The cellular and behavioral consequences of interleukin-1 alpha penetration through the blood–brain barrier of neonatal rats: A critical period for efficacy

Tohmi, Manavu; Tsuda, Noriko; Zheng, Yingjun; Mizuno, Makoto; Sotoyama, Hidekazu; Shibuya, Masako; Kawamura, Minoru; Kakita, Akiyoshi; Takahashi, Hitoshi; Nawa, Hiroyuki

doi:10.1016/j.neuroscience.2007.08.034

Cited by 24 publications

(20 citation statements)

References 72 publications

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“…The maximal activation of ErbB4 was obtained B3 h after injection presumably because of slow penetration rates across BBB as seen with other cytokines. 30 By injecting the biotinylated form of NRG1b1, we confirmed its penetration across the neonatal BBB. Significant levels of biotin signal were detected in the intracellular space as well as on cell surfaces in the midbrain (Figure 1d), potentially representing endocytosis of the ligand-bound ErbB4 receptors.…”

Section: Peripheral Nrg1b1 Crosses Bbb and Reaches The Midbrain Of Momentioning

confidence: 65%

“…NRG1b1 or eNRG1 (both 1.0 mg g -1 body weight) was administered subcutaneously daily to half of the littermates during postnatal days (PNDs) 2-10. 30 Control littermates received an injection of phosphate-buffered saline (vehicle) of the same volume. The given dose of NRG1b1 was the highest one that did not produce growth retardation in neonatal mice.…”

Section: Animals and Drug Treatmentmentioning

confidence: 99%

“…As the blood-brain barrier (BBB) of neonatal mice is not fully developed and may allow cytokines to penetrate into the brain, 30,40 we tested the BBB permeability of the full-length mature type-1 NRG1b1 (hereafter, referred to as NRG1b1) in mouse pups. We administered NRG1b1 (1.0 mg g -1…”

Section: Peripheral Nrg1b1 Crosses Bbb and Reaches The Midbrain Of Momentioning

confidence: 99%

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Transient exposure of neonatal mice to neuregulin-1 results in hyperdopaminergic states in adulthood: implication in neurodevelopmental hypothesis for schizophrenia

et al. 2010

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Neuregulin-1 (NRG1) is implicated in the etiology or pathology of schizophrenia, although its biological roles in this illness are not fully understood. Human midbrain dopaminergic neurons highly express NRG1 receptors (ErbB4). To test its neuropathological role in the neurodevelopmental hypothesis of schizophrenia, we administered type-1 NRG1 protein to neonatal mice and evaluated the immediate and subsequent effects on dopaminergic neurons and their associated behaviors. Peripheral NRG1 administration activated midbrain ErbB4 and elevated the expression, phosphorylation and enzyme activity of tyrosine hydroxylase (TH), which ultimately increased dopamine levels. The hyperdopaminergic state was sustained in the medial prefrontal cortex after puberty. There were marked increases in dopaminergic terminals and TH levels. In agreement, higher amounts of dopamine were released from this brain region of NRG1-treated mice following high potassium stimulation. Furthermore, NRG1-treated mice exhibited behavioral impairments in prepulse inhibition, latent inhibition, social behaviors and hypersensitivity to methamphetamine. However, there were no gross abnormalities in brain structures or other phenotypic features of neurons and glial cells. Collectively, our findings provide novel insights into neurotrophic contribution of NRG1 to dopaminergic maldevelopment and schizophrenia pathogenesis.

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Section: Peripheral Nrg1b1 Crosses Bbb and Reaches The Midbrain Of Momentioning

confidence: 65%

Section: Animals and Drug Treatmentmentioning

confidence: 99%

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Transient exposure of neonatal mice to neuregulin-1 results in hyperdopaminergic states in adulthood: implication in neurodevelopmental hypothesis for schizophrenia

et al. 2010

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“…However, it has been shown that leakage of the BBB is more readily induced in younger mice in the presence of elevated levels of vasoactive cytokines [5]. In addition, the BBB of young mice is more permissive to the trafficking of cytokines [175] that are expressed at elevated levels during peripheral virus replication, a state that may serve to activate resident brain cells, drive immune cell infiltration of the CNS and alter the integrity of the BBB. These characteristics of the developing BBB may contribute to an agedependent increase in barrier permeability in response to an inflammatory insult elicited by flavivirus infection.…”

