NMDA inhibitors cause apoptosis of pyramidal neurons in mature piriform cortex: Evidence for a nitric oxide-mediated effect involving inhibitory interneurons

Abstract

Pyramidal relay neurons in limbic cortex are vulnerable to denervation lesions, i.e. pyramidal neurons in layer IIα of piriform cortex undergo transsynaptic apoptosis after lesions that interrupt their inputs from the olfactory bulb. We have previously established the role of inhibitory interneurons in elaborating signals that lead to the apoptosis of projection neurons in these lesion models, i.e. the upregulation of neuronal NOS and release of nitric oxide. Thus, we have proposed that cortical interneurons play an essential role in transducing injury to degenerative effects for nearby pyramidal neurons. In the present study, we extend the previous findings to a toxic model of degeneration of pyramidal neurons in the adult paralimbic cortex, i.e. after exposure to the NMDA channel blocker MK801. Our findings indicate that treatment of adult rats with MK801 in doses previously found to cause alterations in pyramidal neurons of the retrosplenial cortex (5 mg/kg) results in an active caspase 3 (+), ultrastructurally apoptotic type of cell death involving the same projection neurons of layer IIα that are also vulnerable to bulbotomy lesions. Interneurons of layer I are induced by MK801 treatment to higher levels of nNOS expression and the selective nNOS inhibitor BRNI ameliorates pyramidal cell apoptosis caused by MK801. Our results indicate that certain pyramidal neurons in piriform cortex are very sensitive to NMDA blockade as they are to disconnection from modalityspecific afferents and that inhibitory interneurons play significant roles in mediating various types of pro-apoptotic insults to cortical projection neurons via nNOS/NO signaling.

Targeted knock-down of neuronal nitric oxide synthase expression in basal forebrain with RNA interference

“…Under conditions of excessive activation of the NMDA receptor, NO synthesized in the cytosol by the action of nNOS may initiate both cytosolic and nuclear apoptotic signaling (Garthwaite et al, 1989;Dawson et al, 1991;Bonfoco et al, 1996). As recently shown by us (Koliatsos et al, 2004;Zhou et al, 2006;Zhou et al, 2007) and others (Corso et al, 1997;Parathath et al, 2007), similar processes can be signaled between neurons, i.e. nNOS-expressing interneurons can provide the source of NO that can diffuse and initiate apoptotic cascades in adjacent projection neurons.…”

“…Nitric oxide (NO) is a molecular messenger with prominent roles in neuronal signaling (Garthwaite et al, 1988;Gally et al, 1990;Edelman and Gally, 1992;Schuman and Madison, 1994;West and Grace, 2000) but may also initiate or contribute to neuronal cell death (Nowicki et al, 1991;Zhou et al, 2007). As a diffusible gas that can cross membrane barriers within 100-micrometer distance (Wood and Garthwaite, 1994;Philippides et al, 2000), NO is ideally suited to modulate synaptic plasticity in a spatially constrained fashion (Dawson and Snyder, 1994;Schuman, 1994;Esplugues, 2002;Sunico et al, 2005).…”

Reviewing the ketamine model for schizophrenia

“…Indeed, ketamine-induced release of glutamate in anterior cingulated cortex (ACC) is correlated with positive psychotic symptom scores in healthy human subjects ( r = 0.72) (Stone et al, 2012). Furthermore, NMDAR antagonists play known roles in neurodegenration and excitotoxicity, including apoptosis of mature corticolimbic pyramidal cells (Zhou et al, 2007; Farber and Olney, 2003; Horváth et al, 1997; Wozniak et al, 1998), thus offering NMDAR hypofunction as a possible basis for brain atrophy observed in schizophrenia (Rais et al, 2012; Andreone, et al, 2007; Rais et al, 2008; Goldman et al, 2007; Ferrari et al, 2006). …”

Evidence for the involvement of neuronal nitric oxide synthase and soluble guanylate cyclase on cognitive functions in rats

“…NO can permeate the plasma membrane and destroy post-synaptic structures via the generation of reactive oxygen species within the dendrites and cell body. Therefore, NO especially nNOS induction and activation of layer I interneurons may be a common denominator linking lesion-and NMDA antagonist-induced death of pyramidal neurons in limbic cortex (Zhou et al, 2007).…”