Neonatal exposure to MK801 induces structural reorganization of the central nervous system

Tomé, Carla M. Lema; Nottingham, Charles U.; Smith, Chelsey M.; Beauchamp, Amanda; Leung, Parkson W.; Turner, Christopher P.

doi:10.1097/01.wnr.0000220133.32091.d6

Cited by 18 publications

(14 citation statements)

References 24 publications

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“…Previous studies have shown this region (specifically layers IV and V) is especially sensitive to NMDAR blockade at this age and that AC3 induction peaks at 8-16 hours (Lema Tomé et al, 2006, Turner et al, 2007b, Turner et al, 2009a). For ease of comparison, we remained focused on this region (and these layers) in the present study.…”

Section: Resultsmentioning

confidence: 70%

“…However, we and others have clearly demonstrated that age-dependent injury is to be expected following exposure to such agents (Ikonomidou et al, 1999a, Turner et al, 2002). We have explained this enigmatic outcome using a Calcium Set Point hypothesis (Turner et al, 2002, Lema Tomé et al, 2006, Turner et al, 2007a, Turner et al, 2007b, Ringler et al, 2008, Turner et al, 2009a). Briefly, immature neurons unable to buffer abrupt changes in calcium are vulnerable to such changes.…”

Section: Discussionmentioning

confidence: 99%

“…Since this discovery, many groups have sought to understand mechanisms or expand on the pathological outcomes (McInnis et al, 2002, Olney et al, 2004, Wang et al, 2005, Yon et al, 2005, Kaindl et al, 2006, Lu et al, 2006, Turner et al, 2007b, Stefovska et al, 2008, Turner et al, 2009a). Indeed, in rodents, injury from agents such as MK801, ketamine, or phencyclidine, leads to short-term and long-term molecular changes in functionally diverse protein families (Wang et al, 2004, Lema Tomé et al, 2006, Turner et al, 2007b, Kaindl et al, 2008, Ringler et al, 2008, Turner, 2009, Turner et al, 2009c) that suggest the still developing CNS has been permanently altered (Abekawa et al, 2007, Wang et al, 2007, Lunardi et al, 2009). These changes are not without behavioral consequence, as learning deficits and diminished sensory processing are also observed following NMDAR blockade at or around P7 (Wang et al, 2001, Jevtovic-Todorovic et al, 2003, Wang et al, 2003, Fredriksson et al, 2004, Abekawa et al, 2007, Fredriksson et al, 2007, Boctor et al, 2008, Lyall et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

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Is age-dependent, ketamine-induced apoptosis in the rat somatosensory cortex influenced by temperature?

et al. 2010

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General anesthetics have long been thought to be relatively safe but recent clinical studies have revealed that exposure of very young children (4 years or less) to agents that act by blocking the N-methyl-D-aspartate receptor (NMDAR) can lead to cognitive deficits as they mature. In rodent and non-human primate studies, blockade of this receptor during the perinatal period leads to a number of molecular, cellular and behavioral pathologies. Despite the overwhelming evidence from such studies, doubt remains as to their clinical relevance. A key issue is whether the primary injury (apoptotic cell death) is specific to receptor blockade or due to non-specific, patho-physiological changes. Principal to this argument is that loss of core body temperature following NMDAR blockade could explain why injury is observed hours later. We therefore examined the neurotoxicity of the general anesthetic ketamine in P7, P14 and P21 rats while monitoring core body temperature. We found that, at P7, ketamine induced the pro-apoptotic enzyme activated caspase-3 in a dose-dependent manner. As expected, injury was greatly diminished by P14 and absent by P21. However, contrary to expectations, we found that core body temperature was not a factor in determining injury. Our data imply that injury is directly related to receptor blockade and is unlikely to be overcome by artificially changing core body temperature.

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Section: Resultsmentioning

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Is age-dependent, ketamine-induced apoptosis in the rat somatosensory cortex influenced by temperature?

et al. 2010

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“…In contrast, at P21, agents that block this receptor no longer promote cell death. Numerous mechanisms have been proposed for this age-dependent injury such as loss of neuronal calcium [10–12], disruption of synaptic circuitry, up-regulation of NMDAR protein or absence of trophic support [1,8,9,13,14]. …”

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confidence: 99%

NMDAR blockade-induced neonatal brain injury: Reversal by the calcium channel agonist BayK 8644

