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J Garthwaite

Publications and source records attributed to J Garthwaite.

At least 37 records · Page 2Linked to original sources
PubMed1997

Frequency detection and temporally dispersed synaptic signal association through a metabotropic glutamate receptor pathway.

In the classical view, a central neuron integrates incoming synaptic information by simple algebraic summation of the resultant bioelectrical signals that coincide in time. The voltage dependence of the NMDA (N-methyl-D-aspartate) type of ionotropic glutamate receptor endows neurons with an additional tool that allows one synaptic input to influence another, providing, again, that the two are active simultaneously. Here we identify a new mechanism by which non-coincident signals generated by different synaptic inputs are integrated. The device serves to regulate neuronal excitation through G-protein-coupled, metabotropic glutamate receptors (mGluRs) in a powerful and specific manner. We show that, in cerebellar Purkinje cells, a single activation of the climbing-fibre input markedly potentiates mGluR-mediated excitation at parallel-fibre synapses. The potentiation results from a transient rise in cytosolic Ca2+ which is 'memorized' in such a way that it promotes excitation through mGluRs for about two minutes. A Ca2+-transient is also effective if imposed up to two seconds after parallel-fibre stimulation. By allowing temporally and spatially dispersed synaptic signals to be assimilated, this mechanism adds a new element to the computational power of central neurons.

Action Potentials↗
PubMed1997

Serum S-100 protein, relationship to clinical outcome in acute stroke.

The clinical significance of serum S-100 protein, a protein released by damaged brain tissue, was assessed in patients with acute ischaemic or haemorrhagic stroke and matched controls. Serum S-100 protein concentration was significantly elevated in patients with ischaemic stroke [median (SQR): 0.27 (0.90) microgram/L, n = 68] and haemorrhagic stroke [0.43 (0.23 microgram/L, n = 13] compared to controls [0.11 (0.03) microgram/L, n = 51, P < 0.0001]. Although patients with haemorrhagic stroke had higher serum S-100 concentrations compared to patients with ischaemic stroke, this was not quite statistically significant. Serum S-100 concentrations were related to infarct size, large (total anterior circulation) infarcts concentrations having the highest [0.40 (0.22) microgram/L], and small vessel ('lacunar') infarcts concentrations having the lowest [0.20 (0.60) microgram/L, P < 0.0005] concentrations. S-100 protein concentration was also significantly related to clinical outcome at three months measured using three disability and handicap scales (n = 81): modified Barthel index (rs = -0.285, P = 0.01), modified Rankin score (rs = 0.313, P = 0.004) and Lindley score (rs = 0.262, P = 0.018) with high values associated with poor clinical outcome. Similarly high values of serum S-100 protein were observed in patients who died or were discharged to an institution [median (SQR): 0.63 (0.29) microgram/L and 0.37 (0.13) microgram/L, respectively compared to those who were discharged home [0.26 (0.11) microgram/L, P = 0.13]. The present study suggests measurement of serum S-100 protein could be a useful prognostic marker of clinical outcome in acute stroke. Whether S-100 concentrations can be altered by therapeutic intervention in acute stroke remains to be elucidated.

Age Factors↗
PubMed1997

Serum S-100 protein, relationship to clinical outcome in acute stroke.

The clinical significance of serum S-100 protein, a protein released by damaged brain tissue, was assessed in patients with acute ischaemic or haemorrhagic stroke and matched controls. Serum S-100 protein concentration was significantly elevated in patients with ischaemic stroke [median (SQR): 0.27 (0.09) microgram/L, n = 68] and haemorrhagic stroke [0.43 (0.23) microgram/L, n = 13] compared to controls [0.11 (0.03) microgram/L, n = 51, P < 0.0001]. Although patients with haemorrhagic stroke had higher serum S-100 concentrations compared to patients with ischaemic stroke, this was not quite statistically significant. Serum S-100 concentrations were related to infarct size, large (total anterior circulation) infarcts concentrations having the highest [0.40 (0.22) microgram/L], and small vessel ('lacunar') infarcts concentrations having the lowest [0.20 (0.06) microgram/L, P < 0.0005] concentrations. S-100 protein concentration was also significantly related to clinical outcome at three months measured using three disability and handicap scales (n = 81): modified Barthel index (rs = -0.285, P = 0.01), modified Rankin score (rs = 0.313, P = 0.004) and Lindley score (rs = 0.262, P = 0.018) with high values associated with poor clinical outcome. Similarly high values of serum S-100 protein were observed in patients who died or were discharged to an institution [median (SQR): 0.63 (0.29) microgram/L and 0.37 (0.13) microgram/L, respectively] compared to those who were discharged home [0.26 (0.11) microgram/L, P = 0.13]. The present study suggests measurement of serum S-100 protein could be a useful prognostic marker of clinical outcome in acute stroke. Whether S-100 concentrations can be altered by therapeutic intervention in acute stroke remains to be elucidated.

