ABSTRACT
Magnesium-free medium can be used in brain slice studies to enhance glutamate receptor function, but this manipulation causes seizure-like activity in many cortical areas. The rodent olfactory bulb (OB) slice is a popular preparation, and potentially ictogenic ionic conditions have often been used to study odor processing. We studied low Mg(2+)-induced epileptiform discharges in mouse OB slices using extracellular and whole cell electrophysiological recordings. Low-Mg(2+) medium induced two distinct types of epileptiform activity: an intraglomerular delta-frequency oscillation resembling slow sniff-induced activity and minute-long seizure-like events (SLEs) consisting of large negative-going field potentials accompanied by sustained depolarization of output neurons. SLEs were dependent on N-methyl-D-aspartate receptors and sodium currents and were facilitated by α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptors. The events were initiated in the glomerular layer and propagated laterally through the external plexiform layer at a slow time scale. Our findings confirm that low-Mg(2+) medium should be used with caution in OB slices. Furthermore, the SLEs resembled the so-called slow direct current (DC) shift of clinical and experimental seizures, which has recently been recognized as being of great clinical importance. The OB slice may therefore provide a robust and unique in vitro model of acute seizures in which mechanisms of epileptiform DC shifts can be studied in isolation from fast oscillations.
Subject(s)
Epilepsy, Generalized/physiopathology , Magnesium Deficiency/physiopathology , Magnesium/metabolism , Olfactory Bulb/physiopathology , Action Potentials/drug effects , Action Potentials/physiology , Acute Disease , Animals , Animals, Outbred Strains , Anticonvulsants/pharmacology , Culture Media/pharmacology , Electrophysiology/methods , Epilepsy, Generalized/drug therapy , Epilepsy, Generalized/metabolism , Glutamic Acid/metabolism , Magnesium/pharmacology , Magnesium Deficiency/metabolism , Male , Mice , Neural Inhibition/drug effects , Neural Inhibition/physiology , Neurons/physiology , Olfactory Bulb/cytology , Olfactory Bulb/metabolism , Organ Culture Techniques , Phenytoin/pharmacology , Potassium/metabolism , Potassium/pharmacology , Receptors, AMPA/physiology , Receptors, N-Methyl-D-Aspartate/physiology , Sodium/metabolism , gamma-Aminobutyric Acid/physiologyABSTRACT
The sometimes devastating mood swings of bipolar disorder are prevented by treatment with selected antiepileptic drugs, or with lithium. Abnormal membrane ion channel expression and excitability in brain neurons likely underlie bipolar disorder, but explaining therapeutic effects in these terms has faced an unresolved paradox: the antiepileptic drugs effective in bipolar disorder reduce Na(+) entry through voltage-gated channels, but lithium freely enters neurons through them. Here we show that lithium increases the excitability of output neurons in brain slices of the mouse olfactory bulb, an archetypical cortical structure. Treatment in vitro with lithium (1 to 10mM) depolarizes mitral cells, blocks action potential hyperpolarization, and modulates their responses to synaptic input. We suggest that Na(+) entry through voltage-gated channels normally directly activates K(+) channels regulating neuron excitability, but that at therapeutic concentrations, lithium entry and accumulation reduces this K(+) channel activation. The antiepileptic drugs effective in bipolar disorder and lithium may thus share a membrane target consisting of functionally coupled Na(+) and K(+) channels that together control brain neuron excitability.
Subject(s)
Action Potentials/drug effects , Cerebral Cortex/physiology , Evoked Potentials/drug effects , Lithium/pharmacology , Neurons/physiology , Receptors, Glutamate/drug effects , Action Potentials/physiology , Animals , Anticonvulsants/pharmacology , Cerebral Cortex/drug effects , Evoked Potentials/physiology , Ion Channels/drug effects , Ion Channels/physiology , Kynurenic Acid/pharmacology , Male , Membrane Potentials/drug effects , Membrane Potentials/physiology , Mice , Neurons/drug effects , Olfactory Bulb/drug effects , Olfactory Bulb/physiology , Potassium Channels/drug effects , Potassium Channels/physiology , Receptors, Glutamate/physiologyABSTRACT
With each sniff, the olfactory bulbs of the brain generate a neural activity pattern representing the odour environment, transmitting this to higher brain centres in the form of mitral cell output. Inhibitory circuits in the olfactory bulb glomerular and external plexiform layers may amplify contrast in these patterns, through surround inhibition of mitral cells. These circuits may operate in series, but their respective roles are unclear. A single sniff is sufficient for odour discrimination, but is not clear that the inhibitory circuits act within this timeframe. We used microdissected slices of mouse olfactory bulb to study each circuit in isolation. We found that unlike surround inhibition mediated in the external plexiform layer, surround inhibition mediated in the glomerular layer was activated by sensory synaptic input, but not by mitral cell output. The results also suggest that interactions between olfactory glomeruli are exclusively inhibitory, unlike in antennal lobe, and that surround inhibition mediated within the external plexiform layer may involve neural circuit elements not preserved in slice preparations. Surround inhibition was effective only after an interval corresponding to a single sniff in vivo. Surplus excitation, initiated by sensory input but generated by collective all-or-none responses of mitral cells, may delay surround inhibition and allow the synchronous activation of multiple glomeruli without each suppressing the other. Surround inhibition in the glomerular layer may subsequently allow a fresh representation of the odour environment to be generated with each sniff. These findings are consistent with combinatorial odour coding based on all-or-none glomerular responses.
