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Brain-derived neurotrophic factor (BDNF) plays an important role in synaptic plasticity related to learning and memory. We previously reported that SPARC-related protein containing immunoglobulin domains 1 (SPIG1, also known as Follistatin-like protein 4, FSTL4) binds to pro-BDNF and negatively regulates BDNF maturation; however, its neurological functions, particularly in learning and memory, have not yet been elucidated. We herein examined the electrophysiological and behavioral phenotypes of Spig1-knockout (Spig1-KO) mice. Adult Spig1-KO mice exhibited greater excitability and facilitated long-term potentiation (LTP) in the CA1 region of hippocampal slices than age- and sex-matched wild-type (WT) mice. Facilitated LTP was reduced to the level of WT by the bath application of an anti-BDNF antibody to hippocampal slices. A step-through inhibitory avoidance learning paradigm revealed that the extinction of aversive memories was significantly enhanced in adult Spig1-KO mice, while they showed the normal acquisition of aversive memories; besides, spatial reference memory formation was also normal in the standard Morris water maze task. An intracerebroventricular (icv) injection of anti-BDNF in the process of extinction learning transiently induced the recurrence of aversive memories in Spig1-KO mice, but exerted no effects in WT mice. These results indicate a critical role for SPIG1 in BDNF-mediated synaptic plasticity in extinction of inhibitory avoidance memory., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Manipulation of visual experience can considerably modify visual responses of visual cortical neurons even in adulthood in the mouse, although the modification is less profound than that observed during the critical period. Our previous studies demonstrated that low-frequency (2Hz) stimulation for 15min applied to layer 4 induces T-type Ca 2+ channel-dependent long-term potentiation (LTP) at excitatory synapses in layer 2/3 neurons of visual cortex during the critical period. In this study, we investigated whether low-frequency stimulation could induce synaptic plasticity in adult mice. We found that 2Hz stimulation induced LTP of extracellular field potentials evoked by stimulation of layer 4 in layer 2/3 in adulthood as during the critical period. LTP in adulthood was blocked by L-type, but not T-type, Ca 2+ channel antagonists, whereas LTP during the critical period was blocked by T-type, but not L-type, Ca 2+ channel antagonists. This developmental change in LTP was prevented by dark rearing. Under pharmacological blockade of GABA A receptors, T-type Ca 2+ channel-dependent LTP occurred, whereas L-type Ca 2+ channel-dependent LTP did not occur. These results suggest that different forms of synaptic plasticity can contribute separately to experience-dependent modification of visual responses during the critical period and in adulthood., (Copyright © 2017. Published by Elsevier B.V.)

Monocular deprivation produces depression and potentiation of visual responses evoked in visual cortical neurons by stimulation of deprived and nondeprived eyes, respectively, during the critical period of ocular dominance plasticity. Our previous studies suggested that T-type Ca(2+) channel-dependent long-term potentiation (LTP), induced by 2 Hz stimulation, mediates the potentiation of visual responses. However, it was proposed that the experience-dependent response potentiation is mediated by tumor necrosis factor-α (TNFα)-dependent homeostatic synaptic scaling but not by Hebbian synaptic plasticity, because the potentiation was absent in TNFα knockout (TNFα-KO) mice. In this study, we investigated whether TNFα is required for LTP induced by 2 Hz stimulation using visual cortical slices prepared from critical period mice and rats. The production of LTP was prevented by pharmacological blockade of TNFα in rats and mice. LTP production was also prevented by an inhibitor of TNFα-converting enzyme that converts membrane-bound TNFα to soluble TNFα. In TNFα-KO mice, LTP did not occur and was rescued by exogenous soluble TNFα. Soluble TNFα was required for LTP production only during a restricted time window soon after 2 Hz stimulation. These results strengthen the view that T-type Ca(2+) channel-dependent LTP contributes to the potentiation of nondeprived eye responses following monocular deprivation., (Copyright © 2015 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.)

Visual cortical neurons undergo depression and potentiation of their visual responses to stimulation of the deprived and non-deprived eyes, respectively, after monocular deprivation. This modification occurs predominantly during an early postnatal period in normal development, and this critical period is postponed until adulthood in animals reared in darkness from birth. We have proposed that Ni(2+)-sensitive T-type Ca(2+) channel-dependent long-term potentiation (T-LTP) mediates the potentiation of non-deprived eye responses. In this study, to investigate the development of Ni(2+)-sensitive T-type Ca(2+) channels, presumed CaV3.2 channels, we performed whole-cell recordings from layer 2/3 pyramidal neurons in rat visual cortical slices. T-type Ca(2+) channel currents were activated by voltage steps from -100mV to -40mV under a pharmacological blockade of Na(+) and K(+) channels. We estimated presumed CaV3.2 currents from the currents obtained after subtraction of the currents in the presence of Ni(2+) (50μM) from those in control solution. The estimated currents were very small before eye opening, peaked during the critical period and then returned to a small value by adulthood. Dark rearing prevented the developmental decline in these currents until adulthood. These results suggest that the regulation of CaV3.2 currents underlies the developmental changes in T-LTP and ocular dominance plasticity., (Copyright © 2014 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.)

