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

Abstract

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.

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

“…These findings directly support our previous observations which show that the vulnerability of a given population of still developing neurons is linked to the maturity of their calcium buffering capabilities [5–7,10–12]. More importantly, these new developments [4,15] (in combination with our previous discoveries) suggest that the CSP hypothesis can be used as a conceptual platform from which to more fully understand age-dependent injury following NMDAR blockade.…”

“…In the case of NMDAR blockade, an inability to adapt to loss of calcium entry pushes vulnerable neurons towards cell death [3,10–12]. 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]. …”

MK801-induced activated caspase-3 exhibits selective co-localization with GAD67

“…In this sense, the P7 age contrasts sharply with the end of the postnatal period: robust AC3 at a time when somatic GAD67 is low, low to absent AC3 when somatic GAD67 is elevated. This is remarkably similar to changes in PV expression at these same ages [12, 13], suggesting that the onset of mature expression patterns of both markers takes place at ages associated with a relative absence of MK801 toxicity.…”

Selective reduction of cerebral cortex GABA neurons in a late gestation model of fetal alcohol spectrum disorder

“…It has been proposed that ethanol toxicity in P7 cortex is mediated in large part by inhibition of NMDA receptors and stimulation of GABA-A receptors (Ikonomidou et al, 2000). However, it has not been directly investigated whether P7 ethanol treatment selectively eliminates GABA cells, in part because most GABA-related cell markers are poorly expressed at this age (del Rio et al, 1994; Lema Tomé et al, 2008). …”