An Examination of Calcium Current Function on Heterotopic Neurons in Hippocampal Slices from Rats Exposed to Methylazoxymethanol

Calcagnotto, María Elisa; Baraban, Scott C.

doi:10.1046/j.1528-1157.2003.41102.x

Cited by 8 publications

(5 citation statements)

References 59 publications

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“…Additional evidence points to trauma and infectious diseases during pregnancy contributing to human cortical dysplasia (Marin Padilla 1999;Deukmedjian et al 2004). Typical findings in human malformation disorders include altered excitability and disturbances in GABAergic mechanisms (Di Luca et al 1994;Ross 2002;Calcagnotto and Baraban 2003;Gardoni et al 2003;Bast et al 2004;Deukmedjian et al 2004;Levitt et al 2004 ). Our study shows that in a ferret model of cortical dysplasia, cortical cues are essential to proper migration and positioning of interneurons arising from the GE.…”

Section: Discussionsupporting

confidence: 53%

Alteration of Interneuron Migration in a Ferret Model of Cortical Dysplasia

2007

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During cerebral cortical development, g-aminobutyric acidergic (GABAergic) interneurons arise from a different site than projection neurons. GABAergic cells are generated in the subpallial ganglionic eminence (GE), while excitatory projection neurons arise from the neocortical ventricular zone. Our laboratory studies a model of cortical dysplasia that displays specific disruption of GABAergic mechanisms and an alteration in the overall balance of excitation in the neocortex. To produce this model, the birth of neurons on a specific gestational day in ferrets (embryonic day 33 [E33]) is interrupted by injection of the antimitotic methylazoxymethanol (MAM). We hypothesized that migration of interneurons might be disrupted in this cortical dysplasia paradigm. We observed that although interneurons migrate into the neocortex in both normal and dysplastic cortex, the migrating cells become disoriented over time after E33 MAM treatment. Coculture experiments using normal GE and MAM-treated cortex (and vice versa) demonstrate that cues dictating proper orientation of migrating interneurons arise from the cortex and are not intrinsic to the migrating cells. As a consequence, interneurons in mature brains of MAM-treated animals are abnormally distributed. We report that GABA A receptor activation is crucial to the proper positioning of interneurons migrating into the cortex from the GE in normal and MAM-treated animals.

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Section: Discussionsupporting

confidence: 53%

Alteration of Interneuron Migration in a Ferret Model of Cortical Dysplasia

2007

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“…We found that NMDA receptors did not mediate PE-induced inhibition of eEPSCs. A few studies reported that activation of ␣ 1 -adrenoreceptors can attenuate Ca 2ϩ currents (Calcagnotto and Baraban, 2003;Li and van den Pol, 2005). Since release of neurotransmitters relies on presynaptic Ca 2ϩ entry, this may explain PE-mediated inhibition on EPSCs in our preparation.…”

Section: Discussionmentioning

confidence: 76%

Modulation of Synaptic Transmission to Second-Order Peripheral Chemoreceptor Neurons in Caudal Nucleus Tractus Solitarius by α1-Adrenoreceptors

