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1.
J Neurosci Res ; 66(4): 525-39, 2001 Nov 15.
Article in English | MEDLINE | ID: mdl-11746372

ABSTRACT

Huntington disease (HD) is an autosomal dominant disorder in which degeneration of medium-sized spiny striatal neurons occurs. The HD gene and the protein it encodes, huntingtin, have been identified but their functions remain unknown. Transgenic mouse models for HD have been developed and we examined responses of medium-sized striatal neurons recorded in vitro to application of N-methyl-D-aspartate (NMDA) in two of these. The first model (R6/2) expresses exon 1 of the human HD gene with approximately 150 CAG repeats. In the R6/2 an enhancement of currents induced by selective activation of NMDA receptors as well as an enhancement of intracellular Ca(2+) flux occurred in both presymptomatic and symptomatic mice. These alterations appeared specific for the NMDA receptor because alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor-mediated currents were reduced in symptomatic R6/2s. In R6/2 animals there were parallel increases in NMDA-R1 and decreases in NMDA-R2A/B subunit proteins as established by immunohistochemistry. The second model (YAC72) contains human genomic DNA spanning the full-length gene and all its regulatory elements with 72 CAG repeats. The phenotypical expression of the disorder develops more gradually than in the R6/2. In YAC72 mice we found similar but less marked increases in responses of medium-sized striatal neurons to NMDA. These findings indicate that alterations in NMDA receptor function may predispose striatal neurons to excitotoxic damage, leading to subsequent neuronal degeneration and underscore the functional importance of NMDA receptors in HD.


Subject(s)
Huntington Disease/metabolism , Ion Channels/metabolism , Mutation/physiology , Neostriatum/metabolism , Neurons/metabolism , Receptors, N-Methyl-D-Aspartate/metabolism , Synaptic Transmission/genetics , Animals , Behavior, Animal/physiology , Calcium Channels/drug effects , Calcium Channels/genetics , Calcium Channels/metabolism , Calcium Signaling/drug effects , Calcium Signaling/genetics , Disease Models, Animal , Excitatory Amino Acid Agonists/pharmacology , Excitatory Amino Acid Antagonists/pharmacology , Huntington Disease/genetics , Huntington Disease/physiopathology , Immunohistochemistry , Ion Channels/drug effects , Ion Channels/genetics , Membrane Potentials/drug effects , Membrane Potentials/genetics , Mice , Mice, Neurologic Mutants , Mice, Transgenic , N-Methylaspartate/pharmacology , Neostriatum/drug effects , Neostriatum/physiopathology , Neurons/drug effects , Organ Culture Techniques , Patch-Clamp Techniques , Receptors, N-Methyl-D-Aspartate/drug effects , Receptors, N-Methyl-D-Aspartate/genetics , Synaptic Transmission/drug effects , alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/pharmacology
2.
Brain Res Dev Brain Res ; 130(1): 155-8, 2001 Sep 23.
Article in English | MEDLINE | ID: mdl-11557106

ABSTRACT

GABA neurotransmission plays a role in brainstem circuitry responsible for jaw movements. We investigated the developmental relationship between terminals expressing GAD67 and GABA(A) receptor beta(2)/beta(3) subunit expression within the trigeminal motor nucleus. GAD67 immunoreactivity was intense throughout development. Neuropilar beta(2)/beta(3) immunoreactivity emerged during the 2nd postnatal week. Our data provide anatomical evidence for a GABAergic innervation of neonatal trigeminal motoneurons and suggest that beta(2)/beta(3) subunit expression is developmentally regulated in trigeminal motoneurons.


Subject(s)
Glutamate Decarboxylase/analysis , Isoenzymes/analysis , Receptors, GABA-A/analysis , Trigeminal Nuclei/growth & development , Animals , Animals, Suckling , Antibodies , Glutamate Decarboxylase/immunology , Isoenzymes/immunology , Jaw/innervation , Motor Neurons/chemistry , Motor Neurons/enzymology , Rats , Rats, Sprague-Dawley , Receptors, GABA-A/immunology , Sucking Behavior , Trigeminal Nuclei/cytology
3.
J Neurosci ; 21(11): 3729-39, 2001 Jun 01.
Article in English | MEDLINE | ID: mdl-11356860

ABSTRACT

Trigeminal mesencephalic (Mes V) neurons are critical components of the circuits controlling oral-motor activity. The possibility that they can function as interneurons necessitates a detailed understanding of the factors controlling their soma excitability. Using whole-cell patch-clamp recording, in vitro, we investigated the development of the ionic mechanisms responsible for the previously described subthreshold membrane oscillations and rhythmical burst discharge in Mes V neurons from rats ages postnatal day (P) 2-12. We found that the oscillation amplitude and frequency increased during development, whereas bursting emerged after P6. Furthermore, when bursting was initiated, the spike frequency was largely determined by the oscillation frequency. Frequency domain analysis indicated that these oscillations emerged from the voltage-dependent resonant properties of Mes V neurons. Low doses of 4-aminopyridine (<100 microm) reduced the oscillations and abolished resonance in most neurons, suggesting that the resonant current is a steady-state K(+) current (I(4-AP)). Sodium ion replacement or TTX reduced substantially the oscillations and peak amplitude of the resonance, suggesting the presence of a persistent Na(+) current (I(NaP)) that functions to amplify the resonance and facilitate the emergence of subthreshold oscillations and bursting.