Age Factors↗
PubMed1996

Vicious cycle involving Na+ channels, glutamate release, and NMDA receptors mediates delayed neurodegeneration through nitric oxide formation.

The mechanisms by which neurons die after cerebral ischemia and related conditions in vivo are unclear, but they are thought to involve voltage-dependent Na+ channels, glutamate receptors, and nitric oxide (NO) formation because selective inhibition of each provides neuroprotection. It is not known precisely what their roles are, nor whether they interact within a single cascade or in parallel pathways. These questions were investigated using an in vitro primary cell culture model in which striatal neurons undergo a gradual and delayed neurodegeneration after a brief (5 min) challenge with the glutamate receptor agonist NMDA. Unexpectedly, NO was generated continuously by the cultures for up to 16 hr after the NMDA exposure. Neuronal death followed the same general time course except that its start was delayed by approximately 4 hr. Application of the NO synthase inhibitor nitroarginine after, but not during, the NMDA exposure inhibited NO formation and protected against delayed neuronal death. Blockade of NMDA receptors or of voltage-sensitive Na+ channels [with tetrodotoxin (TTX)] during the postexposure period also inhibited both NO formation and cell death. The NMDA exposure resulted in a selective accumulation of glutamate in the culture medium during the period preceding cell death. This glutamate release could be inhibited by NMDA antagonism or by TTX, but not by nitroarginine. These data suggest that Na+ channels, glutamate receptors, and NO operate interdependently and sequentially to cause neurodegeneration. At the core of the mechanism is a vicious cycle in which NMDA receptor stimulation causes activation of TTX-sensitive Na+ channels, leading to glutamate release and further NMDA receptor stimulation. The output of the cycle is an enduring production of NO from neuronal sources, and this is responsible for delayed neuronal death. The same neurons, however, could be induced to undergo more rapid NMDA receptor-dependent death that required neither TTX-sensitive Na+ channels nor NO.

Amino Acids↗
PubMed1996

The synaptic potential mediated by metabotropic glutamate receptors is not associated with a substantial elevation of cytosolic free calcium concentration in Purkinje cells.

Brief tetanic stimulation of parallel fibres can evoke a slow excitatory postsynaptic potential (EPSP) in cerebellar Purkinje cells that is mediated by metabotropic glutamate receptors (mGluRs). It is likely that the receptor subtype involved is mGluR1, which couples to the production of diacylglycerol and inositol-1,4,5-trisphosphate (IP3). We therefore examined whether the mGluR-EPSP is associated with an increase in cytosolic free calcium [Ca2+]i using simultaneous Ca2+ imaging and electrophysiological recordings. An mGluR-EPSP could be evoked in all nine Purkinje cells tested. In all but one this potential was not associated with measurable changes in [Ca2+]i whereas single calcium spikes produced large Ca2+ transients. In the one Purkinje cell where [Ca2+]i was elevated, the rise was estimated to be roughly 20-fold smaller than that produced by a single Ca2+ spike.

Animals↗
PubMed1996

A biplanar slice preparation for studying cerebellar synaptic transmission.

Unlike certain other brain areas, notably the hippocampal formation, synaptic transmission in the cerebellum, a 3-dimensional anatomical structure, is no ideally studied in a 2-dimensional slice preparation. We describe a method for cutting a cerebellar slice that incorporates two planes of section: one sagittal (in the plane of the Purkinje cell dendrites and of afferent and efferent fibres running in the white matter), and the other in the plane of the parallel fibres (granule cell axons). Details are given of how neurotransmission in the parallel fibre-to-Purkinje cell pathway and in the mossy fibre-to-granule cell pathway can be studied by applying a specially designed grease-gap recording technique to the biplanar slice. We further demonstrate the utility of the slice for intracellular recording.

Afferent Pathways↗
PubMed1996

The nitric oxide-cyclic GMP pathway is required for nociceptive signalling at specific loci within the somatosensory pathway.

