Homozygous GAD65 and heterozygous GAD67 knock-out mice reveal normal retinal development and maintenance despite reduced amounts of GABA.
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Animals↗
Biomedical subjects
Yukio Komatsu
Publications and source records attributed to Yukio Komatsu.
High-frequency stimulation together with adrenoceptor activation facilitates the maintenance of long-term potentiation at visual cortical inhibitory synapses.
Long-term potentiation (LTP) at inhibitory synapses of rat visual cortex requires firing of presynaptic cells for maintenance, at least at a low frequency. We examined the roles of adrenoceptors in this LTP maintenance. Although high-frequency stimulation (HFS) failed to produce LTP in normal Ca2+ medium, it produced pathway-specific LTP with addition of noradrenaline to the medium soon after HFS. However, this LTP disappeared after washout of noradrenaline. HFS applied during noradrenaline application produced LTP persisting even after washout, indicating that HFS together with adrenoceptor activation makes the adrenergic facilitation enduring. After washout, LTP was produced further by HFS of the conditioned, but not the unconditioned, pathway by the first HFS. Pharmacological examination demonstrated that alpha2 and beta, but not alpha1, receptors facilitated LTP maintenance synergistically. Bath application, but not postsynaptic loading, of either the adenylyl cyclase activator forskolin or the protein kinase C (PKC) activator phorbol ester facilitated LTP maintenance. These results suggest that adrenergic facilitation of LTP maintenance is mediated by presynaptic adrenoceptors via a subfamily of adenylyl cyclases stimulated by Gsalpha, Gibetagamma, and PKC. Thus, it is likely that the activity of noradrenergic afferents takes part in the control of LTP duration at visual cortical inhibitory synapses.
Adaptation, Physiological↗
Activity-dependent maturation of excitatory synaptic connections in solitary neuron cultures of mouse neocortex.
Activity plays important roles in the formation and maturation of synaptic connections. We examined these roles using solitary neocortical excitatory neurons, receiving only self-generated synaptic inputs, cultured in a microisland with and without spontaneous spike activity. The amplitude of excitatory postsynaptic currents (EPSCs), evoked by applying brief depolarizing voltage pulses to the cell soma, continued to increase from 7 to 14 days in culture. Short-term depression of EPSCs in response to paired-pulse or 10-train-pulse stimulation decreased with time in culture. These developmental changes were prevented when neurons were cultured in a solution containing tetrodotoxin (TTX). The number of functional synapses estimated by recycled synaptic vesicles with FM4-64 was significantly smaller in TTX-treated than control neurons. However, the miniature EPSC amplitude remained unchanged during development, irrespective of activity. Transmitter release probability, assessed by use-dependent blockade of N-methyl-D-aspartate receptor-mediated EPSCs with MK-801, was higher in TTX-treated than control neurons. Therefore, the activity-dependent increase in EPSC amplitude was mainly ascribed to the increase in synapse number, while activity-dependent alleviation of short-term depression was mostly ascribed to the decrease in release probability. The effect of activity blockade on short-term depression, but not EPSC amplitude, was reversed after 4 days of TTX removal, indicating that synapse number and release probability are controlled by activity in very different ways. These results demonstrate that activity regulates the conversion of immature synapses transmitting low-frequency input signals preferentially to mature synapses transmitting both low- and high-frequency signals effectively, which may be necessary for information processing in mature cortex.
Action Potentials↗
Neuroprotective role of phosphodiesterase inhibitor ibudilast on neuronal cell death induced by activated microglia.
The phosphodiesterase inhibitor, ibudilast, has many effects on lymphocytes, endothelial cells, and glial cells. We examined the neuroprotective role of ibudilast in neuron and microglia co-cultures. Ibudilast significantly suppressed neuronal cell death induced by the activation of microglia with lipopolysaccharide (LPS) and interferon (IFN)-gamma. To examine the mechanisms by which ibudilast exerts a neuroprotective role against the activation of microglia, we examined the production of inflammatory and anti-inflammatory mediators and trophic factors following ibudilast treatment. In a dose-dependent manner, ibudilast suppressed the production of nitric oxide (NO), reactive oxygen species, interleukin (IL)-1beta, IL-6, and tumor necrosis factor (TNF)-alpha and enhanced the production of the inhibitory cytokine, IL-10, and additional neurotrophic factors, including nerve growth factor (NGF), glia-derived neurotrophic factor (GDNF), and neurotrophin (NT)-4 in activated microglia. Thus, ibudilast-mediated neuroprotection was primarily due to the inhibition of inflammatory mediators and the upregulation of neurotrophic factor. In the CA1 region of hippocampal slices, long-term potentiation (LTP) induced by high frequency stimulation (HFS) could be inhibited with LPS and interferon-gamma stimulation. Ibudilast returned this LTP inhibition to the levels observed in controls. These results suggest that ibudilast may be a useful neuroprotective and anti-dementia agent counteracting neurotoxicity in activated microglia.
Animals↗
Presynaptic activity and Ca2+ entry are required for the maintenance of NMDA receptor-independent LTP at visual cortical excitatory synapses.
