Emergent properties of CNS neuronal networks as targets for pharmacology: application to anticonvulsant drug action

Abstract

CNS drugs may act by modifying the emergent properties of complex CNS neuronal networks. Emergent properties are network characteristics that are not predictably based on properties of individual member neurons. Neuronal membership within networks is controlled by several mechanisms, including burst firing, gap junctions, endogenous and exogenous neuroactive substances, extracellular ions, temperature, interneuron activity, astrocytic integration and external stimuli. The effects of many CNS drugs in vivo may critically involve actions on specific brain loci, but this selectivity may be absent when the same neurons are isolated from the network in vitro where emergent properties are lost. Audiogenic seizures (AGS) qualify as an emergent CNS property, since in AGS the acoustic stimulus evokes a non-linear output (motor convulsion), but the identical stimulus evokes minimal behavioral changes normally. The hierarchical neuronal network, subserving AGS in rodents is initiated in inferior colliculus (IC) and progresses to deep layers of superior colliculus (DLSC), pontine reticular formation (PRF) and periaqueductal gray (PAG) in genetic and ethanol withdrawal-induced AGS. In blocking AGS, certain anticonvulsants reduce IC neuronal firing, while other agents act primarily on neurons in other AGS network sites. However, the NMDA receptor channel blocker, MK-801, does not depress neuronal firing in any network site despite potently blocking AGS. Recent findings indicate that MK-801 actually enhances firing in substantia nigra reticulata (SNR) neurons in vivo but not in vitro. Thus, the MK-801-induced firing increases in SNR neurons observed in vivo may involve an indirect effect via disinhibition, involving an action on the emergent properties of this seizure network.