The involvement of nitric oxide in nociceptive processing was examined at the main loci of synaptic transmission within the rat somatosensory pathway from the caudal sural cutaneous nerve. Intrathecal (lumbar 1-3) administration of the nitric oxide synthase inhibitor, N omega-nitro-L-arginine methyl ester (30 micrograms), inhibited nitric oxide synthase in this region of the spinal cord by greater than 80% but had no significant effect on nitric oxide synthase in parietal cerebral cortex, thalamus or medulla/pons. In a rat model of peripheral neuropathy (one to two week ligation of the caudal sural cutaneous nerve), intrathecal administration of the same dose of N omega-nitro-L-arginine methyl ester prevented the hyperalgesic response to thermal stimuli. Administration of 30 micrograms N omega-nitro-L-arginine methyl ester into the lateral ventricle had no effect on nitric oxide synthase in the lumbar 1-3 region of the spinal cord but gave substantial inhibition in higher areas of the somatosensory pathway (parietal cerebral cortex, thalamus and medulla/pons). Nitric oxide synthase in the parietal cerebral cortex (but not thalamus) was inhibited to a greater extent in the hemisphere ipsilateral to the site of administration. Administration of 30 micrograms N omega-nitro-L-arginine methyl ester into the lateral ventricle decreased thermal hyperalgesia, but only when N omega-nitro-L-arginine methyl ester was administered contralateral to the ligated caudal sural cutaneous nerve and therefore ipsilateral to the cortical nociceptive processing from this nerve. Intrathecal and intracerebroventricular administration of the selective inhibitor of nitric oxide-sensitive guanylyl cyclase, 1-H-[1,2,4]oxadiazalo[4,3-a]quinoxalin-1-one, also decreased the hyperalgesic response to thermal stimuli. These data demonstrate that, in a model of neuropathic pain, nitric oxide is involved in nociceptive processing at spinal and cerebrocortical synaptic loci of the somatosensory pathway and that its actions appear to be mediated through guanylyl cyclase.

Animals↗
PubMed1996

State-dependent inhibition of Na+ currents by the neuroprotective agent 619C89 in rat hippocampal neurons and in a mammalian cell line expressing rat brain type IIA Na+ channels.

The compound 619C89 [4-amino-2-(4-methyl-1-piperazinyl)-5-(2,3,5-tricholorophenyl)-pyr imidine] is an effective neuroprotective agent in in vivo models of cerebral ischaemia. It has been suggested to act by inhibiting voltage-gated Na+ channels. To test this hypothesis, the action of 619C89 on recombinant rat brain type IIA Na+ channels expressed in Chinese hamster ovary cells and on native Na+ channels in acutely dissociated rat hippocampal neurons has been studied using whole-cell voltage-clamp recording techniques. In the cell line expressing type IIA Na+ channels, 619C89 caused a reversible inhibition of Na+ currents in a concentration- and voltage-dependent manner. A half-maximal inhibitory concentration (IC50) of approximately 50 microM was obtained at a holding potential of -90 mV whereas, with a conditioning prepulse to -60 mV for 30 s, the IC50 was reduced to 8 microM. Furthermore, the inhibition was markedly enhanced by a use-dependent action, which was dependent not only on the frequency of stimulation, but also on the duration (3.5-40 ms) of the pulses. Trains (10-50 Hz) of up to 60 depolarizing pulses of 0.7 ms duration did not evoke any use-dependent inhibition in the presence of 619C89, suggesting that this compound is not an open channel blocker. The voltage- and use-dependent inhibition by 619C89 was also observed on native Na+ channels in hippocampal neurons. 619C89 (10 microM) produced a small hyperpolarizing shift in the fast inactivation curve and a substantial (13 mV) hyperpolarizing shift in slow inactivation. The compound dramatically delayed the recovery from inactivation without affecting the development of inactivation. Moreover, 619C89 has no effect on the shape of the current-voltage relationship or on the voltage activation curve. These data indicate that 619C89 interacts selectively with the inactivated state of the Na+ channel with an estimated affinity of 3 microM. This primary action of 619C89 may underlie its neuroprotective effects.

Animals↗
PubMed1996

Tyrosine kinase is required for long-term depression in the cerebellum.