We have shown that some neural activity is required for the maintenance of long-term potentiation (LTP) at visual cortical inhibitory synapses. We tested whether this was also the case in N-methyl-d-aspartate (NMDA) receptor-independent LTP of excitatory connections in layer 2/3 cells of developing rat visual cortex. This LTP occurred after 2-Hz stimulation was applied for 15 min and always persisted for several hours while test stimulation was continued at 0.1 Hz. When test stimulation was stopped for 1 h after LTP induction, only one-third of the LTP instances disappeared, but most did disappear under a pharmacological suppression of spontaneous firing, indicating that LTP maintenance requires either evoked or spontaneous activities. LTP was totally abolished by a temporary blockade of action potentials with lidocaine or the removal of extracellular Ca(2+) after LTP induction, but it persisted under a voltage clamp of postsynaptic cells or after a temporary blockade of postsynaptic activity with the glutamate receptor antagonist kynurenate, suggesting that LTP maintenance requires presynaptic, but not postsynaptic, firing and Ca(2+) entry. More than one-half of the LTP instances were abolished after a pharmacological blockade of P-type Ca(2+) channels, whereas it persisted after either L-type or Ni(2+)-sensitive Ca(2+) channel blockades. These results show that the maintenance of NMDA receptor-independent excitatory LTP requires presynaptic firing and Ca(2+) channel activation as inhibitory LTP, although the necessary level of firing and Ca(2+) entry seems lower for the former than the latter and the Ca(2+) channel types involved are only partly the same.
Anesthetics, Local↗
[Age and experience dependence of long-term synaptic modification in visual cortex].
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Aging↗
Two forms of synaptic plasticity with distinct dependence on age, experience, and NMDA receptor subtype in rat visual cortex.
In visual cortex, NMDA receptor (NMDAR) properties depend primarily on NR2A and NR2B subunits, and NR2 subunit composition changes with age and visual experience. We examined the roles of these NR2 subunits in activity-dependent long-term modification of synaptic responses, which were evoked in layer 2/3 cells by stimulation of layer 4 in rat visual cortical slices. We used theta-burst stimulation (TBS) of presynaptic fibers or low-frequency stimulation paired with postsynaptic depolarization, which has been commonly used to induce NMDAR-dependent long-term potentiation (LTP) in visual cortex. In pyramidal cells, however, TBS produced long-term depression (LTD) at inhibitory synapses rather than LTP at excitatory synapses. This was observed in association with LTP of extracellular field potentials that reflect postsynaptic potentials in a population of cells (field-LTP). This result is inconsistent with the previous view that field-LTP reflects LTP of excitatory connections. However, pairing stimulation produced LTP at excitatory synapses of pyramidal cells frequently during development but rarely in adulthood. In contrast, inhibitory LTD and field-LTP occurred similarly in both developing and mature cortex. Experiments using NR2B selective and NR2 subunit nonselective NMDAR antagonists demonstrated that NR2A- and NR2B-containing NMDARs contribute selectively to inhibitory LTD-field-LTP and excitatory LTP, respectively. In addition, we found that the developmental decline in the NR2B component was paralleled by a decline in the incidence of excitatory LTP, and these declines were both prevented by dark rearing. These results implicate NR2 subunit composition in the regulation of neocortical plasticity and demonstrate differential subunit regulation at inhibitory and excitatory connections.
Age Factors↗
Age and experience dependence of N-methyl-D-aspartate receptor-independent long-term potentiation in rat visual cortex.
Dark rearing prolongs the critical period for experience-dependent modification of visual cortical functions. To test whether long-term potentiation (LTP) could potentially underlie this modification, we studied the age and experience dependence of LTP, induced in layer 2/3 cells by layer 4 stimulation continued for 15 min at 2 Hz, in rat visual cortical slices. This LTP was independent of N-methyl-D-aspartate receptor (NMDAR) activation, but it likely required Ni(2+)-sensitive Ca(2+) channel activation for induction. LTP occurred frequently during development, but rarely in adulthood. Dark rearing prevented this developmental decline. These age- and experience-dependent changes were demonstrated in both excitatory postsynaptic potentials recorded from pyramidal cells under a local blockade of inhibition and extracellular field potentials. These results suggest the possible involvement of NMDAR-independent LTP in the experience-dependent development of visual cortex.
2-Amino-5-phosphonovalerate↗
Postsynaptic firing produces long-term depression at inhibitory synapses of rat visual cortex.
High-frequency activation of excitatory synapses produces long-term depression (LTD) at inhibitory synapses in rat visual cortex. The LTD generation mechanism was studied by recording inhibitory postsynaptic potentials from layer V cells in response to layer IV stimulation under pharmacological blockade of excitatory synaptic transmission. LTD occurred after depolarizing current pulses applied to postsynaptic cells elicited repetitive firing. LTD induction was facilitated by a bath application of an L-type Ca(2+) channel activator, 1,4-Dihydro-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl) phenyl]-3-pyridinecarboxylic acid, methyl ester (BAY K 8644), while it was prevented by either the bath application of L-type Ca(2+) channel blocker nifedipine or postsynaptic loading of Ca(2+) chelator 1,2-bis-(o-aminophenoxy)ethane-N,N,N',N',-tetraaceticacid (BAPTA). These results suggest that LTD induction is at least partly mediated by Ca(2+) entry through L-type Ca(2+) channels in association with postsynaptic action potentials.
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