerve root (XIIn). Bath application of the glycine receptor antagonist strychnine (STR; 5-10 microM) reversibly blocked these inspiratory-phase IPSPs, whereas the gamma-aminobutyric acid-A (GABA(A)) receptor antagonist bicuculline (BIC; 10-100 microM) had no effect on these IPSPs. Replacing the control in vitro bathing solution with a Cl(-)-free solution also abolished these IPSPs. Respiratory-related rhythmic activity was not abolished when inspiratory-phase IPSPs were blocked. The frequency and strength of XIIn rhythmic activity increased and seizurelike activity was produced when either STR, BIC, or Cl(-)-free solution was applied. Inspiratory-phase IPSPs were stable after establishment of whole cell patch conditions (patch pipettes contained 7 mM Cl-). Under voltage clamp, the reversal potential of inspiratory-phase inhibitory postsynaptic currents (IPSCs) was -75 mV. The current-voltage (I-V) curve for IPSCs shifted to the right when extracellular Cl- concentration was reduced by 50% (70 mM) and the reversal potential was reduced to -60 mV, close to the new Cl- Nernst potential. In tetrodotoxin (0.5 microM) under voltage clamp (holding potential = -45 mV), local application of glycine (1 mM) over pre-BötC induced an outward current and an increase in membrane conductance in expiratory neurons. The effect was blocked by bath application of STR (0.8-1 microM). Local application of the GABA(A) receptor agonist 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP, 1 mM) induced an outward current and an increase in membrane conductance that was blocked by BIC (10-100 mM). Under voltage clamp (holding potential = -45 mV), we analyzed spontaneous IPSCs during expiration in expiratory neurons. Bath application of BIC (10 microM) reduced the IPSC frequency (from 2.2 to 0.3 per s), whereas the inspiratory-phase IPSCs did not change. Bath application of STR (8-10 microM) abolished both IPSCs. These results indicate that 1) reciprocal inhibition of expiratory neurons is glycinergic and mediated by a glycine-activated Cl- channel that is not required for respiratory-related rhythm generation in neonatal rat medullary slices; 2) endogenous GABA and glycine modulate the excitability of respiratory neurons and affect respiratory pattern in the slice preparation; 3) both glycine and GABA(A) receptors are found on pre-BötC expiratory neurons, and these receptors are sensitive to STR and BIC, respectively; 4) glycine and GABA(A) inhibitory mechanisms play different functional roles in expiratory neurons: both glycine and GABA(A) receptors modulate neuronal excitability, whereas glycinergic transmission alone is responsible for reciprocal inhibition; and 5) intracellular Cl- concentration in these neonatal expiratory neurons is similar to that in adults.

Animals↗
PubMed1997

Functional respiratory rhythm generating networks in neonatal mice lacking NMDAR1 gene.

N-methyl-D-aspartate (NMDA) receptor-mediated synaptic transmission is implicated in activity-dependent developmental reorganization in mammalian brain, including sensory systems and spinal motoneuron circuits. During normal development, synaptic interactions important in activity-dependent modification of neuronal circuits may be driven spontaneously (Shatz 1990b). The respiratory system exhibits substantial spontaneous activity in utero; this activity may be critical in assuring essential and appropriate breathing movements from birth. We tested the hypothesis that NMDA receptors are necessary for prenatal development of central neural circuits underlying respiratory rhythm generation by comparing the responsiveness of control mice and mutant mice lacking the NMDA receptor R1 subunit (NMDAR1) gene to glutamate receptor agonists and antagonists and comparing endogenous respiratory-related oscillations generated in vitro by brain stem-spinal cord and medullary slice preparations from control and mutant mice. In control mice, local application of NMDA and the non-NMDA receptor agonist, (R,S)-alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid hydrobromide (AMPA), over the pre-Bötzinger Complex, the C4 cervical motor neuron pool, and the hypoglossal motor nucleus produced profound increases in inspiratory frequency, tonic discharge on C4 ventral nerve roots, and inward currents in inspiratory hypoglossal motoneurons, respectively. Responses of mutant mice to AMPA were similar. However, mutant mice were completely unresponsive to NMDA applications. Preparations from mutant mice generated a respiratory rhythm virtually identical to control. Results demonstrate that NMDA receptors are not essential for respiratory rhythm generation or drive transmission in the neonate. More importantly, they suggest that NMDA receptors are not obligatory for the prenatal development of circuits producing respiratory rhythm.