Long-term depression (LTD) at the parallel fiber-Purkinje cell synapse in the cerebellum is a well-known example of synaptic plasticity. Although LTD is thought to reflect an enduring loss of postsynaptic AMPA receptor sensitivity, the underlying mechanisms are unclear. Protein-tyrosine kinases (PTKs) are able to modulate ionotropic receptor function and are enriched in Purkinje cells. Using intracellular recording from Purkinje cells, it is shown that two structurally and mechanistically distinct PTK inhibitors, lavendustin A and herbimycin A, block LTD induced by pairing parallel fiber stimulation with postsynaptic Ca2+ spiking. Intracellular application of the protein kinase C (PKC) activator, (-)-indolactam V, consistently depressed parallel fiber-Purkinje cells EPSPs and occluded pairing-induced LTD. Herbimycin A nullified the run-down produced by (-)-indolactam V. These data suggest that PTKs are necessary for LTD at the parallel fiber-Purkinje cell synapse and that PKC-induced synaptic depression requires PTK activity.

Animals↗
PubMed1996

Ex vivo measurement of brain tissue nitrite and nitrate accurately reflects nitric oxide synthase activity in vivo.

The ex vivo tissue concentration of nitrite and nitrate (NOx) was found to correlate closely with the activity of nitric oxide synthase (NOS; EC 1.14.13.39) in various brain regions. Systemic administration of the nonselective NOS inhibitor N omega-nitro-L-arginine (L-NA) at doses that completely inhibited both central and peripheral NOS, depleted whole-brain and CSF NOx by up to 75% but had no effect on plasma NOx. Selective inhibition of central NOS by intracerebroventricular administration of L-NA methyl ester produced similar decreases in levels of whole-brain NOx. A residual concentration of NOx of 10-15 microM remained in all brain regions even after complete inhibition of brain NOS. Brain NOx content decreased rapidly and in parallel with the inhibition of brain NOS. The ex vivo measurement of levels of brain NOx was found to reflect the in vivo efficacy of several different types of NOS inhibitor: L-NA, N omega-monomethyl-l-arginine, and 7-nitroindazole. Intraperitoneal administration of the NOS substrate L-arginine increased brain NOx concentrations by up to 150% of control values. These results demonstrate that the ex vivo measurement of levels of brain tissue NOx is a rapid, reliable, and straightforward technique to determine NOS activity in vivo. This method can be used to assess both the regional distribution and the degree of inhibition of NOS activity in vivo.

Animals↗
PubMed1996

Long-term depression in rat cerebellum requires both NO synthase and NO-sensitive guanylyl cyclase.

Long-term depression (LTD) of synaptic transmission between parallel fibres and Purkinje cells is a well-known example of synaptic plasticity taking place in the cerebellum. Nitric oxide (NO) has been implicated in synaptic plasticity in other brain areas, but its function in cerebellar LTD is controversial. Even when an involvement is suggested, the NO signal transduction pathway is unclear. One candidate is the cyclic GMP-synthesizing enzyme, soluble guanylyl cyclase, whose activity in the brain and elsewhere is powerfully stimulated by NO. By recording intracellularly from Purkinje cells in cerebellar slices, we demonstrate that blockade of NO synthase completely inhibits LTD induced by pairing parallel fibre stimulation with postsynaptic Ca2+ spike firing. LTD was also blocked by intracellular application of 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, a recently identified potent and selective inhibitor of soluble guanylyl cyclase. These findings indicate that soluble guanylyl cyclase is required for cerebellar LTD and suggest that this enzyme, located within Purkinje cells, transduces the NO signal in this form of synaptic plasticity.

Animals↗
PubMed1996

Pharmacological antagonism of the actions of group II and III mGluR agonists in the lateral perforant path of rat hippocampal slices.

