Biomedical subjects

Toshihiko Momiyama

Publications and source records attributed to Toshihiko Momiyama.

8 recordsLinked to original sources

PubMed2006

Somatostatin presynaptically inhibits both GABA and glutamate release onto rat basal forebrain cholinergic neurons.

A whole cell patch-clamp study was carried out in slices obtained from young rat brain to elucidate the roles of somatostatin in the modulation of synaptic transmission onto cholinergic neurons in the basal forebrain (BF), a region that contains cholinergic and GABAergic corticopetal neurons and somatostatin (SS)-containing local circuit neurons. Cholinergic neurons within the BF were identified by in vivo prelabeling with Cy3 IgG. Because in many cases SS is contained in GABAergic neurons in the CNS, we investigated whether exogenously applied SS can influence GABAergic transmission onto cholinergic neurons. Bath application of somatostatin (1 muM) reduced the amplitude of the evoked GABAergic inhibitory presynaptic currents (IPSCs) in cholinergic neurons. SS also reduced the frequency of miniature IPSCs (mIPSCs) without affecting their amplitude distribution. SS-induced effect on the mIPSC frequency was significantly larger in the solution containing 7.2 mM Ca(2+) than in the standard (2.4 mM Ca(2+)) external solution. Similar effects were observed in the case of non-NMDA glutamatergic excitatory postsynaptic currents (EPSCs). SS inhibited the amplitude of evoked EPSCs and reduced the frequency of miniature EPSCs dependent on the external Ca(2+) concentration with no effect on their amplitude distribution. Pharmacological analyses using SS-receptor subtype-specific drugs suggest that SS-induced action of the IPSCs is mediated mostly by the sst(2) subtype, whereas sst subtypes mediating SS-induced inhibition of EPSCs are mainly sst(1) or sst(4). These findings suggest that SS presynaptically inhibits both GABA and glutamate release onto BF cholinergic neurons in a Ca(2+)-dependent way, and that SS-induced effect on IPSCs and EPSCs are mediated by different sst subtypes.

Animals↗

PubMed2005

Potential functional neural repair with grafted neural stem cells of early embryonic neuroepithelial origin.

The fate of grafted neuroepithelial stem cells in the normal mature brain environment was assessed both morphologically and electrophysiologically to confirm their feasibility in the functional repair of damaged neural circuitry. The neuroepithelial stem cells were harvested from the mesencephalic neural plate of transgenic green fluorescence protein-carrying rat embryos, and implanted into the normal adult rat striatum. The short- and long-term differentiation pattern of donor-derived cells was precisely monitored immunohistochemically. The functional abilities of the donor-derived cells and communication between them and the host were investigated using host-rat brain slices incorporating the graft with whole-cell patch-clamp recording. Vigorous differentiation of the neuroepithelial stem cells into mostly neurons was noted in the short-term with positive staining for tyrosine hydroxylase, suggesting that the donor-derived cells were exclusively following their genetically programmed fate, together with gamma-aminobutyric acid (GABA) and glutamate expression. In the long-term, the large number of donor-derived neurons was sustained, but the staining pattern showed expression of dopamine- and adenosine 3':5'-monophosphate-regulated phosphoprotein 32, suggesting that some neurons were following environmental cues, together with the appearance of some cholinergic neurons. Some donor-derived astrocytes were also seen in the graft. Many action potentials indicating the presence of both dopaminergic and non-dopaminergic patterns could be elicited and recorded in the donor-derived neurons in addition to spontaneous glutamatergic and GABAergic post-synaptic currents which were strongly shown to be of host origin. Neuroepithelial stem cells are therefore an attractive candidate as a source of donor material for intracerebral grafting in functional repair.

6-Cyano-7-nitroquinoxaline-2,3-dione↗

PubMed2003

Parallel decrease in omega-conotoxin-sensitive transmission and dopamine-induced inhibition at the striatal synapse of developing rats.

