Regenerative, all-or-none electrographic seizures in the rat hippocampal slice in Mg-free and physiological medium

All-or-none electrographic seizures (EGSs) were studied in hippocampal slices from young (21- to 38-day-old) rats in medium containing low (0 mM) or physiological (0.9 mM) levels of magnesium, with and without the GABAB agonist baclofen. Extracellular recording and stimulation were performed in stratum pyramidale and stratum radiatum of CA3, respectively. EGS activity was induced by exposure to low-Mg medium or by delivering repetitive stimulus trains in physiological Mg medium. After EGS activity had stabilized, the EGSs were tested for all-or-none behavior by varying the number of pulses in a train. An EGS was considered all-or-none if subthreshold stimulation produced no afterdischarge bursts, and if the EGS duration was largely independent of the number of suprathreshold stimulus pulses. According to this measure, EGSs in Mg-free + baclofen medium were all-or-none. EGSs evoked in physiological Mg medium were also all-or-none, although the threshold was higher, and the EGS duration lower, than in Mg-free medium. This all-or-none characteristic was observed whether the EGSs were induced by prior exposure to Mg-free medium or by repetitive stimulation, and in the presence and absence of baclofen. The all-or-none characteristic suggests that while the triggering mechanism for EGSs is strongly dependent on stimulus intensity, regenerative mechanisms--independent of stimulus intensity--are responsible for the maintenance of EGSs. EGSs are also terminated by mechanisms not dependent on stimulus intensity.     

Developmental time course distinguishes changes in spontaneous and light-evoked retinal ganglion cell activity in rd1 and rd10 mice

In a subset of hereditary retinal diseases, early photoreceptor degeneration causes rapidly progressive blindness in children. To better understand how retinal development may interact with degenerative processes, we compared spontaneous and light-evoked activity among retinal ganglion cells in rd1 and rd10 mice, strains with closely related retinal disease. In each, a mutation in the Pde6b gene causes photoreceptor dysfunction and death, but in rd10 mice degeneration starts after a peak in developmental plasticity of retinal circuitry and thereafter progresses more slowly. In vitro multielectrode action potential recordings revealed that spontaneous waves of correlated ganglion cell activity comparable to those in wild-type mice were present in rd1 and rd10 retinas before eye opening [postnatal day (P) 7 to P8]. In both strains, spontaneous firing rates increased by P14-P15 and were many times higher by 4-6 wk of age. Among rd1 ganglion cells, all responses to light had disappeared by ~P28, yet in rd10 retinas vigorous ON and OFF responses were maintained well beyond this age and were not completely lost until after P60. This difference in developmental time course separates mechanisms underlying the hyperactivity from those that alter light-driven responses in rd10 retinas. Moreover, several broad physiological groups of cells remained identifiable according to response polarity and time course as late as P60. This raises hope that visual function might be preserved or restored despite ganglion cell hyperactivity seen in inherited retinal degenerations, particularly if treatment or manipulation of early developmental plasticity were to be timed appropriately.     

Do sympathetic neurons coordinate cellular development in the heart and kidney? Effects of neonatal central and peripheral catecholaminergic lesions on cardiac and renal nucleic acids and proteins

Sympathetic nerve activity has been hypothesized to set the timing of cellular maturational events in target tissues. In the current study, this hypothesis was tested by lesioning catecholamine pathways in the periphery and central nervous system through the use of subcutaneous or intracisternal injections of 6-hydroxydopamine. Systemically administered 6-hydroxydopamine completely depleted peripheral norepinephrine. The central treatment completely ablated the developmental rise in brain norepinephrine and dopamine and had little effect on peripheral norepinephrine levels, but has been shown to reduce sympathetic tone. In both the heart and the kidney, either type of lesion resulted in deficits in cell acquisition (DNA) with some evidence of compensatory increases in other macromolecules involved in cell enlargement (particularly RNA), thus maintaining the tissue growth rate at only slightly subnormal levels. The peak effect was always seen during the stages at which sympathetic neuronal synaptogenesis and impulse activity ordinarily undergo their most rapid development. Most of the 6-hydroxydopamine-induced differences in nucleic acids lessened or disappeared toward weaning, and thus these data support the view that sympathetic neuronal input influences the timing of maturational control of macromolecules, but not their final set-point. In combination with earlier studies showing termination of DNA synthesis caused by exposure of heart and kidney acutely to high levels of catecholamines, the results suggest that neuronal activity provides a biphasic signal, with positive trophic effects predominating during early development when sympathetic tone is low, and negative effects appearing when sympathetic tone is elevated during the late preweanling stage.     