Animals↗
PubMed1997

Calcium-dependent plateau potentials in rostral ambiguus neurons in the newborn mouse brain stem in vitro.

Calcium-dependent plateau potentials in rostral ambiguus neurons in the newborn mouse brain stem in vitro. J. Neurophysiol. 78: 2483-2492, 1997. The nucleus ambiguus contains vagal and glossopharyngeal motoneurons and preganglionic neurons involved in respiration, swallowing, vocalization, and control of heart beat. Here we show that the rostral compact formation's ambiguus neurons, which control the esophageal phase of swallowing, display calcium-dependent plateau potentials in response to tetanic orthodromic stimulation or current injection. Whole cell recordings were made from visualized neurons in the rostral nucleus ambiguus using a slice preparation from the newborn mouse. Biocytin-labeling revealed dendritic trees with pronounced rostrocaudal orientations confined to the nucleus ambiguus, a morphological profile matching that of vagal motoneurons projecting to the esophagus. Single-stimulus orthodromic activation, using an electrode placed in the dorsomedial slice near the nucleus tractus solitarius, evoked single excitatory postsynaptic potentials (EPSPs) or short trains of EPSPs (500 ms to 1 s). However, tetanic stimulation (5 pulses, 10 Hz) induced voltage-dependent afterdepolarizations or long-lasting plateau potentials (>1 min) with a constant firing pattern. Depolarizing or hyperpolarizing current pulses elicited voltage-dependent afterdepolarizations or plateau potentials lasting a few seconds to several minutes. Constant spike activity accompanied the long-lasting plateau potentials, which ended spontaneously or could be terminated by weak hyperpolarizing current pulses. Current-induced afterdepolarizations and plateau potentials were dependent on extracellular and intracellular Ca2+, as they were blocked completely by extracellular Co2+, Cd2+, or intracellular bis-(o-aminophenoxy)-N,N,N',N'-tetraacetic acid (BAPTA). Orthodromically induced afterdepolarizations and plateau potentials were blocked by intracellular BAPTA. Afterdepolarizations and plateau potentials were completely blocked by substitution of extracellular Na+ with choline. Afterdepolarizations persisted in tetrodotoxin. We conclude that rostral ambiguus neurons have a Ca2+-activated inward current carried by Na+. Synaptic activation of this conductance may generate prolonged spike activity in these neurons during the esophageal phase of swallowing.

Animals↗
PubMed1997

Bidirectional electrical coupling between inspiratory motoneurons in the newborn mouse nucleus ambiguus.

Some spinal and brain stem motoneurons are electrically coupled in the early postnatal period. To test whether respiratory motoneurons in the brain stem are electrically coupled, we performed single and dual whole cell patch recordings from presumptive motoneurons in the nucleus ambiguus in a rhythmically active brain stem slice from newborn mice. Two of eight (25%) biocytin-injected neurons showed dye-coupling and 4 of 11 (36%) of intracellularly recorded pairs of neurons showed evidence of bidirectional electrical coupling. Impulse activity in one cell elicited small spikelets in the other and hyperpolarization of one cell led to hyperpolarization of the other with a coupling ratio (DeltaV2:DeltaV1) of 0.03-0.14. We conclude that inspiratory ambiguus motoneurons in the newborn mouse brain stem are bidirectionally electrically coupled, which may serve to transmit or coordinate signals, chemical or electrical.

Animals↗
PubMed1996

Multiple actions of 1S,3R-ACPD in modulating endogenous synaptic transmission to spinal respiratory motoneurons.

