Pharmacodynamics of the Glutamate Receptor Antagonists in the Rat Barrel Cortex.

Epipial application is one of the approaches for drug delivery into the cortex. However, passive diffusion of epipially applied drugs through the cortical depth may be slow, and different drug concentrations may be achieved at different rates across the cortical depth. Here, we explored the pharmacodynamics of the inhibitory effects of epipially applied ionotropic glutamate receptor antagonists CNQX and dAPV on sensory-evoked and spontaneous activity across layers of the cortical barrel column in urethane-anesthetized rats. The inhibitory effects of CNQX and dAPV were observed at concentrations that were an order higher than in slices in vitro, and they slowly developed from the cortical surface to depth after epipial application. The level of the inhibitory effects also followed the surface-to-depth gradient, with full inhibition of sensory evoked potentials (SEPs) in the supragranular layers and L4 and only partial inhibition in L5 and L6. During epipial CNQX and dAPV application, spontaneous activity and the late component of multiple unit activity (MUA) during sensory-evoked responses were suppressed faster than the short-latency MUA component. Despite complete suppression of SEPs in L4, sensory-evoked short-latency multiunit responses in L4 persisted, and they were suppressed by further addition of lidocaine suggesting that spikes in thalamocortical axons contribute ∼20% to early multiunit responses. Epipial CNQX and dAPV also completely suppressed sensory-evoked very fast (∼500 Hz) oscillations and spontaneous slow wave activity in L2/3 and L4. However, delta oscillations persisted in L5/6. Thus, CNQX and dAPV exert inhibitory actions on cortical activity during epipial application at much higher concentrations than in vitro, and the pharmacodynamics of their inhibitory effects is characterized by the surface-to-depth gradients in the rate of development and the level of inhibition of sensory-evoked and spontaneous cortical activity.

Ethanol and the Developing Brain: Inhibition of Neuronal Activity and Neuroapoptosis.

Ethanol induces massive neuroapoptosis in the developing brain. One of the main hypotheses that has been put forward to explain the deleterious actions of ethanol in the immature brain involves an inhibition of neuronal activity. Here, we review recent evidence for this hypothesis obtained in the somatosensory cortex and hippocampus of neonatal rodents. In both structures, ethanol strongly inhibits brain activity. At the doses inducing massive neuroapoptosis, ethanol completely suppresses the early activity patterns of spindle-bursts and gamma oscillations in the neocortex and the early sharp-waves in the hippocampus. The inhibitory effects of ethanol decrease with age and in adult animals, ethanol only mildly depresses neuronal firing and induces delta-wave activity. Suppression of cortical activity in neonatal animals likely involves inhibition of the myoclonic twitches, an important physiological trigger for the early activity bursts, and inhibition of the thalamocortical and intracortical circuits through a potentiation of GABAergic transmission and an inhibition of N-methyl-d-aspartate (NMDA) receptors, that is in keeping with the neuroapoptotic effects of other agents acting on GABA and NMDA receptors. These findings provide support for the hypothesis that the ethanol-induced inhibition of cortical activity is an important pathophysiological mechanism underlying massive neuroapoptosis induced by ethanol in the developing brain.

Direct Current Coupled Recordings of Cortical Spreading Depression Using Silicone Probes.

Electrophysiological assessment of infraslow (<0.1 Hz) brain activities such as cortical spreading depression (SD), which occurs in a number of pathologies including migraine, epilepsy, traumatic brain injury (TBI) and brain ischemia requires direct current (DC) coupled recordings of local field potentials (LFPs). Here, we describe how DC-coupled recordings can be performed using high-density iridium electrode arrays (silicone probes). We found that the DC voltage offset of the silicone probe is large and often exceeds the amplifier input range. Introduction of an offset compensation chain at the signal ground efficiently minimized the DC offsets. Silicone probe DC-coupled recordings across layers of the rat visual and barrel cortices revealed that epipial application of KCl, dura incision or pinprick TBI induced SD which preferentially propagated through the supragranular layers and further spread to the granular and infragranular layers attaining maximal amplitudes of ~-30 mV in the infragranular layers. SD at the superficial cortical layers was nearly two-fold longer than at the deep cortical layers. Continuous epipial KCl evoked multiple recurrent SDs which always started in the supragranular layers but often failed to propagate through the deeper cortical layers. Intracortical KCl injection into the infragranular layers evoked SD which also started in the supragranular layers and spread to the granular and infragranular layers, further indicating that the supragranular layers are particularly prone to SD. Thus, DC-coupled recordings with silicone probes after offset compensation can be successfully used to explore the spatial-temporal dynamics of SD and other slow brain activities.