Whole-cell patch-clamp recordings of GABAergic IPSCs were made from cholinergic interneurones in slices of striatum from developing rats aged 21-60 days postnatal. In addition, the Ca(2+) channel subtypes involved in synaptic transmission, as well as dopamine (DA)-induced presynaptic inhibition, were investigated pharmacologically with development by bath application of Ca(2+) channel blockers and DA receptor agonists. The IPSC amplitude was reduced by omega-conotoxin GVIA (omega-CgTX) or omega-agatoxin TK (omega-Aga-TK) across the whole age range, suggesting that multiple types of Ca(2+) channels mediate transmission of the synapse. The IPSC fraction reduced by omega-CgTX significantly decreased, whereas that reduced by omega-Aga-TK remained unchanged with development. DA or quinpirole, a D(2)-like receptor agonist, presynaptically reduced the IPSC amplitude throughout development. The DA-induced inhibition decreased with age in parallel with the decrease in N-type Ca(2+) channels. DA showed no further inhibition of IPSCs after the inhibitory effect of omega-CgTX had reached steady state throughout development. These results demonstrate that there is a functional link between presynaptic N-type Ca(2+) channels and D(2)-like DA receptors at inhibitory synapses in the striatum. They also demonstrate that the suppression of GABAergic transmission by D(2)-like receptors is mediated by modulation of N-type Ca(2+) channels and decreases in parallel with the developmental decline in the contribution of N-type Ca(2+) channels to exocytosis.

Agatoxins↗

PubMed2003

Osteopetrosis and thalamic hypomyelinosis with synaptic degeneration in DAP12-deficient mice.

Deletions in the DAP12 gene in humans result in Nasu-Hakola disease, characterized by a combination of bone fractures and psychotic symptoms similar to schizophrenia, rapidly progressing to presenile dementia. However, it is not known why these disorders develop upon deficiency in DAP12, an immunoreceptor signal activator protein initially identified in the immune system. Here we show that DAP12-deficient (DAP12(-/-)) mice develop an increased bone mass (osteopetrosis) and a reduction of myelin (hypomyelinosis) accentuated in the thalamus. In vitro osteoclast induction from DAP12(-/-) bone marrow cells yielded immature cells with attenuated bone resorption activity. Moreover, immature oligodendrocytes were arrested in the vicinity of the thalamus, suggesting that the primary defects in DAP12(-/-) mice are the developmental arrest of osteoclasts and oligodendrocytes. In addition, the mutant mice also showed synaptic degeneration, impaired prepulse inhibition, which is commonly observed in several neuropsychiatric diseases in humans including schizophrenia, and aberrant electrophysiological profiles in the thalami. These results provide a molecular basis for a unique combination of skeletal and psychotic characteristics of Nasu-Hakola disease as well as for schizophrenia and presenile dementia.

Alleles↗

PubMed2003

[Analysis of central synaptic transmission with the slice-patch-clamp technique].

More than ten years have passed since the slice-patch-clamp technique was established as a powerful method for the analysis of central synaptic transmission. Although this technique was restricted only to young animal preparations, we can now apply it to several synapses in slices obtained from adult animals, owing to recent advances in optics or slicers. In addition, advanced techniques have been recently available such as paired whole-cell recording from two or more synaptically connected neurons, recording from dendrites or some presynaptic terminals. Further developments are expected in both of the two directions: more microscopic analysis such as investigating glutamatergic sensitivities of single dendritic spines in combination with two-photon photolysis of a caged-glutamate compound and analysis in a more physiological function-oriented manner such as investigation of pain perception mechanisms using in vivo patch-clamp technique.

Animals↗

PubMed2003

[Regulation of psychomotor functions by dopamine: integration of various approaches].