Subject(s)
Biological Clocks/physiology , Cell Membrane/physiology , Mesencephalon/physiology , Neurons/physiology , 4-Aminopyridine/pharmacology , Aging/physiology , Animals , Biological Clocks/drug effects , In Vitro Techniques , Membrane Potentials/drug effects , Membrane Potentials/physiology , Mesencephalon/cytology , Mesencephalon/drug effects , Neurons/drug effects , Patch-Clamp Techniques , Potassium Channel Blockers , Potassium Channels/metabolism , Rats , Rats, Sprague-Dawley , Sensory Thresholds/physiology , Signal Processing, Computer-Assisted , Sodium Channel Blockers , Sodium Channels/metabolism , Tetrodotoxin/pharmacology
4.
Dev Neurosci ; 23(1): 41-54, 2001.
Article in English | MEDLINE | ID: mdl-11173926

ABSTRACT

Trigeminal motoneurons (Mo5), mesencephalic trigeminal neurons (Me5), supratrigeminal neurons (Su5), and intertrigeminal neurons (I5) are important constituents of the neural circuitry responsible for jaw movements. Glutamate neurotransmission, mediated by ionotropic and metabotropic glutamate receptors (mGluRs), is critical for the production of jaw movements. To better understand the role of mGluR-mediated modulation of these neurons during early postnatal development, we conducted a series of experiments to illustrate the ontogeny of mGluRs 1, 5 (group I) and mGluRs 2, 3 (group II) in Mo5, Me5, Su5, and I5 neurons using receptor immunohistochemistry. Results demonstrate that the temporal expression of mGluRs is differentially regulated between, and within these trigeminal nuclei. The localization of group I and II mGluRs in these nuclei suggests a role for these receptors in mediating glutamatergic neurotransmission in brainstem circuits responsible for oral-motor behaviors.


Subject(s)
Motor Neurons/metabolism , Receptors, Metabotropic Glutamate/biosynthesis , Trigeminal Nuclei/metabolism , Age Factors , Animals , Immunohistochemistry , Motor Neurons/chemistry , Rats , Rats, Sprague-Dawley , Receptor, Metabotropic Glutamate 5 , Receptors, Metabotropic Glutamate/analysis , Trigeminal Nuclei/cytology , Trigeminal Nuclei/growth & development
5.
J Comp Neurol ; 427(1): 109-23, 2000 Nov 06.
Article in English | MEDLINE | ID: mdl-11042594

ABSTRACT

Trigeminal motoneurons (Mo5) and mesencephalic trigeminal neurons (Me5) are important constituents of the neural circuitry responsible for jaw movements. Non-N-methyl-D-aspartate (NMDA) glutamate receptors are a critical component of the brainstem circuitry responsible for reflex and centrally activated jaw movements; however, little is known about the expression of these receptors in neonatal oral-motor circuitry. Receptor immunohistochemistry using affinity-purified polyclonal antibodies directed against GluR1, GluR2/3/4c, and GluR4, respectively, and a monoclonal antibody directed against the GluR2 subunit, were used in rats at postnatal day (P)1, P3, P5, P10, P19-21, P32-35, and P60 to describe the expression of the alpha-amino-d-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor in Mo5 and Me5 neurons. In Mo5, immunoreactivity was noted for all antibodies throughout the time frame sampled. Neurons in caudal portions of Me5 displayed immunoreactivity to each antibody except at P60 when GluR2 immunoreactivity was absent. Neurons located in rostral Me5 displayed GluR2/3/4c and GluR4 immunoreactivity throughout the time frame, GluR1 immunoreactivity emerged at P3 and a transient expression of GluR2 expression was observed between P10 and P32-35. The lack of labeling of some neurons in both regions, coupled with differences in temporal expression, suggests that there are differences in the AMPA receptor phenotype within and between Mo5 and Me5 during postnatal development. Differences in AMPA subunit composition suggest a complex role for AMPA-mediated glutamatergic neurotransmission in brainstem circuits controlling jaw movements.


Subject(s)
Animals, Newborn/growth & development , Animals, Newborn/metabolism , Motor Neurons/metabolism , Receptors, AMPA/metabolism , Trigeminal Nuclei/growth & development , Trigeminal Nuclei/metabolism , Age Factors , Animals , Animals, Newborn/anatomy & histology , Cell Count , Glutamic Acid/metabolism , Mastication/physiology , Mesencephalon/growth & development , Mesencephalon/metabolism , Mesencephalon/ultrastructure , Motor Neurons/ultrastructure , Pons/growth & development , Pons/metabolism , Pons/ultrastructure , Rats , Rats, Sprague-Dawley , Synaptic Transmission/physiology , Trigeminal Nuclei/ultrastructure
6.
J Comp Neurol ; 409(2): 237-49, 1999 Jun 28.
Article in English | MEDLINE | ID: mdl-10379917

ABSTRACT

Trigeminal motoneurons (Mo5), mesencephalic trigeminal neurons (Me5), and supratrigeminal (Su5) and intertrigeminal (15) neurons are important constituents of the neural circuitry responsible for jaw movements observed during ingestive behaviors. In addition, in adult animals, N-methyl-D-aspartate (NMDA) receptors are a critical component of the brainstem circuitry responsible for reflex- and centrally activated jaw movements. However, little is known about the expression of this receptor in circuitry used to produce neonatal jaw movements. Receptor immunohistochemistry was used to describe changes in the expression of NMDA NR1 and NR2A/B receptor subunits in Mo5, Me5, Su5, and I5 neurons during postnatal development. Rats at postnatal days (P) 1, 3, 8, 15-16, 21-24, and 28-35 were used. An affinity-purified polyclonal antibody against the NR1 subunit and an affinity-purified polyclonal antibody that recognizes both NR2A and 2B subunits were used to depict the expression of these subunits. In Mo5, immunoreactivity was noted for both antibodies throughout the time frame sampled. NR1 expression in Me5 neurons emerged at P1. NR2A/B expression emerged at P3 in caudal and middle regions of Me5 and at P8 for rostral regions of the nucleus. NR1 immunoreactivity was present at P1 for neurons in I5 and at P3 for neurons in the Su5 region. NR2A/B subunit expression in Su5 and 15 neurons emerged at P8. These results provide evidence for NMDA receptor subunits in neonatal trigeminal neurons used in oral-motor circuitry and suggest a role for the NMDA receptor in synaptogenesis associated with these neurons during postnatal development.