Section: The Role Of Age In the Susceptibility Of Mice To Flaviviral mentioning

confidence: 99%

The contribution of rodent models to the pathological assessment of flaviviral infections of the central nervous system

2012

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Members of the genus Flavivirus are responsible for a spectrum of important neurological syndromes in humans and animals. Rodent models have been used extensively to model flavivirus neurological disease, to discover host-pathogen interactions that influence disease outcome, and as surrogates to determine the efficacy and safety of vaccines and therapeutics. In this review, we discuss the current understanding of flavivirus neuroinvasive disease and outline the host, viral and experimental factors that influence the outcome and reliability of virus infection of smallanimal models.

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“…Enzyme immunoassay revealed the timedependent permeation of eNRG1 into frontal cortex: the concentration of free biotinylated eNRG1 in this brain region was the highest 1 h after injection (0.0 Ϯ 0.2 ng at 0 h, 4.9 Ϯ 0.3 ng at 1 h, and 1.3 Ϯ 0.2 ng at 3 h, all per milligram tissue protein). These observations suggest that peripherally administered NRG1 effi-ciently permeates into the frontal cortex of mouse pups (Kleshcheva, 1988;Tohmi et al, 2007).…”

Section: Peripheral Enrg1 Administration Activates Erbb4 Receptors Inmentioning

confidence: 99%

Neuregulin-1 Signals from the Periphery Regulate AMPA Receptor Sensitivity and Expression in GABAergic Interneurons in Developing Neocortex

Abe¹,

Namba²,

Kato³

et al. 2011

J. Neurosci.

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Neuregulin-1 (NRG1) signaling is thought to contribute to both neuronal development and schizophrenia neuropathology. Here, we describe the developmental effects of excessive peripheral NRG1 signals on synaptic activity and AMPA receptor expression of GABAergic interneurons in postnatal rodent neocortex. A core peptide common to all NRG1 variants (eNRG1) was subcutaneously administered to mouse pups. Injected eNRG1 penetrated the blood-brain barrier and activated ErbB4 NRG1 receptors in the neocortex, in which ErbB4 mRNA is predominantly expressed by parvalbumin-positive GABAergic interneurons. We prepared neocortical slices from juvenile mice that were receiving eNRG1 subchronically and recorded inhibitory synaptic activity from layer V pyramidal neurons. Postnatal eNRG1 treatment significantly enhanced polysynaptic IPSCs, although monosynaptic IPSCs were not affected. Examination of excitatory inputs to parvalbumin-containing GABAergic interneurons revealed that eNRG1 treatment significantly increased AMPA-triggered inward currents and the amplitudes and frequencies of miniature EPSCs (mEPSCs). Similar effects on mEPSCs were observed in mice treated with a soluble, full-length form of NRG1 type I. Consistent with the electrophysiologic data, expression of the AMPA receptor GluA1 (i.e., GluR1, GluRA) was upregulated in the postsynaptic density/cytoskeletal fraction prepared from eNRG1-treated mouse neocortices. Cortical GABAergic neurons cultured with eNRG1 exhibited a significant increase in surface GluA1 immunoreactivity at putative synaptic sites on their dendrites. These results indicate that NRG1 circulating in the periphery influences postnatal development of synaptic AMPA receptor expression in cortical GABAergic interneurons and may play a role in conditions characterized by GABA-associated neuropathologic processes.

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The cellular and behavioral consequences of interleukin-1 alpha penetration through the blood–brain barrier of neonatal rats: A critical period for efficacy

Cited by 24 publications

References 72 publications

Transient exposure of neonatal mice to neuregulin-1 results in hyperdopaminergic states in adulthood: implication in neurodevelopmental hypothesis for schizophrenia

Transient exposure of neonatal mice to neuregulin-1 results in hyperdopaminergic states in adulthood: implication in neurodevelopmental hypothesis for schizophrenia

The contribution of rodent models to the pathological assessment of flaviviral infections of the central nervous system

Neuregulin-1 Signals from the Periphery Regulate AMPA Receptor Sensitivity and Expression in GABAergic Interneurons in Developing Neocortex

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