Pattern of synaptic excitation and inhibition upon direction-selective retinal ganglion cells

The distributions of excitatory and inhibitory synapses upon the dendritic arbor of a direction-selective retinal ganglion cell were compared by triple-labeling techniques. The dendrites were visualized by confocal microscopy after injection of Lucifer yellow. Excitatory inputs from bipolar cells were located by using antibodies against kinesin II, a component of synaptic ribbons. Inhibitory inputs were identified by antibodies against gamma-aminobutyric acid-A receptors. The combined images were examined by visual inspection and by formal, automated analyses, in a search for anisotropies that might contribute to a directional preference of the ganglion cell. Within the limits of our analysis, none was found. If an anatomic specialization underlies direction selectivity, it appears to lie in the geometry and spatial positioning of the neurons afferent to the ganglion cell and/or the microcircuitry among its afferent synapses.     

Functional inhibition in direction-selective retinal ganglion cells: spatiotemporal extent and intralaminar interactions

We recorded from ON-OFF direction-selective ganglion cells (DS cells) in the rabbit retina to investigate in detail the inhibition that contributes to direction selectivity in these cells. Using paired stimuli moving sequentially across the cells' receptive fields in the preferred direction, we directly confirmed the prediction of that a wave of inhibition accompanies any moving excitatory stimulus on its null side, at a fixed spatial offset. Varying the interstimulus distance, stimulus size, luminance, and speed yielded a spatiotemporal map of the strength of inhibition within this region. This "null" inhibition was maximal at an intermediate distance behind a moving stimulus: 1/2 to 11/2 times the width of the receptive field. The strength of inhibition depended more on the distance behind the stimulus than on stimulus speed, and the inhibition often lasted 1-2 s. These spatial and temporal parameters appear to account for the known spatial frequency and velocity tuning of ON-OFF DS cells to drifting contrast gratings. Stimuli that elicit distinct ON and OFF responses to leading and trailing edges revealed that an excitatory response of either polarity could inhibit a subsequent response of either polarity. For example, an OFF response inhibited either an ON or OFF response of a subsequent stimulus. This inhibition apparently is conferred by a neural element or network spanning the ON and OFF sublayers of the inner plexiform layer, such as a multistratified amacrine cell. Trials using a stationary flashing spot as a probe demonstrated that the total amount of inhibition conferred on the DS cell was equivalent for stimuli moving in either the null or preferred direction. Apparently the cell does not act as a classic "integrate and fire" neuron, summing all inputs at the soma. Rather, computation of stimulus direction likely involves interactions between excitatory and inhibitory inputs in local regions of the dendrites.     

Induction of epileptiform activity in hippocampal slices by trains of electrical stimuli

In this paper we present an in vitro model of epileptogenesis based on electrical stimulation rather than pharmacological or ionic manipulations. Hippocampal slices given a series of stimulus trains similar to those used in kindling exhibited 3 types of epileptiform activity in CA3: afterdischarges immediately following the trains; spontaneous bursts of multiple population spikes; and bursts triggered by single stimuli. The afterdischarges and spontaneous bursts may be comparable to those seen in vivo during kindling; also, the progression of these features in this model was similar to their progression during kindling. All epileptiform activities were long-lasting, persisting for up to 3.5 h following the last train. This stimulus train-induced population bursting should be valuable as an acute model of hippocampal epileptogenesis, and may also help elucidate hippocampal participation in the kindling process.     

Emergence of sustained spontaneous hyperactivity and temporary preservation of OFF responses in ganglion cells of the retinal degeneration (rd1) mouse

Complex alterations in the anatomy of outer retinal pathways accompany photoreceptor degeneration in the rd1 mouse model of retinitis pigmentosa, whereas inner retinal neurons appear relatively preserved. However, the progressive loss of photoreceptor input likely alters the neural circuitry of the inner retina. This study investigated resulting changes in the activity of surviving ganglion cells. Multielectrode recording monitored spontaneous and light-evoked extracellular action potentials simultaneously from 30 to 90 retinal ganglion cells of wild-type (wt) or rd1 mice. In rd1 mice, this activity evolves through three phases. First, normal spontaneous "waves" of correlated firing are seen at postnatal day 7 (P7) and last until shortly after eye opening. Second, at P14, full-field light flashes evoke reliable responses in many cells, with preferential preservation of off responses. These diminish as photoreceptor degeneration progresses. Third, once light-evoked responses have disappeared in early adulthood, surviving rd1 ganglion cells fire at a much higher spontaneous frequency than normal, sometimes in rhythmic bursts that are distinct from the developmental "waves." This hyperactivity is sustained well into adulthood, for weeks after photoreceptors have disappeared. Thus striking alterations occur in inner retinal physiology as retinal degeneration progresses in the rd1 mouse. Blindness occurs in the face of sustained hyperactivity among ganglion cells, which remain viable for months despite this activity. On and off responses are differentially affected in early stages of degeneration. While the source of these changes remains to be learned, such features should be considered in designing more effective treatments for these disorders.