Subject(s)
Motor Neurons/chemistry , Receptors, N-Methyl-D-Aspartate/biosynthesis , Trigeminal Nuclei/cytology , Trigeminal Nuclei/growth & development , Animals , Animals, Suckling , Brain Chemistry/physiology , Glutamic Acid/metabolism , Immunohistochemistry , Interneurons/chemistry , Jaw/innervation , Mesencephalon/chemistry , Mesencephalon/cytology , Mesencephalon/growth & development , Rats , Rats, Sprague-Dawley , Receptors, N-Methyl-D-Aspartate/analysis , Trigeminal Nuclei/chemistry
7.
J Neurophysiol ; 81(4): 1478-85, 1999 Apr.
Article in English | MEDLINE | ID: mdl-10200184

ABSTRACT

To initiate and maintain bursts (and plateau potentials) in the presence of serotonin, guinea pig trigeminal motoneurons utilize L-type Ca2+ and persistent Na+ inward currents. However, the intrinsic currents that contribute to burst termination and determine the duration of the interburst interval are unknown. Therefore we investigated the roles of outward currents, whose slow activation is coupled to cytosolic cation (Ca2+ and Na+) accumulation. First we examined a Ca2+-dependent K+ current (IK-Ca) with apamin and Ba2+-substituted, low-Ca2+ solution. Blockade of IK-Ca lengthened burst duration and cycle time but did not abolish bursting. Next we studied the Na+/K+-ATPase pump current (Ip) with cardiac glycosides. In the presence of apamin or low-Ca2+/Ba2+ solution, blocking Ip (with ouabain or strophanthidin) decreased both burst duration and cycle time and ultimately transformed bursting into tonic spiking. We conclude that IK-Ca and Ip contribute to burst termination in trigeminal motoneurons. These currents influence temporal bursting properties such as burst duration and cycle time and may help determine the phasic activity of motoneurons during rhythmic oral-motor behaviors.


Subject(s)
Motor Neurons/enzymology , Periodicity , Trigeminal Nuclei/physiology , Action Potentials/drug effects , Action Potentials/physiology , Animals , Apamin/pharmacology , Barium/pharmacokinetics , Calcium/metabolism , Electric Stimulation , Electrophysiology , Enzyme Inhibitors/pharmacology , Guinea Pigs , Motor Neurons/chemistry , Ouabain/pharmacology , Potassium Channels/physiology , Serotonin/pharmacology , Sodium/metabolism , Sodium-Potassium-Exchanging ATPase/metabolism , Strophanthidin/pharmacology , Trigeminal Nuclei/chemistry
8.
Brain Res ; 821(1): 190-9, 1999 Mar 06.
Article in English | MEDLINE | ID: mdl-10064803

ABSTRACT

Using an in vitro isolated brainstem preparation from neonatal rat (0-2 days), the minimal circuitry for production of rhythmical oral-motor activity was determined. In the presence of the excitatory amino acid agonist, N-methyl-D,L-aspartate (NMA), and the GABAA antagonist, bicuculline (BIC), rhythmical oral-motor activity was recorded from the motor branch of the trigeminal nerve. In preparations where the brainstem was isolated in continuity between the rostral inferior colliculus and the obex, oral-motor activity was not observed. However, when the brainstem was serially transected in the coronal plane starting at the obex and proceeding rostrally, rhythmogenic activity emerged and became more stable until the level of the rostral facial nucleus (facial colliculus, FC) was approached. Transections more rostral than the FC produced rhythms that progressively deteriorated until the trigeminal motor nucleus (MoV) was reached, at which point all activities ceased. Surgical isolation of an ipsilateral quadrant of the brainstem encompassing the tissue between the FC and inferior colliculus, rostro-caudally, and the midline to lateral brainstem, medio-laterally, exhibited oral-motor activity as well. The remaining contralateral side of brainstem was devoid of rhythmical trigeminal activity. However, further coronal transection of the remaining brainstem at the level of the FC induced rhythmical oral-motor activity in the trigeminal nerve. The data suggest the existence of bilaterally coordinated rhythmogenic circuits in each half of brainstem between the rostral trigeminal nucleus and the rostral facial nucleus, which are tonically inhibited by brainstem circuits caudal to the facial nucleus.


Subject(s)
Brain Stem/physiology , Movement/physiology , Periodicity , Animals , Animals, Newborn , Bicuculline/pharmacology , Excitatory Amino Acid Agonists/pharmacology , GABA Antagonists/pharmacology , In Vitro Techniques , Jaw , Movement/drug effects , N-Methylaspartate/pharmacology , Neural Inhibition , Rats , Rats, Sprague-Dawley
9.
J Neurosci ; 18(22): 9216-26, 1998 Nov 15.
Article in English | MEDLINE | ID: mdl-9801361

