Biomedical subjects

Graham L Collingridge

Publications and source records attributed to Graham L Collingridge.

45 records · Page 3Linked to original sources

PubMed2003

Functional roles of protein interactions with AMPA and kainate receptors.

The glutamate receptor subtypes AMPA and kainate are involved in synaptic transmission and synaptic plasticity in the CNS. Recently there has been considerable interest in understanding the molecular regulation of these receptors by proteins that directly bind to AMPA and kainate receptor subunits. Amongst the first interaction partners to be discovered were NSF, ABP, GRIP and PICK1, which bind the AMPA receptor subunit GLUA2. We have studied the functional roles of the interactions of these proteins in regulating AMPA receptor-mediated synaptic transmission and synaptic plasticity in the hippocampus. We have also started to investigate the functions of PICK1 and GRIP on kainate receptor-mediated synaptic transmission in this region. In this article we reflect upon this work, which has led to some new ideas about how AMPA and kainate receptors are regulated at synapses.

Animals↗

PubMed2002

A presynaptic kainate receptor is involved in regulating the dynamic properties of thalamocortical synapses during development.

Previous studies have shown that pharmacological activation of presynaptic kainate receptors at glutamatergic synapses facilitates or depresses transmission in a dose-dependent manner. However, the only synaptically activated kainate autoreceptor described to date is facilitatory. Here, we describe a kainate autoreceptor that depresses synaptic transmission. This autoreceptor is present at developing thalamocortical synapses in the barrel cortex, specifically regulates transmission at frequencies corresponding to those observed in vivo during whisker activation, and is developmentally down regulated during the first postnatal week. This receptor may, therefore, limit the transfer of high-frequency activity to the developing cortex, the loss of which mechanism may be important for the maturation of sensory processing.

Animals↗

PubMed2002

Altered short-term synaptic plasticity in mice lacking the metabotropic glutamate receptor mGlu7.

Eight subtypes of metabotropic glutamate (mGlu) receptors have been identified of which two, mGlu5 and mGlu7, are highly expressed at synapses made between CA3 and CA1 pyramidal neurons in the hippocampus. This input, the Schaffer collateral-commissural pathway, displays robust long-term potentiation (LTP), a process believed to utilise molecular mechanisms that are key processes involved in the synaptic basis of learning and memory. To investigate the possible function in LTP of mGlu7 receptors, a subtype for which no specific antagonists exist, we generated a mouse lacking this receptor, by homologous recombination. We found that LTP could be induced in mGlu7-/- mice and that once the potentiation had reached a stable level there was no difference in the magnitude of LTP between mGlu7-/- mice and their littermate controls. However, the initial decremental phase of LTP, known as short-term potentiation (STP), was greatly attenuated in the mGlu7-/- mouse. In addition, there was less frequency facilitation during, and less post-tetanic potentiation following, a high frequency train in the mGlu7-/- mouse. These results show that the absence of mGlu7 receptors results in alterations in short-term synaptic plasticity in the hippocampus.

Animals↗

PubMed2002

Impairment in hippocampal long-term potentiation in mice under-expressing the Alzheimer's disease related gene presenilin-1.

Presenilin-1 (PS1) is intimately involved in cleavage of amyloid precursor protein to form beta-amyloid peptides, certain forms of which aggregate in the brains of patients with Alzheimer's disease (AD). The function(s) of PS1 and its precise involvement in the development of cognitive deficits associated with AD are unclear. We have utilised genetically modified mice that under-express PS1 (PS1(+/-) mice) to investigate the role of PS1 in hippocampal synaptic plasticity. Field excitatory postsynaptic responses elicited by baseline stimulation were indistinguishable between PS1(+/-) mice and wild-type controls. Likewise, a measure of short-term plasticity, paired-pulse facilitation, was normal in PS1(+/-) mice. However, long-term potentiation induced by multiple tetanus trains was reduced in PS1(+/-) animals. These results demonstrate that chronic reduction of PS1 activity leads to impaired synaptic plasticity, thus suggesting a role for PS1 in normal cognitive function.

Alzheimer Disease↗

PubMed2002

Group I mGluRs modulate the pattern of non-synaptic epileptiform activity in the hippocampus.

