Henry Matthies

The effect of dopaminergic D1 receptor blockade during tetanization on the expression of long-term potentiation in the rat CA1 region in vitro

The effect of dopaminergic D1 receptor blockade on the expression of long-term potentiation (LTP) was investigated in the rat hippocampal CA1 region in vitro by extracellular recordings (by measuring the population spike amplitude and the field EPSP). The presence of the very selective D1 receptor blocker SCH 23390 at a concentration of 0.1 microM during tetanization with 3 trains of 100 impulses (100 Hz) resulted in a prevention of late LTP stages (greater than 1-2 h). When SCH 23390 was added to the bath medium immediately after tetanization, an influence on established LTP could not be observed during the first 3 h investigated.

Brevican-deficient mice display impaired hippocampal CA1 long- term potentiation but show no obvious deficits in learning and memory

ABSTRACT Brevican is a brain-specific proteoglycan which is found in specialized extracellular matrix structures called perineuronal nets. Brevican increases the invasiveness of glioma cells in vivo and has been suggested to play a role in central nervous system fiber tract development. To study the role of brevican in the development and function of the brain, we generated mice lacking a functional brevican gene. These mice are viable and fertile and have a normal life span. Brain anatomy was normal, although alterations in the expression of neurocan were detected. Perineuronal nets formed but appeared to be less prominent in mutant than in wild-type mice. Brevican-deficient mice showed significant deficits in the maintenance of hippocampal long-term potentiation (LTP). However, no obvious impairment of excitatory and inhibitory synaptic transmission was found, suggesting a complex cause for the LTP defect. Detailed behavioral analysis revealed no statistically significant deficits in learning and memory. These data indicate that brevican is not crucial for brain development but has restricted structural and functional roles.

Protein kinase A inhibitors prevent the maintenance of hippocampal long-term potentiation

The possible involvement of cAMP-dependent protein kinase A (PKA) in mechanisms of long-term potentiation of the Schaffer collateral-commissural input of rat CA1 neurones was investigated using several inhibitors in vitro. If 10 microM H-8, 100 nM KT5720 or 50 microM Rp-cAMPs was applied to the bath before a triple 100 Hz/0.5 s tetanization, post-tetanic and short-term potentiation developed almost normally. However, from about 3 h after tetanization the long-term potentiation (LTP) of the field-EPSP declined with respect to the control in an irreversible manner. These data suggest that besides protein kinase C the synergistic activation of PKA is necessary for the maintenance of LTP.

Neurocan is dispensable for brain development.

ABSTRACT Neurocan is a component of the extracellular matrix in brain. Due to its inhibition of neuronal adhesion and outgrowth in vitro and its expression pattern in vivo it was suggested to play an important role in axon guidance and neurite growth. To study the role of neurocan in brain development we generated neurocan-deficient mice by targeted disruption of the neurocan gene. These mice are viable and fertile and have no obvious deficits in reproduction and general performance. Brain anatomy, morphology, and ultrastructure are similar to those of wild-type mice. Perineuronal nets surrounding neurons appear largely normal. Mild deficits in synaptic plasticity may exist, as maintenance of late-phase hippocampal long-term potentiation is reduced. These data indicate that neurocan has either a redundant or a more subtle function in the development of the brain.

Dopamine D1-deficient mutant mice do not express the late phase of hippocampal long-term potentiation.

THE possible involvement of the dopamine D1 receptor subtype in mechanisms of long-term potentiation (LTP) of the Schaffer collateral-commissural input of CA1 neurones was investigated using D1-deficient mutant mice. In transversal hippocampus slices from mice lacking the D1 receptor a normal post-tetanic and shortterm potentiation could be induced after applying a triple 100 Hz tetanization. However, the potentiated fEPSP in the mutant mice declined to control value about 140 min following tetanization, whereas in the wild type mice a normal, non-decremental LTP was observed. These data support the idea that besides the glutamatergic system, the synergistic activation of dopaminergic synapses is necessary for LTP maintenance.

Differential effects of protein kinase inhibitors on pre-established long-term potentiation in rat hippocampal neurons in vitro

The possibility that a permanent protein kinase C (PKC) activity is necessary for the maintenance of long-term potentiation (LTP) was investigated in rat hippocampal slices. The action of the potent kinase inhibitors K-252a, K-252b and staurosporine on LTP of orthodromic population excitatory postsynaptic potentials (EPSPs) recorded from CA1 pyramidal cells was tested both during tetanization and after establishment of LTP. Confirming earlier studies, all inhibitors applied during tetanization at a concentration of 50 nM eliminate late LTP. Only staurosporine, but not K-252a or K-252b, blocked already established late LTP (i.e. late application). Normal synaptic transmission was influenced only weakly by staurosporine. Considering that all inhibitors have similar potencies against PKC and were all effective if applied during tetanization these data suggest that the late maintenance of LTP depends on a staurosporine/H7-sensitive process (or kinase) rather than permanent activation of PKC.