ABSTRACT

We studied how metabotropic glutamate receptor (mGluR) activation modifies the synaptic and intrinsic membrane properties of neonatal rat trigeminal motoneurons using the broad-spectrum mGluR agonist (1S,3R)-1-amino-1,3-cyclopentane-dicarboxylic acid [(1S,3R)-ACPD], group I/II antagonist (+/-)-alpha-methyl-4-carboxy-phenylglycine (MCPG), and group III agonist L-2-amino-4-phosphonobutanoate (L-AP4). (1S,3R)-ACPD depressed excitatory transmission to trigeminal motoneurons presynaptically and postsynaptically via presynaptic inhibition and by reducing the currents carried by ionotropic glutamate receptors selective for AMPA. (1S,3R)-ACPD also depolarized trigeminal motoneurons and increased input resistance by suppressing a Ba2+-sensitive leakage K+ current. These effects were not mimicked by L-AP4 (100-200 microM). High-threshold Ca2+ currents were also suppressed by (1S,3R)-ACPD. Repetitive stimulation of excitatory premotoneurons mimicked the postsynaptic effects of (1S, 3R)-ACPD. The postsynaptic effects of (1S,3R)-ACPD and repetitive stimulation were both antagonized by MCPG, suggesting that mGluRs were similarly activated in both experiments. We conclude that mGluRs can be recruited endogenously by glutamatergic premotoneurons and that mGluR-mediated depression of excitatory transmission, combined with increased postsynaptic excitability, enhances the signal-to-noise ratio of oral-related synaptic input to trigeminal motoneurons during rhythmical jaw movements.


Subject(s)
Motor Neurons/physiology , Receptors, Metabotropic Glutamate/physiology , Synaptic Transmission/physiology , Trigeminal Nuclei/cytology , 6-Cyano-7-nitroquinoxaline-2,3-dione/pharmacology , Animals , Animals, Newborn , Benzoates/pharmacology , Cycloleucine/analogs & derivatives , Cycloleucine/pharmacology , Excitatory Amino Acid Agonists/pharmacology , Excitatory Amino Acid Antagonists/pharmacology , Glycine/analogs & derivatives , Glycine/pharmacology , Membrane Potentials/drug effects , Membrane Potentials/physiology , Motor Neurons/chemistry , N-Methylaspartate/pharmacology , Neuroprotective Agents/pharmacology , Patch-Clamp Techniques , Rats , Tetrodotoxin/pharmacology , Trigeminal Nuclei/chemistry , alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/pharmacology
10.
Biophys J ; 75(1): 174-82, 1998 Jul.
Article in English | MEDLINE | ID: mdl-9649377

ABSTRACT

We investigated bursting behavior in rodent trigeminal neurons. The essential mechanisms operating in the biological systems were determined based on testable predictions of mathematical models. Bursting activity in trigeminal motoneurons is consistent with a traditional mechanism employing a region of negative slope resistance in the steady-state current-voltage relationship (Smith, T. G. 1975. Nature. 253:450-452). However, the bursting dynamics of trigeminal interneurons is inconsistent with the traditional mechanisms, and is far more effectively explained by a new model of bursting that exploits the unique stability properties associated with spike threshold (Baer, S. M., T. Erneux, and J. Rinzel. 1989. SIAM J. Appl. Math. 49:55-71).


Subject(s)
Interneurons/physiology , Motor Neurons/physiology , Trigeminal Nuclei/cytology , Trigeminal Nuclei/physiology , Action Potentials/physiology , Animals , Animals, Newborn , Biophysical Phenomena , Biophysics , Electrophysiology , In Vitro Techniques , Membrane Potentials/physiology , Models, Neurological , Rats
11.
J Neurophysiol ; 79(6): 2847-56, 1998 Jun.
Article in English | MEDLINE | ID: mdl-9636091

ABSTRACT

Intracellular recordings and pharmacological manipulations were employed to investigate the ionic basis for serotonin-induced bistable membrane behaviors in guinea pig trigeminal motoneurons (TMNs). In voltage clamp, 10 microM serotonin (5-HT) induced a region of negative slope resistance (NSR) in the steady-state current-voltage (I-V) relationship at potentials less negative than -58 mV, creating the necessary conditions for membrane bistability. The contributions of sustained Na+ and Ca2+ currents to the generation of the NSR were investigated using specific ion channel antagonists and agonists. The NSR was eliminated by the L-type Ca2+ channel antagonist nifedipine (5-10 microM), indicating the contribution of L channels. In nifedipine, inward rectification was present in the I-V relationship in a similar voltage range (greater than -58 mV). This region was subsequently linearized by tetrodotoxin (TTX), indicating the presence of a persistent Na+ current. When the 5-HT-induced NSR was eliminated by perfusion in low Ca2+ solution (0.4 mM), it was restored by the Na+ channel agonist veratridine (10 microM). Commensurate with bistability, in current clamp during bath application of 5-HT, plateau potentials were elicited by transient depolarizing or hyperpolarizing stimuli. Plateau potentials evoked by depolarization were observed under control and TTX conditions, but were blocked by nifedipine, suggesting the participation of an L-type Ca2+ current. Plateau potentials initiated after release from hyperpolarization (anode break) were blocked by 300 microM Ni2+, suggesting the responses relied on deinactivation of a T-type Ca2+ current. Conditional bursting was also observed in 5-HT. Nifedipine or low Ca2+ solutions blocked bursting, and the L-channel agonist Bay K 8644 (10 microM) extended the duration of individual bursts, demonstrating the role of L-type Ca2+ currents. Interestingly, when bursting was blocked by nifedipine or low Ca2+, it could be restored by veratridine application via enhancement of the persistent Na+ current. We conclude that bistable membrane behaviors in TMNs are mediated by L-type Ca2+ and persistent Na+ currents. 5-HT is associated with enhancement of TMN activity during oral-motor activity; the induction of bistable membrane properties by 5-HT represents a cellular mechanism for this enhancement.