Turner

DeBenedetto

2009

Neuroscience Letters

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We have previously shown that P7 rat pups injected with the N-methyl-D-aspartate receptor (NMDAR) blockerMK801 displayed robust apoptotic injury within hours after injection. Further studies from our lab suggest that loss of calcium cannot be compensated for when vulnerable neurons lack calcium buffering capabilities. Thus, to elevate calcium in these neurons prior to MK801 exposure, we injected P7 rats with the calcium channel agonist BayK 8644. Whereas BayK 8644 did not induce apoptosis by itself, it was found to block MK801-induced injury in a dose-dependent manner. Reversal of MK801 toxicity was complete in the caudate-putamen, partial in the somatosensory cortex but was not observed in the retrosplenial cortex. These results suggest that postnatal brain injury resulting from agents that block the NMDAR, which include commonly used anesthetics as well as drugs of abuse, may be prevented in vulnerable neurons by compensatory increases in calcium prior to exposure to these antagonists. KeywordsRat; Postnatal; Apoptosis; Set point hypothesis; MK801; Dizocilpine We and others have previously shown that blockade of the Nmethyl-D-aspartate receptor (NMDAR) in postnatal day 7 (P7) rat pups causes profound apoptotic injury [2,12]. In contrast, at P21, agents that block this receptor no longer promote cell death. Numerous mechanisms have been proposed for this age-dependent injury such as loss of neuronal calcium [10][11][12], disruption of synaptic circuitry, up-regulation of NMDAR protein or absence of trophic support [1,8,9,13,14].We proposed some time ago that at P7 the regulatory mechanisms that determine optimal calcium levels may not have matured in some neuronal populations [12]. In its simplest form, this calcium set point (CSP) hypothesis [3] states that excessive gain or loss of calcium will result in neuronal injury. In the case of NMDAR blockade, an inability to adapt to loss of calcium entry pushes vulnerable neurons towards cell death [3,[10][11][12]. Indeed, we were the first to show that MK801-induced expression of the pro-apoptotic marker activated caspase-3 (AC3) in P7 rat brains was almost exclusively found in cells that lacked the calcium binding proteins calbindin (CB), calretinin (CR), or parvalbumin (PV) [5], and that gain of these proteins (in particular PV) coincided with loss of MK801 sensitivity [6,7].

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“…For example, the somatosensory cortex (S1) and layer II of primary and secondary motor cortex (M1 and M2) are regions susceptible to age-dependent MK801-induced apoptosis (Lema Tomé et al, 2006a; Lema Tomé, Nottingham, Smith, Beauchamp, Leung, & Turner, 2006b; Turner et al, 2007b). The neuronal populations found in these regions include both pyramidal and non-pyramidal cells that are immunoreactive for CaBPs (Alcantara, Ferrer, & Soriano, 1993; Alcantara, Soriano, & Ferrer, 1996; Celio, 1990; Conde, Lund, Jacobowitz, Baimbridge, & Lewis, 1994; de Lecea, del Rio, & Soriano, 1995).…”

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confidence: 99%

Decline in age‐dependent, MK801‐induced injury coincides with developmental switch in parvalbumin expression: Somatosensory and motor cortex

Tomé

Miller

Bauer

et al. 2008

Developmental Psychobiology

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MK801-induced activation of caspase-3 is developmentally regulated, peaking at postnatal day (P) 7 and decreasing with increasing postnatal age thereafter. Further, at P7, cells displaying activation of caspase-3 lack expression of calcium binding proteins (CaBPs). To further explore this relationship, we investigated postnatal expression of calbindin (CB), calretinin (CR) and parvalbumin (PV) in two brain regions susceptible to MK801-induced injury, the somatosensory cortex (S1) and layer II/III of motor cortex (M1/M2). Expression of CB and especially PV was low to absent prior to P7 but substantially increased from P7 through to P21 and adulthood. In contrast, CR expression was more variable at early developmental ages, stabilized to lower levels after P7 and showed a marked decline by P21. The results suggest that not only does calcium buffering capacity increase developmentally but acquisition of enhanced buffering may be one mechanism by which neurons survive agent-induced alterations in calcium homeostasis.

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Neonatal exposure to MK801 induces structural reorganization of the central nervous system

Cited by 18 publications

References 24 publications

Is age-dependent, ketamine-induced apoptosis in the rat somatosensory cortex influenced by temperature?

Is age-dependent, ketamine-induced apoptosis in the rat somatosensory cortex influenced by temperature?

NMDAR blockade-induced neonatal brain injury: Reversal by the calcium channel agonist BayK 8644

Decline in age‐dependent, MK801‐induced injury coincides with developmental switch in parvalbumin expression: Somatosensory and motor cortex

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