Biomedical subjects

Ke-Zhong Shen

Publications and source records attributed to Ke-Zhong Shen.

9 recordsLinked to original sources

PubMed2006

Subthalamic stimulation evokes complex EPSCs in the rat substantia nigra pars reticulata in vitro.

The subthalamic nucleus (STN) plays an important role in movement control by exerting its excitatory influence on the substantia nigra pars reticulata (SNR), a major output structure of the basal ganglia. Moreover, excessive burst firing of SNR neurons seen in Parkinson's disease has been attributed to excessive transmission in the subthalamonigral pathway. Using the 'blind' whole-cell patch clamp recording technique in rat brain slices, we found that focal electrical stimulation of the STN evoked complex, long-duration excitatory postsynaptic currents (EPSCs) in SNR neurons. Complex EPSCs lasted 200-500 ms and consisted of an initial monosynaptic EPSC followed by a series of late EPSCs superimposed on a slow inward shift in holding current. Focal stimulation of regions outside the STN failed to evoke complex EPSCs. The late component of complex EPSCs was markedly reduced by ionotropic glutamate receptor antagonists (2-amino-5-phosphonopentanoic acid and 6-cyano-7-nitro-quinoxalone) and by a GABAA receptor agonist (isoguvacine) when these agents were applied directly to the STN using a fast-flow microapplicator. Moreover, the complex EPSC was greatly enhanced by bath application of the GABAA receptor antagonists picrotoxin or bicuculline. These data suggest that recurrent glutamate synapses in the STN generate polysynaptic, complex EPSCs that are under tonic inhibition by GABA. Because complex EPSCs are expected to generate bursts of action potentials in SNR neurons, we suggest that complex EPSCs may contribute to the pathological burst firing that is associated with the symptoms of Parkinson's disease.

2-Amino-5-phosphonovalerate↗

PubMed2005

Dopamine depletion alters responses to glutamate and GABA in the rat subthalamic nucleus.

We used whole-cell recordings to compare currents evoked by glutamate and GABA receptor agonists in subthalamic nucleus neurons located ipsilateral and contralateral to unilateral 6-hydroxydopamine (6-OHDA) injections into the substantia nigra zona compacta. The ratio of currents evoked by AMPA (0.6 microM) and NMDA (20 microM) was significantly greater in neurons recorded ipsilateral to 6-OHDA lesions compared with the ratio of currents recorded in control (contralateral) neurons. Both the GABA(A) agonist isoguvacine (20 microM) and the GABA(B) agonist baclofen (10 microM) evoked significantly greater outward currents in subthalamic nucleus neurons ipsilateral to the lesion compared to contralateral neurons. We conclude that chronic dopamine depletion up-regulates expression of GABA receptors and shifts the functional expression of ionotropic glutamate receptor subtype from NMDA to AMPA receptors in subthalamic nucleus.

Animals↗

PubMed2005

NMDA enhances a depolarization-activated inward current in subthalamic neurons.

Previous studies have shown that N-methyl-D-aspartate (NMDA) receptor stimulation evokes Ca2+- and Na+-dependent burst firing in subthalamic nucleus (STN) neurons. Using whole-cell patch pipettes to record currents under voltage-clamp, we identified a time-dependent depolarization-activated inward current (DIC) that may underlie NMDA-induced burst firing in STN neurons in rat brain slices. Continuous superfusion with NMDA (20 microM) elicited a marked TTX-insensitive inward current when the membrane was depolarized to the level of -70 or -50 mV, from a holding potential of -100 mV. This current had a long duration, and its peak amplitude occurred at a test potential of -60 mV. DIC could not be evoked using the non-NMDA receptor agonist D,L-alpha-amino-3-hydroxy-5-methylisoxalone-4-propionic acid (AMPA). DIC was blocked by either intracellular BAPTA or by removal of extracellular Ca2+, but selective blockers of T-type (mibefradil), L-type (nifedipine) and N-type (omega-conotoxin GVIA) Ca2+ channels did not. Perfusing slices with a low extracellular concentration of sodium abolished the NMDA-induced DIC, implying that both Ca2+ and Na+ are necessary for the expression of DIC. Transient receptor potential (TRP) channel blockers flufenamic acid and SKF96365 severely reduced DIC amplitude, whereas NMDA-gated currents were either increased or were unchanged. These results suggest that the activation of NMDA receptors enhances a Ca2+-activated non-selective cation current that may be mediated by a member of the TRP channel family in STN neurons.

Animals↗

PubMed2004

Calcium-dependent subthreshold oscillations determine bursting activity induced by N-methyl-D-aspartate in rat subthalamic neurons in vitro.