To determine physiological roles of metabotropic glutamate receptors (mGluRs) affecting breathing, we examined the effects of (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) on synaptic transmission and excitability of phrenic motoneurons (PMNs) in an in vitro neonatal rat brainstem/spinal cord preparation. The effects of 1S,3R-ACPD were multiple, including reduction of inspiratory-modulated synaptic currents and increase of neuronal excitability via an inward current (Iacpd) associated with a decrease of membrane conductance. The mechanism underlying synaptic depression was examined. We found that 1S,3R-ACPD reduced the frequency but not the amplitude of miniature excitatory postsynaptic currents. The current induced by exogenous AMPA was not significantly affected by 1S,3R-ACPD. These results suggest that 1S,3R-ACPD-induced reduction of inspiratory synaptic currents is mediated by presynaptic mGluRs. We also examined the ionic basis for Iacpd. We found that Iacpd had a reversal potential of approximately -100 mV, close to the estimated, EK+ (-95 mV). Elevating extracellular [K+] to 9 mM reduced the Iacpd reversal potential to -75 mV. The K+ channel blocker Ba2+ induced an inward current with a reversal potential at -93 mV associated with a decrease of membrane conductance, closely resembling the effect of 1S,3R-ACPD. Moreover, Ba2+, occluded 1S,3R-ACPD effects. In the presence of Ba2+, Iacpd and the 1S,3R-ACPD-induced decrease of membrane conductance were diminished. Our data indicate that the dominant component of Iacpd results from the blockade of a Ba(2+)-sensitive resting K+ conductance. We conclude that the activation of mGluRs affects the inspiratory-modulated activity of PMNs via distinct mechanisms at pre- and postsynaptic sites.

Animals↗
PubMed1996

Isolation and characterization of an avian slow myosin heavy chain gene expressed during embryonic skeletal muscle fiber formation.

We have isolated and begun characterization of the quail slow myosin heavy chain (MyHC) 3 gene, the first reported avian slow MyHC gene. Expression of slow MyHC 3 in skeletal muscle is restricted to the embryonic period of development, when the fiber pattern of future fast and slow muscle is established. In embryonic hindlimb development, slow MyHC 3 gene expression coincides with slow muscle fiber formation as distinguished by slow MyHC-specific antibody staining. In addition to expression in embryonic appendicular muscle, slow MyHC 3 is expressed continuously in the atria. Transfection of slow MyHC 3 promoter-reporter constructs into embryonic myoblasts that form slow MyHC-expressing fibers identified two regions regulating expression of this gene in skeletal muscle. The proximal promoter, containing potential muscle-specific regulatory motifs, permits expression of a reporter gene in embryonic slow muscle fibers, while a distal element, located greater than 2600 base pairs upstream, further enhances expression 3-fold. The slow muscle fiber-restricted expression of slow MyHC 3 during embryonic development, and expression of slow MyHC 3 promoter-reporter constructs in embryonic muscle fibers in vitro, makes this gene a useful marker to study the mechanism establishing the slow fiber lineage in the embryo.

Amino Acid Sequence↗
PubMed1996

Modulation of respiratory rhythm in vitro: role of Gi/o protein-mediated mechanisms.

Slice preparations from neonatal rat medulla that generate respiratory rhythm in vitro were used to test for Gi/o protein-mediated mechanisms affecting breathing rhythm in mammals. The frequency of inspiratory motor discharge recorded from hypoglossal (XII) nerve roots decreased with bath application of gamma-aminobutyric acid (GABA) and norepinephrine, as well as agonists specific for GABAB, alpha 2-adrenergic, and mu-opioid receptors; 5-hydroxytryptamine had little effect on frequency. Microinjection of these specific agonists into the pre-Bötzinger complex, the site of respiratory rhythm generation in vitro, also decreased frequency. In contrast, substance P (SP) increased frequency when it was bath applied or microinjected into the pre-Bötzinger complex. To test for involvement of Gi/o proteins, pertussis toxin (PTX) was injected into the cerebrospinal fluid of newborn rats, and slices from these animals were tested 48 h later for block of drug effects on rhythm. In PTX-treated slices the frequency decrease due to GABAB, mu-opioid, and alpha 2-adrenergic receptor activation was attenuated (P < or = 0.05), whereas the SP receptor-mediated response was unaltered. To test for involvement of K+ conductances linked to Gi/o proteins Ba2+ (0.2 mM) was added to the bath before application of drugs. Ba2+ attenuated the decrease in frequency associated with GABAB (P < or = 0.05) and mu-opioid (0.10 < or = P < or = 0.05) receptor activation, whereas the alpha 2-adrenergic and SP responses were unaltered. We conclude that GABAB and mu-opioid, but not alpha 2-adrenergic and SP, receptor activation modulates respiratory frequency via a Gi/o protein-dependent Ba(2+)-sensitive ionic conductance mechanism on neurons within the medullary locus for rhythm generation. This mechanism may be a convergent pathway for control of respiratory frequency.