1. An understanding of the physiological and pathological roles of metabotropic glutamate receptors (mGluRs) is currently hampered by the lack of selective antagonists. Standard extracellular recording techniques were used to investigate the activity of recently reported mGluR antagonists on agonist-induced depressions of synaptic transmission in the lateral perforant path of hippocampal slices obtained from 12-16 day-old rats. 2. The group III specific mGluR agonist, (S)-2-amino-4-phosphonobutanoate (L-AP4) depressed basal synaptic transmission in a reversible and dose-dependent manner. The mean (+/-s.e. mean) depression obtained with 100 microM L-AP4 (the maximum concentration tested) was 74 +/- 3% and the IC50 value was 3 +/- 1 microM (n = 5). 3. The selective group II mGluR agonists, (1S,3S)-1-aminocyclopentane-1, 3-dicarboxylate ((1S,3s)-ACPD) and (2S, 1'R, 2'R, 3'R)-2-(2',3'-dicarboxycyclopropyl)glycine (DCG-IV) also depressed basal synaptic transmission in a reversible and dose-dependent manner. The mean depression obtained with 200 microM (1S,3S)-ACPD was 83 +/- 8% and the IC50 value was 12 +/- 3 microM (n = 5). The mean depression obtained with 1 microM DCG-IV was 73 +/- 7% and the IC50 value was 88 +/- 15 nM (n = 4). 4. Synaptic depressions induced by the actions of 20 microM (1S,3S)-ACPD and 10 microM L-AP4 were antagonized by the mGluR antagonists (+)-alpha-methyl-4-carboxyphenylglycine ((+)-MCPG), (S)-2-methyl-2-amino-4-phosphonobutanoate (MAP4), (2S,1'S,2'S)-2-methyl-2(2'-carboxycyclopropyl)glycine (MCCG), (RS)-alpha-methyl-4-tetrazolylphenylglycine (MTPG), (RS)-alpha-methyl-4-sulphonophenylglycine (MSPG) and (RS)-alpha-methyl-4-phosphonophenylglycine (MPPG) (all tested at 500 microM). 5. (+)-MCPG was a weak antagonist of both L-AP4 and (1S,3S)-ACPD-induced depressions. MCCG was selective towards (1S,3S)-ACPD, but analysis of its effects were complicated by apparent partial agonist activity. MAP4 showed good selectivity for L-AP4-induced effects. 6. The most effective antagonist tested against 10 microM L-AP4 was MPPG (mean reversal 90 +/- 3%; n = 4). In contrast, the most effective antagonist tested against 20 microM (1S,3S)-ACPD induced depressions was MTPG (mean reversal 64 +/- 4%; n = 4). Both antagonists produced parallel shifts in agonist dose-response curves. Schild analysis yielded estimated KD values of 11.7 microM and 27.5 microM, respectively. Neither antagonist had any effect on basal transmission or on depressions induced by the adenosine receptor agonist, 2-chloroadenosine (500 nM; n = 3). 7. We conclude that both group II and group III mGluRs can mediate synaptic depressions induced by mGluR agonists in the lateral perforant path. The mGlur antagonists MTPG, MPPG and MAP4 should be useful in determining the roles of group II and III mGluRs in the central nervous system.

2-Chloroadenosine↗
PubMed1996

The nitric oxide-cyclic GMP pathway and synaptic plasticity in the rat superior cervical ganglion.

1. We have investigated the possibility that nitric oxide (NO) and soluble guanylyl cyclase, an enzyme that synthesizes guanosine 3':5'-cyclic monophosphate (cyclic GMP) in response to NO, contributes to plasticity of synaptic transmission in the rat isolated superior cervical ganglion (SCG). 2. Exposure of ganglia to the NO donor, nitroprusside, caused a concentration-dependent accumulation of cyclic GMP which was augmented in the presence of the phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine. The compound, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), a selective inhibitor of soluble guanylyl cyclase, completely blocked this cyclic GMP response. 3. As assessed by extracellular recording, nitroprusside (100 microM) and another NO donor, S-nitrosoglutathione (30 microM) increased the efficacy of ganglionic synaptic transmission in response to electrical stimulation of the preganglionic nerve, an effect that was reversible and which could be replicated by the cyclic GMP analogue, 8-bromo-cyclic GMP. Ganglionic depolarizations resulting from stimulation of nicotinic receptors with carbachol were not increased by nitroprusside. The potentiating actions of the NO donors on synaptic transmission, but not that of 8-bromo-cyclic GMP, were inhibited by ODQ. 4. Brief tetanic stimulation of the preganglionic nerve resulted in a long-term potentiation (LTP) of synaptic transmission that was unaffected by ODQ, either in the absence or presence of the NO synthase inhibitor, NG-nitro-L-arginine (L-NOARG, 100 microM). A lack of influence of L-NOARG was confirmed in intracellular recordings of LTP of the excitatory postsynaptic potential. Furthermore, under conditions where tetanically-induced LTP was saturated, nitroprusside was still able to potentiate synaptic transmission, as judged from extracellular recording. 5. We conclude that NO is capable of potentiating ganglionic neurotransmission and this effect is mediated through the stimulation of soluble guanylyl cyclase and the accumulation of cyclic GMP. However, this potentiation is distinct from LTP of nicotinic synaptic transmission, in which neither NO nor soluble guanylyl cyclase appear to participate.

Animals↗
PubMed1996

Serum neuron-specific enolase, carnosinase, and their ratio in acute stroke. An enzymatic test for predicting outcome?

