Biomedical subjects

K M Huber

Publications and source records attributed to K M Huber.

8 recordsLinked to original sources

PubMed2001

PLC-beta1, activated via mGluRs, mediates activity-dependent differentiation in cerebral cortex.

During development of the cerebral cortex, the invasion of thalamic axons and subsequent differentiation of cortical neurons are tightly coordinated. Here we provide evidence that glutamate neurotransmission triggers a critical signaling mechanism involving the activation of phospholipase C-beta1 (PLC-beta1) by metabotropic glutamate receptors (mGluRs). Homozygous null mutation of either PLC-beta1 or mGluR5 dramatically disrupts the cytoarchitectural differentiation of 'barrels' in the mouse somatosensory cortex, despite segregation in the pattern of thalamic innervation. Furthermore, group 1 mGluR-stimulated phosphoinositide hydrolysis is dramatically reduced in PLC-beta1-/- mice during barrel development. Our data indicate that PLC-beta1 activation via mGluR5 is critical for the coordinated development of the neocortex, and that presynaptic and postsynaptic components of cortical differentiation can be genetically dissociated.

Animals↗

PubMed2000

Role for rapid dendritic protein synthesis in hippocampal mGluR-dependent long-term depression.

A hippocampal pyramidal neuron receives more than 10(4) excitatory glutamatergic synapses. Many of these synapses contain the molecular machinery for messenger RNA translation, suggesting that the protein complement (and thus function) of each synapse can be regulated on the basis of activity. Here, local postsynaptic protein synthesis, triggered by synaptic activation of metabotropic glutamate receptors, was found to modify synaptic transmission within minutes.

Amino Acids↗

PubMed1999

Induction of NMDA receptor-dependent long-term depression in visual cortex does not require metabotropic glutamate receptors.

We tested the role of group I mGluRs in the induction of long-term depression (LTD) in the visual cortex, using the novel mGluR antagonist LY341495 and mice lacking mGluR5, the predominant phosphoinositide (PI)-linked mGluR in the visual cortex. We find that LY341495 is a potent blocker of glutamate-stimulated PI hydrolysis in visual cortical synaptoneurosomes, and that it effectively antagonizes the actions of the mGluR agonist 1S, 3R-aminocyclopentane-1,3-dicarboxylic acid (ACPD) on synaptic transmission in visual cortical slices. However, LY341495 has no effect on the induction of LTD by low-frequency stimulation. Furthermore, mice lacking mGluR5 show normal NMDA receptor-dependent LTD. These results indicate that group I mGluR activation is not required for the induction of NMDA receptor-dependent LTD in the visual cortex.

Amino Acids↗

PubMed1998

Effects of the metabotropic glutamate receptor antagonist MCPG on phosphoinositide turnover and synaptic plasticity in visual cortex.

The neurotransmitter glutamate, in addition to activating ligand-gated ion channels, also stimulates phosphoinositide (PI) hydrolysis in neurons by activating a group of G-protein-coupled metabotropic glutamate receptors (mGluRs). A role for mGluRs in synaptic plasticity originally was hypothesized based on the observation that the developmental decline in glutamate-stimulated PI turnover is well correlated with the decline in experience-dependent synaptic plasticity in visual cortex. Over the past few years, the compound alpha-methyl-4-carboxyphenylglycine (MCPG) has been widely used to test the role of PI-coupled mGluRs in a number of types of synaptic plasticity, including long-term potentiation (LTP), long-term depression (LTD), ocular dominance plasticity in visual cortex, and the neural plasticity underlying learning and memory. The conclusions of most of these studies were based on the assumption that MCPG blocks the actions of glutamate at PI-coupled mGluRs in the cerebral cortex. Here we show that this assumption is not valid in visual cortex. Although MCPG does antagonize the actions of the synthetic mGluR agonist 1S, 3R-aminocyclopentane-1,3-dicarboxylic acid, it fails to block PI turnover and changes in spike adaptation stimulated by glutamate, the endogenous mGluR ligand. In addition, we find that MCPG fails to block the NMDA receptor-dependent forms of LTP, LTD, and depotentiation in visual cortex.

Action Potentials↗

PubMed1995

LTP induced by activation of voltage-dependent Ca2+ channels requires protein kinase activity.

We have examined the requirement for protein kinase activity in long-term potentiation (LTP) induced by activation of voltage-dependent Ca2+ channels (VDCCs) in hippocampal slices. We previously demonstrated that LTP induced by application of the K+ channel blocker tetraethylammonium (TEA-LTP) consisted of two distinct components, an NMDA receptor-dependent component and a VDCC-dependent component. The results herein demonstrate that both the NMDA and VDCC-dependent components of TEA-LTP are blocked by K-252a, a broad spectrum protein kinase inhibitor. Furthermore, VDCC-dependent TEA-LTP is attenuated by KN-62, a specific inhibitor of Ca2+/calmodulin dependent protein kinase II (CaM-KII). These results demonstrate that LTP induced by VDCC activation requires protein kinase activity and suggest that different routes of postsynaptic Ca2+ influx activate protein kinases to trigger the induction of LTP but that these enzyme systems may be contained in different cell compartments.