Subject(s)
Ion Channels/physiology , Motor Neurons/physiology , Serotonin/pharmacology , Trigeminal Nerve/physiology , 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester/pharmacology , Animals , Calcium Channel Agonists/pharmacology , Calcium Channel Blockers/pharmacology , Cesium/pharmacology , Electrophysiology , Guinea Pigs , In Vitro Techniques , Membrane Potentials/drug effects , Membrane Potentials/physiology , Membranes/chemistry , Membranes/drug effects , Membranes/physiology , Motor Neurons/chemistry , Motor Neurons/drug effects , Nifedipine/pharmacology , Serotonin/chemistry , Sodium Channels/drug effects , Sodium Channels/metabolism , Trigeminal Nerve/chemistry , Trigeminal Nerve/cytology
12.
J Neurophysiol ; 79(1): 82-94, 1998 Jan.
Article in English | MEDLINE | ID: mdl-9425179

ABSTRACT

The present experiments were designed to examine dopamine (DA) modulation of whole cell currents mediated by activation of N-methyl-D-aspartate (NMDA) receptors in visualized neostriatal neurons in slices. First, we assessed the ability of DA, D1 and D2 receptor agonists to modulate membrane currents induced by activation of NMDA receptors. The results of these experiments demonstrated that DA potentiated NMDA-induced currents in medium-sized neostriatal neurons. Potentiation of NMDA currents occurred at three different holding potentials, although it was more pronounced at -30 mV. It was mediated by D1 receptors, because it was mimicked by D1 agonists and blocked by exposure to a D1 antagonist. Activation of D2 receptors produced inconsistent effects on NMDA-induced membrane currents. Either decreases, increases, or no effects on NMDA currents occurred. Second, we examined the contributions of intrinsic, voltage-dependent conductances to DA potentiation of NMDA currents. Blockade of K+ conductances did not prevent DA enhancement of NMDA currents. However, voltage-activated Ca2+ conductances provided a major contribution to DA modulation. The dihydropyridine L-type Ca2+ channel blockers, nifedipine, and methoxyverapamil (D-600), markedly reduced but did not totally eliminate the ability of DA to modulate NMDA currents. The D1 receptor agonist SKF 38393 also enhanced Ba2+ currents in neostriatal neurons. Together, these findings provide evidence for a complex interplay between DA, NMDA receptor activation and dihydropyridine-sensitive Ca2+ conductances in controlling responsiveness of neostriatal medium-sized neurons.


Subject(s)
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine/pharmacology , Calcium Channel Blockers/pharmacology , Calcium Channels/physiology , Dopamine Agonists/pharmacology , Dopamine/pharmacology , N-Methylaspartate/pharmacology , Neostriatum/physiology , Neurons/physiology , Receptors, Dopamine D1/physiology , Receptors, Dopamine D2/physiology , Animals , Barium/metabolism , Calcium Channels/drug effects , Calcium Channels, L-Type , Evoked Potentials/drug effects , In Vitro Techniques , Kinetics , Membrane Potentials/physiology , Neurons/drug effects , Potassium Channel Blockers , Potassium Channels/physiology , Rats , Rats, Sprague-Dawley , Receptors, N-Methyl-D-Aspartate/physiology
13.
Somatosens Mot Res ; 15(3): 200-10, 1998.
Article in English | MEDLINE | ID: mdl-9874519

ABSTRACT

An in vitro jaw-attached brainstem preparation was developed to investigate the relationship between jaw opener and closer muscle activity during chemically induced rhythmical jaw movements in neonatal rats. In the majority of preparations examined, where a defined region of brainstem was isolated and the neuronal innervation of the jaw opener and closer muscles was left intact, bath application of the excitatory amino acid agonist N-methyl-D,L-aspartate (NMA, 20-40 microM) in combination with bicuculline (BIC 10 microM), a GABA(A) antagonist, produced rhythmical electromyogram (EMG) activity in jaw opener and closer muscles, bilaterally, in conjunction with rhythmical jaw movements. Low concentrations of NMA (20 microM) in combination with BIC produced temporally coordinated activity between the jaw opener and closer muscles, ipsilaterally. With higher doses of NMA (40 microM), each muscle group exhibited bursting, but temporal coordination between them was difficult to establish. Similarly, NMA application in combination with the glycine antagonist strychnine (STR, 10 microM), also produced rhythmical EMG activity from both opener and closer muscles, ipsilaterally, but showed no temporal coordination between the antagonist muscle pair. However, coordination of opener and closer muscle discharge could be restored by the addition of BIC to the bath. We suggest that there exist separate, but coordinated, rhythm generator circuits for opener and closer motoneuronal discharge located in close proximity to the trigeminal motor nucleus and under GABAergic control for production of temporal coordination between rhythmogenic circuits.


Subject(s)
Brain Stem/physiology , Masseter Muscle/physiology , Muscle Contraction/physiology , Muscle Relaxation/physiology , Periodicity , gamma-Aminobutyric Acid/physiology , Animals , Bicuculline/pharmacology , Electromyography , GABA Antagonists/pharmacology , Jaw , N-Methylaspartate/pharmacology , Rats , Rats, Sprague-Dawley
14.
J Neurophysiol ; 77(6): 2910-24, 1997 Jun.
Article in English | MEDLINE | ID: mdl-9212246