BACKGROUND AND PURPOSE: Few admission variables adequately predict neuronal damage and prognosis in individual patients after stroke. Therefore, there is a need for a reliable non-invasive surrogate measure of clinical outcome. METHODS: We have developed a surrogate measure of stroke outcome using the ratio of serum neuron-specific enolase (NSE) to human serum carnosinase (HSC) in 124 patients with acute ischemic or hemorrhagic stroke and 61 matched control subjects. Serum NSE is known to rise and HSC to fall after neuronal injury such as cerebral ischemia. RESULTS: Serum NSE levels were significantly higher and HSC levels lower in the patient group. The NSE/HSC ratio was elevated in patients with stroke: median (semiquartile) hemorrhages, 0.072 (0.033); infarcts, 0.039 (0.026); and control subjects, 0.019 (0.014), P = .0001. Patients with a primary intracerebral hemorrhage had nonsignificantly higher ratios than those with an infarct (P = .082). The NSE/HSC ratio was significantly associated with 90-day outcome measured in two out of three disability and handicap scales: modified Barthel Index (rs = -.34, P = .001), modified Rankin Scale (rs = .30, P = .002), and Lindley Score (rs = .19, P = .057). Patients who died or were institutionalized had higher ratios than those who were discharged home: 0.069 (0.043) versus 0.038 (0.024), P = .011. Correlations between the NSE/HSC ratio and outcome were comparable to those between patient age or consciousness level on admission and clinical outcome. CONCLUSIONS: We believe that measurement of NSE, HSC, or their ratio may be useful in the assessment of patients with acute stroke with respect to diagnosis and prediction of clinical outcome.

Acute Disease↗
PubMed1995

Interaction of the antiepileptic drug lamotrigine with recombinant rat brain type IIA Na+ channels and with native Na+ channels in rat hippocampal neurones.

Actions of the new antiepileptic drug lamotrigine (LTG, Lamictal) were characterised using recombinant rat brain type IIA Na+ channels expressed in Chinese hamster ovary (CHO) cells and native Na+ channels in rat hippocampal pyramidal neurones, using whole-cell recording and intracellular recording techniques. In CHO cells, LTG caused a tonic inhibition of Na+ currents in a concentration-dependent and voltage-dependent manner. The half-maximal inhibitory concentration (IC50) of approximately 500 microM was obtained at a holding potential (Vh) of -90 mV compared with an IC50 of 100 microM at a Vh of -60 mV. LTG (50 microM) caused a 10-mV negative shift in the slow, steady-state inactivation curve and delayed considerably the recovery from inactivation, but had no significant effects on the voltage dependence of activation or fast inactivation, suggesting that LTG acts mainly on the slow inactivated state. The affinity for the inactivated channels was estimated at 12 microM. The tonic inhibition was augmented by a use-dependent action in which a further inhibition by the drug developed during rapid repetitive stimulation using a train of 20-ms duration pulses (11 Hz). These results were consistent with the drug action being on firing properties of pyramidal neurones. Only in those epilepti-form bursts which caused cumulative inactivation of Na+ spikes did LTG produce a potent inhibition. Our data suggest that the inactivated channel is a primary target for LTG action at therapeutic concentrations.

Action Potentials↗
PubMed1995

Synaptic excitation mediated by AMPA receptors in rat cerebellar slices is selectively enhanced by aniracetam and cyclothiazide.

AMPA receptors mediate fast, glutamatergic synaptic transmission in the central nervous system. The time-course of the associated postsynaptic current has been suggested to be determined principally by the kinetics of glutamate binding and receptor desensitization. Aniracetam and cyclothiazide are drugs capable of selectively preventing desensitization of the AMPA receptor. To investigate the relevance of desensitization to fast synaptic transmission in the cerebellum we have tested these compounds against AMPA-induced depolarizations and postsynaptic potentials using the grease-gap recording technique. Aniracetam (1 microM-5 mM) and cyclothiazide (1 microM-500 microM) both enhanced the depolarising action of AMPA (1 microM) on Purkinje cells in a concentration-dependent manner. At the highest concentrations tested, the increases over controls were approximately 600% and 800% respectively. Aniracetam also increased, in a concentration-dependent manner, the amplitude of the evoked synaptic potentials of both parallel fibre-Purkinje cell and mossy fibre-granule cell pathways, with the highest concentrations tested enhancing the potentials by approximately 60% and 75% respectively. These data suggest that, at two different synapses in the cerebellum, AMPA receptor desensitization occurs physiologically and is likely to contribute to the shape of fast synaptic currents.

Animals↗