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PubMed1995

Distinct LTP induction mechanisms: contribution of NMDA receptors and voltage-dependent calcium channels.

1. Our results indicate that there are two distinct components of long-term potentiation (LTP) induced by the K+ channel blocker tetraethylammonium chloride (TEA) at synapses of hippocampal CA1 pyramidal neurons. Preincubation of hippocampal slices in the N-methyl-D-aspartate (NMDA) receptor antagonist D,L-2-amino-5 phosphonovalerate (D,L-APV, 50 microM), reduced the magnitude of TEA LTP. In addition, the L-type voltage-dependent Ca2+ channel (VDCC) antagonist nifedipine (10 microM) attenuated TEA LTP. Only the combined application of D,L-APV plus nifedipine blocked the induction of TEA LTP. 2. Occlusion experiments demonstrated that saturation of VDCC-dependent TEA LTP did not reduce or occlude NMDA-receptor-dependent TEA LTP. These results indicate that the mechanisms underlying VDCC and NMDA receptor components of TEA LTP are different and do not share a common saturable mechanism. 3. TEA LTP was strictly dependent on NMDA receptor activity in slices with CA3-CA1 connections severed (isolated CA1 slices). In contrast to results obtained in slices with intact CA3-CA1 connections, the NMDA receptor antagonists APV (50 microM) or MK-801 dizocilpine (10 microM) completely blocked TEA LTP in isolated CA1. Consistent with this observation, the properties of TEA LTP in isolated CA1 were very similar to other types of NMDA-receptor-dependent plasticity such as tetanus-induced LTP; TEA LTP required presynaptic stimulation, displayed pathway specificity, and was occluded by tetanus-induced LTP.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMedDate not supplied

Brain-derived neurotrophic factor alters the synaptic modification threshold in visual cortex.

The effects of brain-derived neurotrophic factor (BDNF) were investigated on synaptic transmission and two forms of activity-dependent synaptic plasticity, long-term potentiation (LTP) and long-term depression (LTD), in visual cortex slices prepared from young (P21 -28) rats. The slices treated for 2-5 h in BDNF showed no difference from control slices when a 'strong' tetanus was used (theta-burst stimulation) to elicit a maximal level of LTP but displayed significantly greater synaptic potentiation in response to a 'weak' (20 Hz) tetanus. The BDNF-treated slices also showed significantly less LTD in response to a 1 Hz tetanus. Thus, BDNF treatment alters the relationship between stimulation frequency and synaptic plasticity in the visual cortex, shifting the modification threshold to the left. The effects of BDNF on LTP and LTD induction may be attributed to the significant enhancement of synaptic responses that was observed during conditioning stimulation. These data suggest that one role of BDNF during development of the visual cortex may be to modulate the properties of synaptic plasticity, enhancing synaptic strengthening and reducing synaptic weakening processes which contribute to the formation of specific synaptic connections.

Animals↗

PubMedDate not supplied

A critical period of protein kinase activity after tetanic stimulation is required for the induction of long-term potentiation.

A critical period of protein kinase activity required for the induction of long-term potentiation (LTP) was determined in area CA1 or hippocampal slices using the broad-range and potent protein kinase inhibitors K-252a and staurosporine. As reported previously, K-252a and staurosporine blocked LTP induction when applied before, during, and after high-frequency stimulation (HFS). In contrast, K-252a did not block LTP when applied only before and during HFS and washed out immediately after HFS. K-252a and staurosporine both attenuated LTP magnitude when applied immediately after or as late as 5 min after HFS. However, K-252a applications beginning 30-45 min after HFS did not affect LTP expression significantly. K-252a had no detectable effect on isolated N-methyl-D-aspartate (NMDA) receptor-mediated EPSPs but significantly inhibited the in situ phosphorylation of specific hippocampal proteins (synapsin I, MARCKS, and B-50). In addition, K-252a attenuated 4 beta-phorbol-12,13-dibutyrate (PDBu)-enhanced synaptic transmission. Our results indicate that there is a critical period of protein kinase activity required for LTP induction that extends for approximately 20 min after HFS. In addition, our results suggest that protein kinase activity during and immediately after HFS is not sufficient for LTP induction. These results provide new information about the mechanisms that underlie LTP induction and expression and provide evidence for persistent and/or Ca(2+)-independent protein kinase activity involvement in LTP.

Animals↗