T-type Ca2+ channel-dependent long-term potentiation (LTP) occurs predominantly during the critical period of ocular dominance plasticity in rat and cat visual cortex. Noradrenaline and serotonin are known to facilitate ocular dominance plasticity. In this study using rat visual cortical slices, we tested whether this LTP is modulated by these neuromodulators in the same way as ocular dominance plasticity. Extracellular field potentials evoked by layer 4 stimulation were recorded from layer 2/3 and LTP was induced by low-frequency (2 Hz) stimulation continued for 15 min. The induction of LTP was suppressed by beta, but not alpha, adrenergic receptor antagonists. LTP induction was also inhibited by selective antagonists for 5-HT(1A) or 5-HT(2) receptors. In slices prepared from rats in which noradrenaline or serotonin was depleted by selective neurotoxins, the magnitude of LTP was significantly smaller compared with control slices. These results indicate that the same types of adrenergic and serotonergic receptors facilitate both LTP and ocular dominance plasticity, supporting our hypothesis that T-type Ca2+ channel-dependent LTP mediates experience-dependent enhancement of visual responses of cortical neurons during the critical period.

High-frequency stimulation (HFS) induces long-term potentiation (LTP) at inhibitory synapses of layer 5 pyramidal neurons in developing rat visual cortex. This LTP requires postsynaptic Ca2+ rise for induction, while the maintenance mechanism is present at the presynaptic site, suggesting presynaptic LTP expression and the necessity of retrograde signaling. We investigated whether the supposed signal is mediated by brain-derived neurotrophic factor (BDNF), which is expressed in pyramidal neurons but not inhibitory interneurons. LTP did not occur when HFS was applied in the presence of the Trk receptor tyrosine kinase inhibitor K252a in the perfusion medium. HFS produced LTP when bath application of K252a was started after HFS or when K252a was loaded into postsynaptic cells. LTP did not occur in the presence of TrkB-IgG scavenging BDNF or function-blocking anti-BDNF antibody in the medium. In cells loaded with the Ca2+ chelator BAPTA, the addition of BDNF to the medium enabled HFS to induce LTP without affecting baseline synaptic transmission. These results suggest that BDNF released from postsynaptic cells activates presynaptic TrkB, leading to LTP. Because BDNF, expressed activity dependently, regulates the maturation of cortical inhibition, inhibitory LTP may contribute to this developmental process, and hence experience-dependent functional maturation of visual cortex.

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.

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.

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.

Neocortical neuronal circuits are refined by experience during the critical period of early postnatal life. The shift of ocular dominance in the visual cortex following monocular deprivation has been intensively studied to unravel the mechanisms underlying the experience-dependent modification. Synaptic plasticity is considered to be involved in this process. We previously showed in layer 2/3 pyramidal neurons of rat visual cortex that low-frequency stimulation-induced long-term potentiation (LTP) at excitatory synapses, which requires the activation of Ni2+-sensitive (R-type or T-type) voltage-gated Ca2+ channels (VGCCs) for induction, shared a similar age and experience dependence with ocular dominance plasticity. In this study, we examined whether this LTP is involved in ocular dominance plasticity. In visual cortical slices, LTP was blocked by mibefradil, kurtoxin and R-(−)-efonidipine, T-type VGCC blockers, but not by SNX-482, an R-type VGCC blocker, indicating that LTP induction requires T-type VGCC activation. Mibefradil did not affect synaptic transmission even at a dose about 30 times higher than that required for LTP blockade. Therefore, this drug was used to test the effect of T-type VGCC blockade on ocular dominance shift produced by 6 days of monocular deprivation during the critical period using visual evoked potentials (VEPs). Although this monocular deprivation commonly produced both depression of deprived eye responses and potentiation of nondeprived eye responses, only the former change occurred when mibefradil was infused into the visual cortex during monocular deprivation. Mibefradil infusion produced no acute effects on VEPs. These results suggest that T-type VGCC-dependent LTP contributes to the experience-dependent enhancement of visual responses. [ABSTRACT FROM AUTHOR]

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)-γ. 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)-1β, IL-6, and tumor necrosis factor (TNF)-α 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-γ 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. [Copyright &y& Elsevier]

Proteoglycans play important roles in regulating the development and functions of the brain. They consist of a core protein and glycosaminoglycans, which are long sugar chains of repeating disaccharide units with sulfation. A recent study demonstrated that the sulfation pattern of chondroitin sulfate on proteoglycans contributes to regulation of the critical period of experience-dependent plasticity in the mouse visual cortex. In the present study, we investigated the role of keratan sulfate (KS), another glycosaminoglycan, in critical period plasticity in the mouse visual cortex. Immunohistochemical analyses demonstrated the presence of KS containing disaccharide units of N -acetylglucosamine (GlcNAc)-6-sulfate and nonsulfated galactose during the critical period, although KS containing disaccharide units of GlcNAc-6-sulfate and galactose-6-sulfate was already known to disappear before that period. The KS chains were distributed diffusely in the extracellular space and densely around the soma of a large population of excitatory and inhibitory neurons. Electron microscopic analysis revealed that the KS was localized within the perisynaptic spaces and dendrites but not in presynaptic sites. KS was mainly located on phosphacan. In mice deficient in GlcNAc-6- O -sulfotransferase 1, which is one of the enzymes necessary for the synthesis of KS chains, the expression of KS was one half that in wild-type mice. In the knockout mice, monocular deprivation during the critical period resulted in a depression of deprived-eye responses but failed to produce potentiation of nondeprived-eye responses. In addition, T-type Ca 2 + channel-dependent long-term potentiation (LTP), which occurs only during the critical period, was not observed. These results suggest that regulation by KS-phosphacan with a specific sulfation pattern is necessary for the generation of LTP and hence the potentiation of nondeprived-eye responses after monocular deprivation. [ABSTRACT FROM AUTHOR]