The hippocampus is well known for its susceptibility to epileptic seizures, in part because of its neuronal architecture that facilitates synchronization. Although synaptic networks are important for the genesis and spread of epileptiform activity, synchronization of neuronal activity can occur when action potential-dependent chemical synaptic transmission is absent. In particular, it is possible to induce epileptiform activity by perfusing hippocampal slices with a low-Ca(2+)/high-K(+) mediums. Using extracellular recording in area CA1 we have characterized the effects of metabotropic glutamate receptor (mGluR) activation on this non-synaptic bursting activity. Under control conditions, bursting occurred at intervals of 14-86 s with each burst comprising a long (up to 44 s) negative-going field potential of 2 to 13 mV superimposed upon which was sustained firing of population spikes. Activation of group I mGluRs by (S)-3,5-dihydroxyphenylglycine (DHPG) (25 microM) caused a dramatic increase in burst frequency (up to five-fold), which was accompanied by a decrease in the duration and amplitude of bursts. The selective mGluR(1) antagonist 2-methyl-4-carboxyphenylglycine (LY367385) and the selective mGluR(5) antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP) both restricted the increase in burst frequency induced by DHPG. However, only LY367385 inhibited the decrease in burst duration and amplitude. Combined application of both antagonists prevented all DHPG-induced changes in bursting activity. These data provide evidence for a role of both mGluR(1) and mGluR(5) subtypes in changing the frequency of non-synaptic bursting, with mGluR(1) alone causing alterations in burst duration and amplitude. These effects are likely to contribute to the group I mGluR-induced changes in synaptic epileptic activity that are already well documented.

Action Potentials↗

PubMed2002

Tyrosine dephosphorylation underlies DHPG-induced LTD.

A form of long-term depression (LTD) of synaptic transmission can be induced by bath application of the group I metabotropic glutamate (mGlu) receptor agonist (RS)-3,5-dihydroxyphenylglycine (DHPG). The mechanisms responsible for the induction and expression of DHPG-induced LTD in the CA1 region of the hippocampus are currently the subject of intense investigation. Here we show that two protein tyrosine kinase (PTK) inhibitors (10 microM lavendustin A or 30 microM genistein) have little effect on DHPG-induced LTD. In contrast two protein tyrosine phosphatase (PTP) inhibitors (1 mM orthovanadate or 15 microM phenyl-arsine oxide) significantly inhibited DHPG-induced LTD. These data suggest that DHPG-induced LTD involves activation of a protein tyrosine phosphatase.

Animals↗

PubMed2002

Antagonists of GLU(K5)-containing kainate receptors prevent pilocarpine-induced limbic seizures.

Developments in the molecular biology and pharmacology of GLU(K5), a subtype of the kainate class of ionotropic glutamate receptors, have enabled insights into the roles of this subunit in synaptic transmission and plasticity. However, little is known about the possible functions of GLU(K5)-containing kainate receptors in pathological conditions. We report here that, in hippocampal slices, selective antagonists of GLU(K5)-containing kainate receptors prevented development of epileptiform activity--evoked by the muscarinic agonist, pilocarpine--and inhibited the activity when it was pre-established. In conscious rats, these GLU(K5) antagonists prevented and interrupted limbic seizures induced by intra-hippocampal pilocarpine perfusion, and attenuated accompanying rises in extracellular L-glutamate and GABA. This anticonvulsant activity occurred without overt side effects. GLU(K5) antagonism also prevented epileptiform activity induced by electrical stimulation, both in vitro and in vivo. Therefore, we propose that subtype-selective GLU(K5) kainate receptor antagonists offer a potential new therapy for epilepsy.

Action Potentials↗

PubMed2002

Phosphatidylinositol 3 kinase regulates synapse specificity of hippocampal long-term depression.

To investigate the role of phosphatidylinositol 3 kinase (PI3 kinase) in hippocampal synaptic plasticity, we used whole-cell patch clamp recordings from rat CA1 neurons to determine the effects of PI3 kinase inhibitors on long-term depression (LTD). PI3 kinase blockade caused a loss of synapse specificity of LTD that was dependent on the co-activation of NMDA-type glutamate receptors (NMDARs) and metabotropic glutamate receptors (mGluRs), and involved release of Ca(2+) from intracellular stores. These findings suggest that the synapse specificity of hippocampal LTD may not be an intrinsic property of this form of homosynaptic plasticity, but rather that it can be regulated by PI3 kinase.

Animals↗

PubMedDate not supplied

Calcium stores and synaptic plasticity.

Chemical transmission at central synapses is known to be highly plastic; the strength of synaptic connections can be modified bi-directionally as a result of activity at individual synapses. Long-term changes in synaptic efficacy, both increases and decreases, are thought to be involved in the development of the nervous system, and in ongoing changes in response to external cues such as during learning and addiction. Other, shorter lasting changes in synaptic transmission are also likely to be important in normal functioning of the CNS. Calcium mobilisation is an important step in multiple forms of plasticity and, although entry into neurones from the extracellular space is often the initial trigger for plasticity changes, release of calcium from intracellular stores also has an important part to play in a variety of forms of synaptic plasticity.

Animals↗