Analgesics↗
PubMed1995

Differential innervation of protruder and retractor muscles of the tongue in rat.

Protrusion and retraction of the tongue are essential components of such orofacial behaviors as mastication, respiration, and swallowing. Stimulation of the medial branch of the hypoglossal nerve yields tongue protrusion, while stimulation of the lateral branch yields tongue retraction in rat. We exploited the transsynaptic transport capabilities of pseudorabies virus to determine specific circuits that innervate protruder and retractor muscles of the rat tongue. Each group of muscles is innervated by distinct populations of hypoglossal motoneurons: caudal ventral and ventrolateral motoneurons form the largest proportion of those innervating protruders, whereas rostral dorsal motoneurons innervate retractors. Our primary finding was differential innervation of protruder and retractor motoneurons by premotoneurons in the lateral tegmental field: premotoneurons innervating protruder motoneurons were more ventral and ventromedial than those innervating retractor motoneurons. In addition, protruder motoneurons received projections from the ipsilateral lateral parabrachial nucleus but not spinal trigeminal nucleus or medial and ventral subnuclei of the solitary tract; the converse was true for retractor motoneurons. These results suggest segregation of functional networks that control hypoglossal motoneurons. The dorsal medulla, in or around the solitary tract, contains neurons specific to retractor motoneurons, and the region ventrolateral to the hypoglossal nucleus contains circuitry specific to protruder motoneurons. Common innervation of medial and lateral branch motoneurons is provided by premotoneurons in the raphe and gigantocellular reticular formation of the medial medulla. The midline medullary nuclei with diverse projections may coordinate complex behavior or modulate general motoneuron excitability, whereas the lateral reticular formation, with anatomically discrete projections, may control motoneurons that contribute to distinct orofacial behaviors.

Animals↗
PubMed1995

In vitro brainstem-gastric preparation with intact vagi for study of primary visceral afferent input to dorsal vagal complex in caudal medulla.

An in vitro neonatal rat preparation, consisting of the isolated caudal brainstem and stomach joined by the intact vagi, was developed using Sprague-Dawley rats. The animals were 0 to 4 days of age. This preparation provided an opportunity to investigate the extracellular and intracellular responses of neurons in the nucleus tractus solitarius (NTS) of the brainstem to electrical stimulation of subdiaphragmatic vagal fibers. The dorsal and ventral vagal branches were electrically stimulated at the point of the common subdiaphragmatic vagal trunk. The isolated preparation was superfused in a recording chamber at 28 degrees C with a modified Krebs solution, equilibrated with 95% O2 and 5% CO2. Suction microelectrodes, for electrical stimulation, were positioned on the common vagal trunk just below the diaphragm to evaluate extracellular and intracellular evoked responses in NTS. A total of 204 subdiaphragmatic vagally-evoked (SDVe) brainstem unitary responses in the NTS were recorded. The mean latency of the extracellular SDVe brainstem responses was 89 +/- 12.9 ms (mean +/- SD). The peripheral gastric effects of CCK-8 on SDVe unitary responses in NTS neurons were evaluated. The peptide caused a significant increase in the excitability of these NTS neurons which was blocked by the CCKA receptor antagonist L-364,718. Neurons in the NTS and the dorsal motor nucleus of the vagus which showed excitatory responses to vagal stimulation were filled with Lucifer Yellow to evaluate their morphology.

Afferent Pathways↗
PubMed1995

Elective hand surgery in the breast cancer patient with prior ipsilateral axillary dissection.