ABSTRACT

Intracellular recordings from guinea pig trigeminal motoneurons (TMNs) in brain stem slices were used to determine the underlying ionic mechanisms responsible for our previously demonstrated enhancement of TMN excitability during jaw movements by serotonin (5-HT). 5-HT (0.5-100 microM) depolarized motoneurons and increased input resistance in the majority of neurons tested. Additionally, 5-HT reduced the amplitude of the postspike medium-duration afterhyperpolarization, decreased the current threshold for maintained spike discharge, and increased the maximum slope of the steady-state spike frequency-current relationship. Under voltage clamp, from holding potentials close to resting potential, 5-HT produced an inward current and a decrease in instantaneous slope conductance, suggesting a reduction in a resting K+ leak conductance (I(leak)). The instantaneous current-voltage (I-V) relationship for the inward 5-HT current (I(5-HT)) was linear throughout most of the voltage range tested. However, the steady-state I-V relationship showed some degree of inward rectification at potentials starting around -70 mV. The mean reversal potential for the instantaneous I(5-HT) was -86.2 +/- 4.5 (SE) mV (n = 9), a value slightly negative to the predicted potassium equilibrium potential of -82 mV in these neurons. In the presence of 2 mM Ba2+, 5-HT application did not produce a further reduction in input conductance, but did expose a Ba2+-insensitive residual inward current that was resistant to Cs+ application. The instantaneous I-V relationship during 5-HT application in the presence of Ba2+ was shifted downward and parallel to control, suggesting that Ba2+ and 5-HT block the same resting I(leak). The residual Ba2+- and Cs+-insensitive component of the total inward I(5-HT) was voltage independent and was blocked when the extracellular Na+ was replaced by choline, suggesting that the predominant charge carrier for this residual current is Na+. 5-HT enhanced a hyperpolarization-activated cationic current, I(h). In the presence of Ba2+, the time course of I(5-HT) resembled that of I(h) and showed a similar voltage dependence that was blocked by extracellular Cs+ (1-3 mM). The effects of 5-HT on membrane potential, input resistance, and I(h) were partially mimicked by 5-HT2 agonists and suppressed by 5-HT2 antagonists. It is concluded that 5-HT enhances TMN membrane excitability through modulation of multiple intrinsic membrane conductances. This provides for a mechanism(s) to fine tune the input-output discharge properties of these neurons, thus providing them with greater flexibility in output in response to time-varying synaptic inputs during various movements of the jaw.


Subject(s)
Motor Neurons/physiology , Serotonin/physiology , Synaptic Transmission/physiology , Trigeminal Nuclei/physiology , Animals , Culture Techniques , Guinea Pigs , Ion Channels/physiology , Male , Membrane Potentials/physiology , Receptors, Serotonin/physiology
15.
J Neurophysiol ; 77(2): 537-53, 1997 Feb.
Article in English | MEDLINE | ID: mdl-9065827

ABSTRACT

Whole cell voltage- and current-clamp recordings were obtained from mesencephalic trigeminal sensory (Mes 5) neurons identified visually in thin brain stem slices of neonatal rats with the use of infrared video microscopy. These cells exhibited accommodation in spike discharge responses to depolarizing current injection protocols whose duration differed as a function of holding potential (-50 vs. -65 mV). Several spikes were elicited before the membrane response accommodated from -50 mV, whereas from -65 mV only single action potentials were evoked. In response to similar protocols, application of the K+ channel blocker 4-aminopyridine (4-AP) (50 microM to 2 mM) caused sustained repetitive spiking whereas tetraethylammonium (TEA) (10-30 mM) did not cause repetitive spiking. In voltage clamp, 4-AP application (100 microM) revealed a sustained outward current (I4-AP) that was active between -60 and -30 mV. I4-AP was responsible for suppressing sustained repetitive spiking behavior, producing accommodation under normal circumstances. TEA application in voltage clamp revealed a sustained outward current evoked positive to -40 mV. Two transient outward currents (TOCs) were identified by prepulse protocols typically used to characterize A-type currents: a 4-AP-insensitive fast TOC, and a slow TOC (ITOC-S) sensitive to 4-AP (> 500 microM). A Ca(2+)-dependent outward current that activated positive to -30 mV was also characterized. A mathematical model of a Mes 5 neuron was assembled from our voltage-clamp records to simulate the dynamic interaction of outward currents during membrane excitation. We conclude that in Mes 5 neurons, the 4-AP-sensitive currents ITOC-S and I4-AP determine the duration of spike trains. In particular, the noninactivating I4-AP determines whether cells exhibit sustained repetitive discharge or accommodate in response to depolarizing current. Neurotransmitter modulation of this current or modulation of the resting membrane potential could modify the output properties of Mes 5 neurons, and therefore the properties of these currents must be incorporated into our current understanding of how these cells contribute to shaping oral-motor pattern generation.


Subject(s)
Animals, Newborn/physiology , Mesencephalon/physiology , Neurons/physiology , Potassium Channels/physiology , Trigeminal Nerve/physiology , Animals , Patch-Clamp Techniques , Rats
16.
J Neurophysiol ; 76(4): 2461-73, 1996 Oct.
Article in English | MEDLINE | ID: mdl-8899619