(1)The basal ganglia circuitry mediates a wide rage of brain functions such as motor control, behavioral planning, and reward prediction. Dopamine (DA) transmission plays an essential role in the regulation of these brain functions. DA action not only regulates the firing activity of target neurons but also is involved in the pattern formation of their firing. The striatopallidal neurons containing dopamine D(2) receptor plays a dual role in motor coordination dependent on DA transmission. (2)Activation of presynaptic D(2)-like receptors on GABAergic terminals onto striatal cholinergic interneurons selectively blocks N-type Ca(2+) channels, thereby inhibiting GABA release. In addition, contribution of N-type channels and D(2)-like receptor-mediated presynaptic inhibition decreases in parallel with development, implying some relationship between basal ganglia-related function or dysfunction and age. (3)As an approach to determine dopamine neuronal activity, we monitored neuronal activities by measuring cytosolic Ca(2+) concentration in VTA dopamine neurons. The present study indicates that VTA dopamine neurons are the direct targets of orexin-A and psychostimulants, and the [Ca(2+)](i) signaling is thought to play a significant role in the regulation of dopamine neuronal activity. (4)The excitability of neostriatal neurons is regulated by a balance of glutamatergic and dopaminergic inputs. Glutamate has been shown to modulate dopaminergic signaling. Studies on the regulation of DARPP-32 phosphorylation by glutamate provide a molecular basis for both the synergistic and antagonistic effects of glutamate on dopaminergic signaling. (5) Impairment of function of stem/progenitor cells may be implicated in the pathogenesis of schizophrenia. To test this hypothesis, several experiments are currently ongoing in our laboratory, and the preliminary results obtained are described here.

Animals↗

PubMed2002

[Calcium channel subtypes mediating central synaptic transmission].

It is well established that neurotransmitter release is triggered by Ca2+ entry into the presynaptic terminals through voltage-dependent Ca2+ channels. In the mammalian central nervous system, multiple types of Ca2+ channels including N-type, P/Q-type and other types mediate fast synaptic transmission. Electrophysiological studies using type-specific antagonists for Ca2+ channels have estimated the relative contribution of N-, P/Q- and other types of Ca2+ channels in excitatory and inhibitory synaptic transmission in the hippocampus, cerebellum, spinal cord, brain stem, and striatum. A recent study has demonstrated that activation of presynaptic dopamine D2-like receptors selectively block N-type Ca2+ channels to reduce GABA release onto cholinergic interneurons in the rat striatum. In addition, it has been recently clarified that the contribution of N-type Ca2+ channels to synaptic transmission is restricted to the early postnatal period at synapses in auditory brain stem, cerebellum, or thalamus. Advanced morphological studies are necessary for the further understanding of the subcellular localization of each subtype of Ca2+ channels and receptors modulating the transmitter release through Ca2+ channel activity in relation to the release sites in the presynaptic terminals.

Animals↗

PubMed2002

[Dopamine receptors and calcium channels regulating striatal inhibitory synaptic transmission].

A whole-cell patch-clamp study was performed to investigate the modulatory role of dopamine (DA), its ionic mechanisms and their developmental changes in the GABAergic synaptic transmission onto cholinergic interneurones in the rat striatal slices. Inhibitory postsynaptic currents (IPSCs) were evoked by focal stimulation. Bath application of DA inhibited the IPSCs in a concentration-dependent manner with an IC50 value of 10 microM. Pharmacological studies with DA receptor agonists and antagonists suggest the involvement of D2-like receptors. DA reduced the frequency of miniature inhibitory postsynaptic currents without affecting their amplitude distribution. Analyses using selective blockers for N-, or P/Q type Ca2+ channels could estimate the contribution of each Ca2+ channel subtype to the GABAergic transmission. DA had no longer affected the IPSCs after the effect of an N-type channel blocker, omega-conotoxin (omega-CgTX) had reached its steady state. The inhibitory effects of omega-CgTX and DA or a D2-like receptor agonist decreased in parallel during postnatal 12-60 days. DA's action was occluded by omega-CgTX throughout these developmental stages. These results suggest that activation of presynaptic D2-like receptors selectively blocks N-type Ca2+ channels, thereby inhibiting GABA release, and that contribution of N-type channels and D2-like receptor-mediated presynaptic inhibition decrease in parallel with development.

Animals↗