BACKGROUND: We wished to determine if complications after elective hand surgery were greater in women with previous mastectomy and axillary dissection than in those without. METHODS: We surveyed records of all women undergoing carpal tunnel release by the senior author (W.J.D.) from 1983 to 1993. The postaxillary dissection group (group A) was made up of 15 women; seven had some postdissection lymphedema. Group B was made up of 302 other patients who had not undergone breast surgery or axillary dissection. Anesthetic and surgical techniques were identical for both groups, with i.v. regional anesthesia used most commonly. RESULTS: No patient in the axillary dissection group developed any postoperative infection or had any worsening of preexisting lymphedema or onset of new arm swelling after ipsilateral carpal tunnel release. The nonaxillary dissection group had a postoperative infection rate of 3.6%; all infections were superficial and resolved with conservative therapy. In addition, 31 women experienced other complications, including 13 with hand/finger stiffness and four with reflex dystrophy. Fifteen required formal hand therapy. CONCLUSIONS: Women with prior ipsilateral axillary dissection can safely undergo elective upper extremity surgery, provided strict sterile technique and appropriate anesthetic and surgical precautions are observed. Patients having undergone previous axillary dissection should not be prohibited from future limb manipulations, including venepunctures, blood pressure measurements, or elective surgery.

Adult↗
PubMed1995

Generation of respiratory rhythm and pattern in mammals: insights from developmental studies.

Our understanding of the cellular, synaptic and network mechanisms underlying respiratory rhythm generation in mammals is progressing rapidly as researchers focus on a site hypothesized as the source of rhythm generation, the preBötzinger complex, in the rostral ventrolateral medulla. Furthermore, ontogenetic and modulatory factors affecting respiratory neuronal circuits are receiving considerable attention, as postnatal development of motor systems becomes increasingly apparent.

Animals↗
PubMed1995

Modulation of inspiratory drive to phrenic motoneurons by presynaptic adenosine A1 receptors.

The involvement and mechanisms of adenosine A1 receptors in regulating bulbospinal synaptic transmission of inspiratory drive to phrenic motoneurons were investigated. The adenosine analog N6-cyclopentyladenosine (CPA) induced a dose-dependent decrease of both inspiratory-modulated activity of C4 ventral roots and synaptic currents of phrenic motoneurons in an in vitro brainstem/spinal cord preparation from neonatal rats. No significant changes were observed in steady-state membrane current (during the expiratory phase). The depressant action of CPA on inspiratory drive was blocked by the selective A1 receptor antagonist 8-cyclopentyltheophylline (CPT). The adenosine receptor antagonist 3-isobutyl-1-methylxanthine (IBMX) induced varying degrees of enhancement of inspiratory-modulated synaptic current, as did CPT. This suggests a role of endogenous adenosine in synaptic transmission of respiratory drive to phrenic motoneurons. The relative contribution of pre- and postsynaptic adenosine receptors was examined by looking at the effects of CPA on postsynaptic membrane properties and on spontaneous or miniature excitatory postsynaptic currents (EPSCs). CPA had no detectable effect on the input resistance of phrenic moto-neurons. Moreover, the inward currents of phrenic moto-neurons in response to exogenously applied glutamate were not affected by adenosine-related compounds. On the other hand, CPA produced a significant decrease in the frequency of spontaneous and of miniature EPSCs. We conclude that adenosine can modulate transmission of inspiratory drive from bulbospinal neurons to phrenic motoneurons via presynaptic A1 receptors.

1-Methyl-3-isobutylxanthine↗
PubMed1995

Modulation of neural network activity in vitro by cyclothiazide, a drug that blocks desensitization of AMPA receptors.

To determine whether AMPA receptor channel desensitization has a physiological role in shaping network activity by modulating signal transmission through excitatory circuits, we examined the effects of cyclothiazide (CYT), the most potent known blocker of AMPA receptor desensitization, on the behavior of an endogenously active neural system in vitro, the brainstem network generating rhythmic respiratory oscillations in neonatal rat medullary slices. Bath application of 100 microM CYT significantly increased the frequency of endogenously generated rhythm and increased the amplitude of the circuit output [i.e., discharge of hypoglossal (XII) respiratory motoneurons]. Local application of CYT within the XII motor nucleus produced a concentration-dependent increase (up to 35%) in amplitude of the motoneuron population discharge as well as an increase in the peak current (23%) and total charge transfer of the rhythmic inspiratory synaptic drive (33%) to individual XII motoneurons. CYT also acted postsynaptically to increase the amplitude of spontaneous EPSCs in motoneurons. In addition, CYT produced a profound, long-term augmentation of network frequency and motor output that may be secondary to block of desensitization. These results suggest that AMPA receptor desensitization has functionally significant effects on the temporal behavior and output of the rhythmic, respiratory neural network, and, by extrapolation, on other integrative actions of the mammalian CNS.

Animals↗