ABSTRACT

1. Intracellular recordings were made from guinea pig trigeminal motoneurons in brain stem slices. Monosynaptic excitatory postsynaptic potentials (EPSPs) were evoked in trigeminal motoneurons by focal stimulation of the mesencephalic nucleus of V (Mes V), a region containing cell bodies of primary afferent fibers of jaw muscle spindle and periodontal receptor origin. 2. The presence of N-methyl-D,L-aspartate (NMDA) and non-NMDA excitatory amino acid receptors (EAAs) was determined by iontophoretic application of NMDA and (+/-)-alpha-amino-3-hydroxy methylisoxazole-4-propionic acid (AMPA) from multi-barreled micropipettes. Application of either agonist in normal Mg(2+)-containing extracellular solutions produced a membrane depolarization or inward current from resting potential in current-or voltage-clamp modes, respectively. However, the voltage and current responses to NMDA and AMPA differed in their dependence on initial membrane potential. In voltage clamp between -70 and -50 mV, the peak current response to NMDA application increased whereas the response to AMPA application decreased as a function of holding potential. 3. Mes-V-induced synaptic potentials were examined for the presence of NMDA and non-NMDA components in extracellular solutions devoid of Mg2+. In the presence of DL-2-amino-5-phosphonopentanoic acid (30 microM), the peak amplitude and half-amplitude duration were decreased 52 and 36% (n = 2), respectively, compared with control. In the presence of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10-15 microM), a specific non-NMDA antagonist, the mean decrease in evoked synaptic potential amplitude was 55% (n = 5), but the half-amplitude duration increased by a mean of 63% (n = 5). 4. The non-NMDA component of the evoked EPSP obtained in the presence of DL-2-amino-5-phosphonovaleric acid showed a linear decrease in peak amplitude as a function of holding potential. In contrast, the NMDA EPSP component obtained in the presence of CNQX increased in peak amplitude as a function of holding potential between -70 and -40 mV. The increase in EPSP peak amplitude was abolished by removal of Mg2+ from the extracellular media. 5. Bath application of serotonin (5-HT) (50-100 microM) increased the peak NMDA and non-NMDA EPSP components by 31% (n = 10) and 23% (n = 8), respectively, while producing a mean increase in half-amplitude duration of 67 and 88%, respectively. Concomitantly, 5-HT increased input resistance by approximately 40% and produced a membrane depolarization. 6. In the presence of tetrodotoxin, 5-HT enhanced both iontophoretic NMDA and AMPA voltage responses. In cells voltage clamped between -60 and -70 mV in Mg(2+)-free solutions, iontophoretic NMDA and AMPA peak currents were enhanced 27 and 32%, respectively, by 5-HT. 7. The enhancement of the iontophoretic NMDA and non-NMDA responses was mimicked by (+/-)-1-(2,5-dimethyoxy-4-iodophenyl)-2- aminopropane HCL and blocked by 3-[2-[4-(fluorobenzoyl)-1-piperdinyl]-2,4 (1H,3H)-quinazolinedione-tartrate and N'-[(8a)-1,6-dimethylergolin-8-yl]-N,N-dimethyl-sulfamide hydrochloride, suggesting 5-HT2 receptor involvement. 8. The results demonstrate that trigeminal motoneurons possess both NMDA and non-NMDA receptors that are activated during Mes-V-induced synaptic transmission. The data suggest that EAA-mediated responses in trigeminal motoneurons are substrates for modulation by 5-HT via changes in membrane resistance and modulation of the EAA-induced synaptic current.


Subject(s)
Excitatory Amino Acids/physiology , Motor Neurons/physiology , Serotonin/physiology , Trigeminal Nuclei/physiology , Animals , Electric Stimulation , Evoked Potentials/physiology , Guinea Pigs , In Vitro Techniques , Iontophoresis , Male , Neuronal Plasticity/physiology , Receptors, AMPA/physiology , Receptors, N-Methyl-D-Aspartate/physiology , Trigeminal Nuclei/cytology
17.
Somatosens Mot Res ; 13(1): 39-48, 1996.
Article in English | MEDLINE | ID: mdl-8725647

ABSTRACT

The present study employed the neonatal rat isolated brainstem preparation to determine whether oral-motor rhythmical activity, a substrate for the complex behaviors of suckling and chewing, could be elicited in vitro by path application of excitatory amino acids (EAAs). Bath application of EAA agonists (kainate [KA], [+/-]-a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid [AMPA], N-methyl-D, L-aspartate [NMA]), in conjunction with the gamma-aminobutyric acid antagonist bicuculline, either failed to induce rhythmic activity (n = 17 preparations) or induced a low-amplitude, low-frequency burst discharge (< 1 Hz, n = 10 preparations) from the motor branches of the trigeminal nerves when the brainstem was contiguous from the spinomedullary junction to the superior colliculus. Burst activity was in most cases bilaterally synchronous. However, when a discrete coronal transection was made at the level of the facial colliculus, between the trigeminal and facial motor nuclei, the rhythmic bursts produced by the resultant 3- to 5-mm block of tissue following bath application of EAA agonists increased in amplitude and frequency (4-8 Hz, n = 35). Application of 6-cyano-7-nitroquinoxaline-2, 3-dione (CNQX), a non-N-methyl-D-aspartate (non-NMDA) receptor antagonist, blocked the rhythm induced by non-NMDA receptor agonist (n = 4) but was less effective in suppressing NMA-induced rhythmicity. In contrast, D, L-2-amino-5-phosphonovaleric acid (APV) blocked by both NMA-induced (n = 5) and, in most cases, KA-induced (n = 5) rhythmicity, suggesting an essential role for NMA receptors in production of EAA-induced rhythmical oral-motor activity in the neonatal rat. The present data demonstrate that a narrow, bilaterally distributed region of brainstem surrounding the trigeminal motor nucleus contains sufficient neuronal circuitry for the production of oral-motor rhythmogenesis.


Subject(s)
Brain Stem/physiology , Excitatory Amino Acids/physiology , Mastication/physiology , Sucking Behavior/physiology , Animals , Animals, Newborn , Brain Mapping , Electromyography , In Vitro Techniques , Masticatory Muscles/innervation , Motor Neurons/physiology , Rats , Receptors, N-Methyl-D-Aspartate/physiology , Spinal Cord/physiology , Trigeminal Nuclei/physiology
18.
Brain Res ; 695(2): 217-26, 1995 Oct 16.
Article in English | MEDLINE | ID: mdl-8556333

ABSTRACT

A fast transient voltage dependent outward current (TOC) in trigeminal motoneurons (TMNs) was studied in guinea pig brainstem slices by use of sharp electrodes in combination with single electrode voltage clamp techniques. In solutions containing TTX, low Ca2+/Mn2+ and 20 mM TEA this current activated around -55 to -60 mV from holding potentials negative to resting potential, obtained its peak amplitude within 5 ms and decayed as a single exponential with a time constant of 6-8 ms. Half maximal values for inactivation and activation were -72 and -37 mV, respectively. Bath application of 5 mM 4-AP suppressed this current by approximately 90% and eliminated the early depolarizing transient membrane rectification observed in response to a constant depolarizing current pulse, prolonged the action potential duration, and reduced the threshold voltage and delay to onset of the action potential. It is suggested that this current resembles the typical A-current observed in many CNS neurons and, as a result of its voltage and time dependent properties, could contribute to control of motoneuronal discharge and timing of burst onset during rhythmical jaw movements. Therefore, any cellular models of masticatory activity should include the properties of this current.