We used whole-cell patch recordings in current clamp to investigate the ionic dependence of burst firing induced by N-methyl-d-aspartate (NMDA) in neurons of the subthalamic nucleus (STN) in slices of rat brain. NMDA (20 microm) converted single-spike firing to burst firing in 87% of STN neurons tested. NMDA-induced bursting was blocked by AP5 (50 microm), and was not mimicked by the non-NMDA receptor agonist AMPA (0.6 microm). Tetrodotoxin (1 microm) converted bursts to oscillations of membrane potential, which were most robust when oscillations ranged between -50 and -70 mV. The NMDA bursts were blocked by an elevated extracellular concentration of Mg(2+), but superfusate containing no added Mg(2+) either reduced or increased burst firing, depending upon the amount of intracellular current injection. Block of K(+) conductances by apamin and tetraethylammonium prolonged burst duration, but iberiotoxin had no effect. NMDA-induced burst firing and membrane oscillations were completely blocked by superfusate containing no added Ca(2+), and they were significantly reduced when patch pipettes contained BAPTA. Selective antagonists for T-type (mibefradil, 10 microm), L-type (nifedipine, 3 microm), and N-type (omega-conotoxin GVIA, 1 micro m) Ca(2+) channels had no effect on NMDA burst firing. Superfusate containing a low concentration of Na(+) (20 mm) completely abolished NMDA-induced burst firing. Flufenamic acid (10 microm), which blocks current mediated by Ca(2+)-activated nonselective cation channels (I(CAN)), reversibly abolished NMDA-depended bursting. These results are consistent with the hypothesis that NMDA-induced burst firing in STN neurons requires activation of either an I(CAN) or a Na(+)-Ca(2+) exchanger.

Animals↗

PubMed2003

Synaptic plasticity in rat subthalamic nucleus induced by high-frequency stimulation.

The technique of deep brain stimulation (DBS) has become a preferred surgical choice for the treatment of advanced Parkinson's disease. The subthalamic nucleus (STN) is presently the most promising target for such DBS. In this study, whole-cell patch-clamp recordings were made from 46 STN neurons in rat brain slices to examine the effect of high-frequency stimulation (HFS) of the STN on glutamatergic synaptic transmission in STN neurons. HFS, consisting of trains of stimuli at a frequency of 100 Hz for 1 min, produced three types of synaptic plasticity in 17 STN neurons. First, HFS of the STN induced short-term potentiation (STP) of evoked postsynaptic current (EPSC) amplitude in four neurons. STP was associated with a reduction in the EPSC paired-pulse ratio, suggesting a presynaptic site of action. Second, HFS of the STN generated long-term potentiation (LTP) of EPSC amplitude in eight neurons. Although the EPSC paired-pulse ratio was reduced transiently in the first 2 min following HFS, ratios measured 6-20 min after HFS were unchanged from control. This suggests that LTP is maintained by a postsynaptic mechanism. Third, HFS produced long-term depression (LTD) of EPSC amplitude in five STN neurons. LTD was associated with a significant increase in EPSC paired-pulse ratios, indicating a presynaptic site of action. These results suggest that HFS can produce long-term changes in the efficacy of synaptic transmission in the STN. HFS-induced synaptic plasticity might be one mechanism underlying the effectiveness of DBS in the STN as a treatment of advanced Parkinson's disease.

6-Cyano-7-nitroquinoxaline-2,3-dione↗

PubMed2003

Group II metabotropic glutamate receptor modulation of excitatory transmission in rat subthalamic nucleus.

Patch pipettes were used to record currents in whole-cell configuration to study the effects of group II metabotropic glutamate receptor (mGluR) stimulation on synaptic transmission in slices of rat subthalamic nucleus. Evoked glutamatergic excitatory postsynaptic currents (EPSCs) were reversibly reduced by the selective group II mGluR agonist (2'S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine (DCG IV) in a concentration-dependent manner, with an IC50 of 0.19 +/- 0.05 microM. DCG IV (1 microM) had no effect on inhibitory postsynaptic currents mediated by GABA. DCG IV-induced inhibition of EPSCs was reversed by the selective group II mGluR antagonist LY 341495 (100 nM) and mimicked by another selective group II agonist (2S,1'S,2'S)-2-(carboxycyclopropyl)glycine (L-CCG-I). Inhibition of EPSC amplitude by DCG IV and L-CCG-I was associated with an increase in the paired-pulse ratio of EPSCs. The protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (2 microM) reduced the inhibitory effect of DCG IV on EPSCs. However, the response to DCG IV was not affected by the protein kinase A (PKA) activator forskolin (20 microM), by the adenylyl cyclase inhibitor MDL 12230A (20 microM), or by the phosphodiesterase inhibitor Ro 20-1724 (50 microM). DCG IV-induced inhibition of EPSCs was reduced by the non-selective protein kinase inhibitors H-7 (100 microM), H-8 (50 microM) and HA-1004 (100 microM). These results suggest that group II mGluR stimulation acts presynaptically to inhibit glutamate release by a PKC-dependent mechanism in the subthalamic nucleus.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

PubMed2003

Dopamine receptor supersensitivity in rat subthalamus after 6-hydroxydopamine lesions.

