Motor cortical network oscillations driven by voltage‐ and ligand‐gated currents

Neuronal oscillations are a characteristic feature of neocortical networks in the mammalian brain. Varying in frequency depending on the behavioural state of the organism, neocortical oscillations are thought to be an important substrate for synchronizing large ensembles of neurons both in time and in space (reviewed in Buzsaki & Draguhn, 2004). Not surprisingly, the mechanisms of rhythmogenesis and the role of neuronal oscillations in cortical function has been the topic of much empirical and theoretical investigation. Perturbation of neocortical circuits and synapses as a result of injury, disease or genetic/developmental disruption often results in aberrant neuronal oscillations, hyper-synchrony, and the emergence of epileptiform activity. What are the mechanisms that transform normal oscillations into pathological ones? The answer to this question has remained elusive. In a recent study in The Journal of Physiology, Castro-Alamancos et al. (2007) reveal the role of a number of voltage-dependent ion channels and neurotransmitter receptors in the generation of neocortical ∼10 Hz oscillations in vitro, similar to those oscillations observed in humans and rats in vivo during myoclonus. Castro-Alamancos et al. (2007) used field potential recordings from slices of adult rat motor cortex and evoked spontaneous ictal spikes with the addition of a GABAA receptor antagonist to the extracellular recording solution. Additional application of a GABAB receptor antagonist or lowering of the extracellular Mg2+ ([Mg2+]o) concentration to 0.1 mm, resulted in the generation of ∼10 Hz oscillations following each ictal spike. Armed with an in vitro preparation (Castro-Alamancos & Rigas, 2002) which models ∼10 Hz oscillations observed in vivo (Castro-Alamancos, 2000, 2006), these authors dissected the role played by several glutamate receptors as well as voltage-gated ion channels on cortical rhythmogenesis. Using pharmacological blockers of glutamate receptors, Castro-Alamancos et al. (2007) revealed that low [Mg2+]o-induced ∼10 Hz oscillations were completely blocked by AMPA receptor antagonism, while an increased shift in the frequency of the oscillation was observed following NMDA receptor antagonism (see Fig. 1 of Castro-Alamancos et al. 2007). Interestingly, these data are identical to the effects of AMPA and NMDA receptor antagonism on GABAB-induced ∼10 Hz oscillations (Castro-Alamancos & Rigas, 2002) and demonstrate the important role both glutamate receptor-subtypes play in the generation of rhythmic activity in the neocortex. Using pharmacological blockers of voltage-gated ion channels, these authors observed that antagonism of persistent Na+ currents (INaP) completely blocked ∼10 oscillations induced by GABAB blockade (see Fig. 2 of Castro-Alamancos et al. 2007) as well as low [Mg2+]o recording solutions (see Fig. 3 of Castro-Alamancos et al. 2007). Similar results were revealed after antagonism of the M-type potassium current (IM; see Fig. 11 of Castro-Alamancos et al. 2007) but not after blockade of the hyperpolarization-activated potassium current, IH (see Figs 8 and 9 of Castro-Alamancos et al. 2007). Interestingly, oscillations were abolished only after combined antagonism of both slowly and rapidly adapting potassium currents, ID and IA (respectively; see Fig. 10 of Castro-Alamancos et al. 2007) but not after blockade of either currents alone. Finally, blockade of the low-threshold T-type Ca2+ current (IT; see Figs 6 and 7 of Castro-Alamancos et al. 2007) had no effect on ∼10 Hz oscillations. Results from Castro-Alamancos et al. (2007) demonstrate the complexity of ionic currents underlying paroxysmal rhythmogenesis in disinhibited slices of rat motor cortex which include those mediated by voltage-gated ion channels as well as glutamaturgic receptors. The description of currents that participate in ∼10 Hz oscillations is as interesting as the identification of those currents that do not. Among those that do not participate, IH and IT are of interest because of the widespread expression of H- and T-type channels in neocortical neurons. Figure 1 contains representative photomicrographs taken from the Allen Brain Atlas (http://www.brain-map.org) demonstrating mRNA expression of mouse Hcn1 and Cav3.2 genes, each belonging to the family of genes that encode ion channels responsible for H- and T-type currents, respectively. High level of expression, as quantified by colourimetric analyses, is particularly evident in layer V neurons, known to have projections to subcortical targets such as the brainstem and spinal cord. Interestingly, in a recent study by this same group (Castro-Alamancos, 2006), rhythmic ∼10 Hz whisker movements were observed in awake–behaving rats following disinhibition of motor cortex, an effect probably caused by activation of layer V corticospinal and corticobulbar neurons. Thus, neurons demonstrating significant levels of H- and T-type channels may participate in ∼10 Hz oscillations in motor cortex (and myoclonus) without recruitment of IH and IT. In light of the fact that Castro-Alamancos et al. (2007) did not observe changes following blockade of IH and IT, membrane potential changes during ∼10 Hz oscillations in cortical neurons containing H- and T-type currents, are probably outside the voltage range of activation of these two ion channel types. Consistent with this hypothesis, activation if both IH and IT require strong hyperpolarization, like that from GABAergic synaptic potentials, in order to reach their activation voltages. Hyperpolarization into these membrane potential regimes may not occur during ∼10 Hz oscillations due to the fact that GABAergic transmission has been blocked. Figure 1 Expression of Hcn1 and Cav3.2 mRNA in the mouse brain Lack of IH and IT blockers to alter ∼10 Hz oscillations is also of interest because of the important roles these currents play in the generation of sleep spindles, a prominent oscillation present in the electroencephalogram of the neocortex during slow-wave sleep. These currents have also been implicated in absence epilepsies characterized by spike-wave discharges. Interestingly, spindle oscillations and spike-wave discharges differ from ∼10 Hz oscillatiosn in two very important ways. First, unlike spindle oscillations, which are dependent on functional thalamocortical connections, and absence epilepsies, which are characterized by thalamocortical dysfunction, ∼10 Hz oscillations are generated exclusively within intracortical circuits and persist even after thalamic inactivation with TTX (Castro-Alamancos, 2000). Moreover, whereas normal and abnormal thalamocortical rhythms require GABAergic synaptic transmission (from the thalamic reticular nucleus), ∼10 Hz oscillations are found following blockade of GABAergic transmission. Given these differences, it may not be surprising that IH and IT do not participate in ∼10 Hz oscillations – a unique, intracortical, glutamatergic rhythm. The study by Castro-Alamancos et al. (2007) represents an important additional chapter in a series of studies on the mechanism and functional consequences of disinhibited cortical networks and their ability to generate rhythmic activity. While dishibition by blockade of GABAergic synapses models a pathological state similar to those that lead to epileptiform activity, the observation that intracortical circuits can generate ∼10 Hz rhythms suggests that other oscillations might emerge from these cortical networks depending on the activation of a given complement of currents carried by ion channels and/or neurotransmitter receptors. How normal oscillatory activity in motor cortex might modulate subcortical targets and generate rhythmic motor patterns is an interesting and open question. Whether other abnormal cortical oscillations participate in movement disorders is an equally interesting and clinically relevant topic for further investigation.