Neuronal metabolism governs cortical network response state

Abstract

The level of arousal in mammals is correlated with metabolic state and specific patterns of cortical neuronal responsivity. In particular, rhythmic transitions between periods of high activity (up phases) and low activity (down phases) vary between wakefulness and deep sleep͞anesthesia. Current opinion about changes in cortical response state between sleep and wakefulness is split between neuronal network-mediated mechanisms and neuronal metabolism-related mechanisms. Here, we demonstrate that slow oscillations in network state are a consequence of interactions between both mechanisms. Specifically, recurrent networks of excitatory neurons, whose membrane potential is partly governed by ATPmodulated potassium (KATP) channels, mediate response-state oscillations via the interaction between excitatory network activity involving slow, kainate receptor-mediated events and the resulting activation of ATP-dependent homeostatic mechanisms. These findings suggest that K ATP channels function as an interface between neuronal metabolic state and network responsivity in mammalian cortex.glutamate ͉ slow-wave oscillation ͉ potassium channel ͉ rhythm S low-wave oscillations (SWO) occur in the cerebral cortex and associated areas (1). They are particularly manifest during periods of behavioral quiescence and are an ubiquitous feature of deep sleep (2-5). Two hypotheses dominate the possible functional significance of such activity (6). SWO have been shown to be critical for learning and plasticity (2, 7). Additionally it has been proposed that they allow for, or are generated by, reduced neuronal metabolism, whereby restorative cellular processes take place to reset the deficit induced by a period of wakefulness (8-10). At the cellular level, slow-wave electroencephalogram activity correlates with fluctuations in the membrane potential of cortical neurones (3, 11), where periods of hyperpolarization (down phase) alternate between periods of depolarization (up phase). Such bistable behavior is thought to depend on a balance of recurrent excitation and local inhibition (12, 13) in addition to slow-wave input from the thalamus (14). However, persistent depolarized states might also occur through synaptic excitation alone, with kinetically slow excitatory synaptic potentials (EPSPs) such as those generated by kainate receptors (15) or NMDA receptors (but see below), temporally summating with sufficient background activity (16). In addition, such a maintained depolarization can be generated purely by intrinsic ionic currents in bistable neurons (17).The nature of the relationship between neuronal metabolic state and SWO is also unclear. From a network perspective, a number of synaptic conductances, most notably those mediated by NMDA receptors (18), are modulated by metabolism. However, some neurons have intrinsic conductances specifically designed to sense aspects of metabolic state. During wakefulness, constant neuronal activity is metabolically demanding (8,19). Measurements of cerebral metabolism during slow-wave sleep have de...

Differential contribution of kainate receptors to excitatory postsynaptic currents in superficial layer neurons of the rat medial entorhinal cortex

“…In doing so, we demonstrate in a number of ways that KAR EPSCs recorded from the "No Sag", pyramidal neurons in Layer III contributed significantly more to the non-NMDA EPSC than did those recorded from either "Sag" stellate neurons in Layer II or "Intermediate Sag" neurons in Layers II/III. This is intriguing due to the recent observation that KAR activation in Layer III pyramidal neurons, as in the hippocampus (Fisahn et al, 2004), may contribute to slow wave and gamma frequency oscillations in this brain region (Cunningham et al, 2003, Cunningham et al, 2006. Additionally, given the established roles of KARs in mediating excitotoxicity, particularly in CA3 neurons of the hippocampus, we speculate that the greater functional expression of KARs in layer III pyramidal neurons of the mEC may contribute to their selective vulnerability in TLE and animal models of TLE.…”

“…Furthermore, the slow decay kinetics of KARs appear to mediate a large influence on membrane potential due to summation of EPSCs at physiologically relevant firing rates (Frerking and Ohliger-Frerking, 2002). This temporal summation of KAR mediated EPSCs may also play a role in the generation and maintenance of slow wave oscillations in layer III pyramidal neurons of the mEC (Cunningham et al, 2006).…”

“…As in the hippocampus (Fisahn et al, 2004), the mEC can generate gamma frequency oscillations in response to agonists of KARs (Cunningham et al, 2003). Additionally, Cunningham et al have recently demonstrated that activation of postsynaptic KARs in layer III pyramidal neurons of the mEC may underlie slow wave oscillations in this brain region (Cunningham et al, 2006). Although KAR mRNA has been shown to be highly expressed in neurons of the mEC Seeburg, 1993, Bahn et al, 1994), functional expression of postsynaptic KARs in this brain region has not been examined in detail.…”

A beta2-frequency (20–30 Hz) oscillation in nonsynaptic networks of somatosensory cortex

“…These active states can be generated by kainate receptor-mediated activity alone in some areas of cortex (15), and exogenously applied kainate generates a persistent gamma frequency oscillation in all layers of auditory cortex (16). In contrast, in somatosensory cortex directly adjacent to auditory cortex (17), kainate application generated two distinct, coexistent frequencies of network rhythm.…”

Interaction between neocortical and hippocampal networks via slow oscillations

“…Extensive recurrent collaterals and balanced excitation and inhibition have been hypothesized to be the major requirements for the persistence of the UP state (Shu et al, 2003;Steriade et al, 1993e). Several factors can contribute to the transition from the UP to the DOWN state, including a gradual decrease of extracellular Ca 2+ and a corresponding decrease in synaptic transmission (Massimini and Amzica, 2001), inactivation of Ih channels (Luthi and McCormick, 1998), and metabolic processes in the neurons (Cunningham et al, 2006). Ca 2+ imaging in vitro reveals somewhat similar, although irregular, dynamics in cortical networks, which also fluctuate between brief UP states of synchronous activation of spatially organized ensembles of neurons (attractors), and prolonged DOWN states.…”