Zhang

Mifflin²

2007

The Journal of Pharmacology and Experimental Therapeutics

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Norepinephrine (NE) is an important neurotransmitter in central autonomic regulation. Peripheral chemoreceptor stimulation activates central noradrenergic structures. These structures innervate and therefore could modulate neurons in caudal nucleus tractus solitarius (cNTS), which receives the first central projections from peripheral chemoreceptors. However, the role of ␣ 1 -adrenoreceptors in synaptic transmission of peripheral chemoreceptor inputs in cNTS is unknown. We investigated the responses to activation of ␣ 1 -adrenoreceptors on glutamatergic and GABAergic inputs in NTS slices using whole-cell recording. Second-order neurons were identified by 1,1Ј-dilinoleyl-3,3,3Ј,3Ј-tetra-methylindocarbocyanine, 4-chlorobenzenesulphonate (DiA) labeling of carotid bodies. Electrical stimulation of ipsilateral tractus solitarius was used to evoke excitatory postsynaptic currents (eEPSCs), whereas inhibitory postsynaptic currents were evoked (eIPSCs) by electrically stimulating NTS near the recorded neuron. Application of ␣ 1 -adrenoreceptor agonist phenylephrine (PE) at 20 M significantly decreased amplitudes of eEPSCs (78 Ϯ 1% of control; n ϭ 16; p Ͻ 0.01), and it increased amplitudes of eIPSCs (120 Ϯ 13% of control; n ϭ 7; p Ͻ 0.01). Both effects were blocked by the ␣ 1 -adrenoreceptor antagonist prazosin at 10 M. PE did not change holding current, input resistance, and current-voltage relationship in cNTS neurons. PE significantly changed paired pulse ratios of eEPSC/eIPSCs, increased the frequency of miniature IPSCs (329 Ϯ 10% of control; n ϭ 6; p Ͻ 0.05), but it decreased that of miniature EPSCs (69 Ϯ 6% of control; n ϭ 5; p Ͻ 0.01). PE-induced inhibition of eEPSCs was independent of N-methyl-D-aspartate or GABA B receptors. These results suggest that activation of ␣ 1 -adrenoreceptors reduces excitatory and enhances inhibitory inputs to second-order peripheral chemoreceptor neurons in cNTS via a presynaptic mechanism. These actions result in the inhibition of synaptic transmission and could play a role in the autonomic responses to hypoxia.

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“…Battaglia et al, 2003a,b;Flagstad et al, 2005;Flagstad et al, 2004;Lavin et al, 2005;Lu et al, 2000). Even if several reports, including the majority of those addressing the altered neuronal excitability (Calcagnotto et al, 2002, Calcagnotto andBaraban, 2003;Castro et al, 2002) in MAM animals, have used a single injection approach with higher MAM doses, presumably leading to lower and less persistent levels of the toxic period, our data apply to both procedures of MAM treatment. Furthermore, studies support our conclusions, including those demonstrating a clear-cut interdependence of the cerebrovasculature with neuronal malformations and adult neurogenesis (Bardosi et al, 1985a,b;Bardosi et al, 1987;Palmer et al, 2000).…”

Section: Discussionmentioning

confidence: 87%

Early cerebrovascular and parenchymal events following prenatal exposure to the putative neurotoxin methylazoxymethanol

Bassanini¹,

Hallene²,

Battaglia³

et al. 2007

Neurobiology of Disease

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One of the most common causes of neurological disabilities are malformations of cortical development (MCD). A useful animal model of MCD consists of prenatal exposure to methylazoxymethanol (MAM), resulting in a postnatal phenotype characterized by cytological aberrations reminiscent of human MCD. Although postnatal effects of MAM are likely a consequence of prenatal events, little is known on how the developing brain reacts to MAM. General assumption is the effects of prenatally administered MAM are short lived (24 h) and neuroblast-specific. MAM persisted for several days after exposure in utero in both maternal serum and fetal brain, but at levels lower than predicted by a neurotoxic action. MAM levels and time course were consistent with a different mechanism of indirect neuronal toxicity. The most prominent acute effects of MAM were cortical swelling associated with mild cortical disorganization and neurodegeneration occurring in absence of massive neuronal cell death. Delayed or aborted vasculogenesis was demonstrated by MAM's ability to hinder vessel formation. In vitro, MAM reduced synthesis and release of VEGF by endothelial cells. Decreased expression of VEGF, AQP1, and lectin-B was consistent with a vascular target in prenatal brain. The effects of MAM on cerebral blood vessels persisted postnatally, as indicated by capillary hypodensity in heterotopic areas of adult rat brain. In conclusion, these results show that MAM does not act only as a neurotoxin per se, but may additionally cause a short-lived toxic effect secondary to cerebrovascular dysfunction, possibly due to a direct anti-angiogenic effect of MAM itself.

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An Examination of Calcium Current Function on Heterotopic Neurons in Hippocampal Slices from Rats Exposed to Methylazoxymethanol

Cited by 8 publications

References 59 publications

Alteration of Interneuron Migration in a Ferret Model of Cortical Dysplasia

Alteration of Interneuron Migration in a Ferret Model of Cortical Dysplasia

Modulation of Synaptic Transmission to Second-Order Peripheral Chemoreceptor Neurons in Caudal Nucleus Tractus Solitarius by α1-Adrenoreceptors

Early cerebrovascular and parenchymal events following prenatal exposure to the putative neurotoxin methylazoxymethanol

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