Subject(s)
Motor Neurons/physiology , Trigeminal Nuclei/physiology , 4-Aminopyridine/pharmacology , Action Potentials/drug effects , Animals , Calcium/physiology , Calcium Channel Blockers/pharmacology , Electrophysiology , Guinea Pigs , In Vitro Techniques , Manganese/physiology , Membrane Potentials/drug effects , Membrane Potentials/physiology , Patch-Clamp Techniques , Tetraethylammonium Compounds/pharmacology , Tetrodotoxin/pharmacology , Trigeminal Nuclei/cytology
19.
J Neurophysiol ; 74(3): 1343-8, 1995 Sep.
Article in English | MEDLINE | ID: mdl-7500155

ABSTRACT

1. In the present study we investigate the expression of a persistent Na+ conductance (INaP) in identified medium-sized neostriatal neurons. Nomarski optics and infrared videomicroscopy were used for cell visualization and identification in thick slices (350 microns). Current- and voltage-clamp recordings were obtained utilizing whole cell patch-clamp methodology. 2. Application of depolarizing ramp voltage commands from a holding potential of -70 mV induced a slow, noninactivating inward current that occurred before and independent of the rapidly inactivating sodium current that subserves action potential generation. INaP began to activate at potentials less negative than -70 mV and peaked at -34 +/- 1 (SE) mV. Its average peak amplitude was -100 +/- 17 pA. INaP was abolished by tetrodotoxin (TTX, 0.5-1 microM) or an Na(+)-free solution. In contrast, it was not affected by Ca2+ channel blockers. Depolarizing ramp commands also induced tetraethylammonium-sensitive outward currents. 3. Dopamine (DA) (20-100 microM) produced a significant reduction of INaP. 4. These results demonstrate the existence of a TTX-sensitive persistent Na+ conductance in medium-sized neostriatal neurons. This conductance is modulated by DA and could play a role in the generation of rhythmic oscillations and in supporting repetitive firing.


Subject(s)
Microscopy, Video/methods , Neostriatum/physiology , Neurons/physiology , Patch-Clamp Techniques/methods , Sodium Channels/physiology , Animals , Animals, Newborn , Rats , Rats, Sprague-Dawley , Time Factors
20.
J Neurophysiol ; 74(1): 334-46, 1995 Jul.
Article in English | MEDLINE | ID: mdl-7472335

ABSTRACT

1. The responses of guinea pig trigeminal motoneurons (TMNs) to N-methyl-D,L-aspartate (NMA) were studied using brain stem slice preparations and whole cell patch-clamp (n = 89) or conventional microelectrode (n = 22) recording techniques. The primary goals of this study were to determine whether N-methyl-D-aspartate (NMDA) receptor activation would produce spontaneous bursting activity in TMNs and, if so, the underlying mechanisms responsible for the generation of these bursts. 2. Bath-applied NMA (100-300 microM, n = 80) in standard perfusion medium elicited depolarization, increase in apparent input resistance (Rinp), and rhythmic burst discharges (1-90 s in duration) from TMNs. These effects were blocked by the NMDA receptor antagonist DL-2-amino-5-phosphonopentanoic acid (AP5, 30 microM, n = 6), but not by the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 5-10 microM, n = 10). Furthermore, the burst-inducing effect of NMA was not mimicked by the non-NMDA receptor agonists kainate (KA, 5-10 microM, n = 6) and (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA, 5-10 microM, n = 5). 3. In tetrodotoxin (TTX) treatment conditions (n = 13), NMA elicited depolarization, an increase in apparent Rinp, and rhythmic membrane potential oscillations without action potential bursts (i.e., plateau potentials), suggesting that the effects of NMA observed in the TTX-free condition resulted from activation of postsynaptic NMDA receptors. 4. Graded depolarization of neurons (n = 20) by intracellular direct current injection generally led to a graded increase in frequency and duration of the NMA-induced bursts and plateau potentials until these rhythmic events eventually became transformed into continuous spike discharge and maintained depolarization, respectively. Removal of Mg2+ from the perfusion medium (n = 11) also turned the bursts and plateau potentials into continuous spike discharge and maintained depolarization, respectively. 5. The effects of NMA on the current-voltage (I-V) curve after a depolarizing ramp voltage-clamp command (15-20 mV/s) were examined (n = 40). Under NMA (100-300 microM) conditions, the I-V relationship exhibited a region of negative slope conductance (NSC) between -60 and -35 mV, thus making the I-V relationship N-shaped. The NSC was abolished by AP5 (30 microM, n = 8), but not by CNQX (5-10 microM, n = 6). The I-V relationship in AMPA (3-10 microM, n = 5) or KA (3-10 microM, n = 5) was almost linear between -80 and -30 mV.(ABSTRACT TRUNCATED AT 400 WORDS)


Subject(s)
Excitatory Amino Acid Agonists/pharmacology , Motor Neurons/drug effects , N-Methylaspartate/pharmacology , Trigeminal Nerve/physiology , 2-Amino-5-phosphonovalerate/pharmacology , Animals , Electrophysiology , Guinea Pigs , In Vitro Techniques , Magnesium/physiology , Male , Membrane Potentials/drug effects , Membrane Potentials/physiology , Microelectrodes , Patch-Clamp Techniques , Potassium Channels/drug effects , Potassium Channels/metabolism , Receptors, N-Methyl-D-Aspartate/drug effects , Tetrodotoxin/pharmacology , Trigeminal Nerve/cytology , Trigeminal Nerve/drug effects
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