The subthalamic nucleus (STN) receives direct dopaminergic innervation from the substantia nigra pars compacta, but the importance of this input in the pathophysiology of parkinsonism remains to be determined. We used whole-cell patch-clamp recordings in brain slices to study presynaptic dopaminergic modulation of synaptic inputs to the STN in unilateral 6-hydroxydopamine (6-OHDA)-lesioned rats. Here, we report that dopamine was more potent for inhibiting GABA IPSCs and glutamate EPSCs in the STN ipsilateral to the lesion, and was less potent for suppressing IPSCs and EPSCs in the STN contralateral to the lesion, compared with the effects of dopamine in control STN. Dopamine reduced IPSCs with an IC50 value of 20.9 +/- 3.6 microM in control STN, whereas IC50 values were 0.83 +/- 0.15 and 55.1 +/- 11.1 microM in STN ipsilateral and contralateral to 6-OHDA lesions, respectively. Dopamine also inhibited EPSCs with an IC50 value of 12.8 +/- 2.8 microM in control STN, whereas IC50 values were 4.5 +/- 0.9 and 41.6 +/- 9.8 microM in STN ipsilateral and contralateral to 6-OHDA lesions, respectively. Results with paired stimuli to evoke EPSCs and IPSCs suggest that endogenous dopamine acts presynaptically to inhibit transmitter release in the STN. These results show that chronic dopamine denervation significantly alters the regulation of synaptic input to the STN. Our results also suggest that the STN may be an important target for levodopa therapy in Parkinson's disease.

6-Cyano-7-nitroquinoxaline-2,3-dione↗

PubMed2002

Presynaptic modulation of synaptic transmission by opioid receptor in rat subthalamic nucleus in vitro.

Presynaptic modulation of synaptic transmission in rat subthalamic nucleus (STN) neurons was investigated using whole-cell patch-clamp recordings in brain slices. Evoked GABAergic inhibitory postsynaptic currents (IPSCs) were reversibly reduced by methionine enkephalin (ME) with an IC(50) value of 1.1 +/- 0.3 microM. The action of ME was mimicked by the mu-selective agonist [D-Ala(2), N-Me-Phe(4), Gly(5)-ol]-enkephalin (DAMGO), and was partially blocked by the mu-selective antagonists naloxonazine and D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH(2) (CTAP). Evoked GABA(A) IPSCs were also inhibited by the delta-selective agonist [D-Pen(2,5)]-enkephalin (DPDPE), but not by the kappa-selective agonist (+)-(5 alpha,7 alpha,8 beta)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]-benzeneacetamide (U-69593) and the orphan receptor agonist orphanin FQ/nociceptin (OFQ). DPDPE-induced inhibition was completely blocked by the delta-selective antagonist N,N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH (ICI 174,864). ME, DAMGO and DPDPE increased the paired-pulse ratio of IPSCs. Evoked excitatory postsynaptic currents (EPSCs) were reversibly reduced by ME with an IC(50) value of 0.35 +/- 0.14 microM. Inhibition by ME was associated with an increase in the paired-pulse ratio of EPSCs. The action of ME was mimicked by DAMGO, and blocked by naloxonazine. DPDPE had little effect on evoked EPSCs. Neither U-69593 nor OFQ had any effect. ME significantly decreased the frequency of spontaneous miniature EPSCs (mEPSCs) without change in their amplitude. The action of ME was mimicked by DAMGO. DPDPE had no effect. The presynaptic voltage-dependent potassium conductance blocker 4-aminopyridine (4-AP, 100 microM) abolished the inhibitory effects of ME on evoked IPSCs and EPSCs. In contrast, 4-AP only partially blocked the actions of baclofen. These results suggest that opioids inhibit inhibitory synaptic transmission in the STN through the activation of presynaptic mu- and delta- receptors. In contrast, inhibition of excitatory synaptic inputs to the STN occurs through the activation of only mu-receptors. Both inhibitions may be mediated by blockade of voltage-dependent potassium conductance.

Animals↗

PubMed2002

Pharmacological identification of inward current evoked by dopamine in rat subthalamic neurons in vitro.

Dopaminergic mechanisms in the subthalamic nucleus (STN) are implicated in the pathophysiology of Parkinson's disease. Here, electrophysiological responses of STN neurons to dopamine (DA) were investigated by using whole-cell patch-clamp recordings in the rat brain slice preparation. Under current-clamp, DA depolarized membrane potential and increased the frequency of spontaneous action potentials of STN neurons. Under voltage-clamp, DA (3-300 microM) produced a reversible concentration-dependent inward current (I(DA); 6-40 pA) with an EC(50) of 13 microM. This DA-induced current had a negative slope conductance which reversed at -102 mV. It was partially reduced by barium and by superfusion with an elevated concentration of extracellular K(+). Moreover, TTX and glutamate receptor antagonists (CNQX and AP5) did not significantly affect the DA responses, indicating that I(DA) is not dependent upon afferent synaptic activity in the STN. Quinpirole, a D(2) receptor agonist, mimicked the DA action more effectively than did the D(1) agonist SKF-38393. The D(2) antagonist sulpiride, but not the D(1) antagonist SCH-23390, blocked responses induced by DA. Intracellular application of G-protein inhibitor GDP-beta-S also suppressed I(DA). GTP-gamma-S, added to the pipette solution, evoked a sustained inward shift in the absence of DA. These results suggest that DA increases the activity of STN neurons via activation of G-protein-coupled D(2)-like receptors which reduce a K(+) conductance.

Action Potentials↗