Fucose and fucosyllactose enhance in-vitro hippocampal long-term potentiation

Bath application of L-fucose and 2-fucosyllactose (2FI) increases the potentiation of the population spike amplitude (POP-spike) and the field excitatory postsynaptic potential (fEPSP) after tetanization of the Schaffer collaterals of the rat hippocampus. The ineffective isomers D-fucose and 3-fucosyllactose (3-FI) have no such effect. Since not only the maintenance of long-term potentiation LTP is influenced but also its induction is drastically improved, an effect of the sugars via the formation of glycoproteins but also via different actions on induction mechanisms is discussed.

Lack of expression of long-term potentiation in the dentate gyrus but not in the CA1 region of the hippocampus of μ-opioid receptor-deficient mice

The possible involvement of the mu-opioid receptor subtype in mechanisms of long-term potentiation (LTP) of the lateral perforant pathway to the dentate gyrus neurons, as well as of the Schaffer collateral-commissural input of CA1 neurons, was investigated using mu-opioid receptor-deficient mutant mice. In transversal hippocampal slices from mice lacking the mu-opioid receptor (MOR) only a short potentiation in the dentate gyrus after tetanization of the lateral perforant pathway was found. In contrast, the loss of the mu-opioid receptor in the CA1 region did not affect the potentiation of the field potentials induced by tetanization of the Schaffer collaterals. In parallel experiments, the application of 10 microM of the selective MOR-antagonist, funaltrexamine, decreased LTP in the dentate gyrus of wild-type mice but again did not alter the potentiation of the field potentials in the CA1. The loss of MOR-binding in the hippocampus was accompanied by a reduction in D2-binding sites indicating a possible compensatory role of the dopaminergic system. The D1- and glutamate binding was not affected. These observations confirm earlier results with pharmacological blockade of opioid receptors in the dentate gyrus and demonstrate an essential role of MOR activation for the generation of LTP in the dentate gyrus of the mouse but not necessarily in the CA1 region.

Glycosylation of proteins during a critical time window is necessary for the maintenance of long-term potentiation in the hippocampal CA1 region

This paper focuses on the role of glycoproteins in activity-dependent synaptic plasticity. The effect of the different inhibitors of protein glycosylation, Tunicamycin, Brefeldin A and Swainsonine, on long-term potentiation was studied in the CA1 region of rat hippocampal slices. Bath application of the inhibitors 60 min before and during tetanization did not interfere with the induction of long-term potentiation of the field excitatory postsynaptic potential. However, the potentiation in inhibitor-treated slices decreased to baseline levels during 90-180 min. Significant differences in the potentiation in non-treated slices were detectable 80 min (Tunicamycin), 60 min (Brefeldin A) and 75 min (Swainsonine) after tetanization, thus indicating the prevention of long-term potentiation maintenance. The application of Swainsonine 120 and 240 min after tetanization did not influence the potentiated field excitatory postsynaptic potential. These data demonstrate the need for undisturbed glycoprotein processing in a time window around long-term potentiation induction to maintain later phases of long-term potentiation and essential functional implications of protein glycosylation in mechanisms underlying synaptic plasticity.

Inhibition by compactin demonstrates a requirement of isoprenoid metabolism for long-term potentiation in rat hippocampal slices

Hippocampal long-term potentiation of synaptic transmission is the primary experimental model of learning and memory in the vertebrate brain. However, the detailed intracellular mechanisms giving rise to this persistent increase in synaptic efficacy remain incompletely understood. Mevalonic acid constitutes the basic precursor not only for cholesterol, dolichol and ubichinone but also for farnesyl-pyrophosphate and geranylgeranylpyrophosphate, which are required for post-translational modification of proteins. We have used the specific 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor, compactin, to examine the role of isoprenoid metabolism for long-term potentiation in rat hippocampal slices. Compactin was applied at a concentration of 25 microM for 70 min before and during tetanization and the orthodromic population spike amplitude and field excitatory postsynaptic potentials were recorded from CA1 pyramidal cells. Compactin had no effect on the initial tetanization. However, compactin-treated slices were not able to maintain long-term potentiation for more than 60 min and population spike as well as field excitatory postsynaptic potentiation returned to basal levels after 120 min. When the slices were retetanized after 180 min, an almost full potentiation of the population spike and an only partial potentiation of the field excitatory postsynaptic potentials were observed. These results suggest an essential role of isoprenoid intermediates for maintenance of hippocampal long-term potentiation.