Fever-associated seizures or epilepsy (FASE) is primarily characterised by the occurrence of a seizure or epilepsy usually accompanied by a fever. It is common in infants and children, and generally includes febrile seizures (FS), febrile seizures plus (FS+), Dravet syndrome (DS) and genetic epilepsy with febrile seizures plus (GEFSP). The aetiology of FASE is unclear. Genetic factors may play crucial roles in FASE. Mutations in certain genes may cause a wide spectrum of phenotypical overlap ranging from isolated FS, FS+ and GEFSP to DS. Synapse-associated proteins, postsynaptic GABAA receptor, and sodium channels play important roles in synaptic transmission. Mutations in these genes may involve in the pathogenesis of FASE. Elevated temperature promotes synaptic vesicle (SV) recycling and enlarges SV size, which may enhance synaptic transmission and contribute to FASE occurring. This review provides an overview of the loci, genes, underlying pathogenesis and the fever-inducing effect of FASE. It may provide a more comprehensive understanding of pathogenesis and contribute to the clinical diagnosis of FASE.

The thalamocortical (TC) relay neuron of the dorsoLateral Geniculate Nucleus (dLGN) has borne its imprecise label for many decades in spite of strong evidence that its role in visual processing transcends the implied simplicity of the term “relay”. The retinogeniculate synapse is the site of communication between a retinal ganglion cell and a TC neuron of the dLGN. Activation of retinal fibers in the optic tract causes reliable, rapid, and robust postsynaptic potentials that drive postsynaptics spikes in a TC neuron. Cortical and subcortical modulatory systems have been known for decades to regulate retinogeniculate transmission. The dynamic properties that the retinogeniculate synapse itself exhibits during and after developmental refinement further enrich the role of the dLGN in the transmission of the retinal signal. Here we consider the structural and functional substrates for retinogeniculate synaptic transmission and plasticity, and reflect on how the complexity of the retinogeniculate synapse imparts a novel dynamic and influential capacity to subcortical processing of visual information.

Metabotropic glutamate receptors (mGluRs) have been shown to be involved in the modulation of retinocollicular neurotransmission. In glaucoma, retinal ganglion cells (RGCs) degenerate, which may have an implication on this transmission as the superior colliculus is their major central target in the much-used rodent models of the disease. We have investigated this using an in vitro slice preparation of the superior colliculus by eliciting field excitatory postsynaptic potentials (fEPSPs) through optic tract stimulation in a rat ocular hypertension model of glaucoma. Application of the group III mGluR agonist L-AP4 reduced the peak amplitude of the fEPSP in superior colliculus slices through presynaptic mechanisms as previously shown in our lab. At 3 and 16 weeks after surgery, there were no significant differences in the effect of L-AP4 on fEPSP peak amplitude in the superior colliculus slices receiving input from the glaucomatous eyes [elevated intraocular pressure (IOP)] compared to those with input from the unoperated eyes (normal IOP). However, at 32 weeks, the fEPSP peak amplitude was reduced to a significantly greater degree during L-AP4 application in the elevated IOP slices compared to normal IOP slices. At all time points, there were no significant changes in the baseline amplitudes of fEPSPs or the stimulus intensities required to evoke fEPSPs. These results suggest that the modulation of synaptic transmission through group III mGluRs on RGC terminals to the superior colliculus is changed at later stages due to RGC degeneration through IOP elevation. These changes may be compensatory changes possibly through plasticity in the RGC terminals of surviving cells, which may be due to increases in the numbers of group III mGluRs. This result may have implications on further treatment studies carried out using these models of glaucoma as changes in the central visual system may need to be considered along with the retinal changes that occur.

There is no question about the fact that astrocytes and other glial cells release neurotransmitters that activate receptors on neurons, glia and vascular cells, and that calcium is an important second messenger regulating the release. This occurs in cell culture, tissue slice and in vivo. Negative results from informative experiments designed to test the mechanism of calcium-dependent neurotransmitter release from astrocytes and the ensuing effects on synaptic transmission, have been cited as evidence calling into question whether astrocytes release neurotransmitters under normal circumstances with effects on synaptic transmission. The special feature section in this issue of Neuron Glia Biology addresses these issues and other aspects of neurotransmitter release from astrocytes in communicating with neurons and glial cells. Together these studies suggest that application of vocabulary and concepts developed for synaptic communication between neurons can lead to confusion and apparent paradoxes with respect to communication by extracellular signaling molecules released from glia in response to functional activity.

AMPA and NMDA type glutamate receptors were studied in isolated catfish cone horizontal cells using the whole-cell and outside-out patch-recording techniques. In whole-cell recordings, cyclothiazide (CTZ) enhanced the peak current in response to glutamate (in the presence of NMDA receptor antagonists). In patch recordings, currents evoked by rapid and maintained applications of glutamate desensitized with a time constant of one millisecond. CTZ blocked this rapid desensitization. Recovery from desensitization of the AMPA receptors was rapid, having a time constant of 8.65 ms. In contrast, the whole-cell and patch responses to applications of NMDA were much smaller than the AMPA receptor responses and did not desensitize. The relative contribution of these two receptor subtypes depends critically on the condition of the synapse: if glutamate levels are tonically present, the NMDA receptors contribute significantly to the postsynaptic response. If glutamate levels fall rapidly following the release of a single quantum of glutamate, then AMPA receptor currents will dominate the postsynaptic response.

The effects of cobalt ions on 502-nm rod- and 575-nm cone-driven components of the b-wave of the electroretinogram were studied in the isolated frog retina. Addition of 100–150 μM cobalt initially caused a suppression of rod-driven responses and an enhancement of cone-driven responses. In the continued presence of cobalt, however, the rod-driven responses gradually recovered and the cone-driven responses became suppressed. These concentrations of cobalt had no effect on the rod- and cone-driven mass receptor potentials which were isolated in the presence of 4 mM glutamate. At higher concentrations of cobalt (1 mM or greater), both rod- and cone-driven b-wave responses were eliminated and there was no recovery in the continued presence of cobalt. The results suggest that cobalt has markedly different, time-dependent effects on signal transmission from rods and cones to second-order cells.

We have developed two brain slice preparations for studying tectofugal visual pathways in the chick: conventional, 400-μm slices (“thin slices”), and “thick slices” which encompass the rostral pole of the optic tectum and the contralateral optic nerve. Stimulation was delivered with a bipolar electrode positioned in stratum opticum in thin slices and in the contralateral optic nerve in thick slices. While the latter preparation provided a means of exclusively and unambiguously activating retinal afferents, several lines of evidence also indicated that the evoked field potentials in thin slices were chiefly consequent to retinal afferent excitation: (1) the similarity of evoked field potentials in thin slices to those in thick slice preparations; (2) their precise localization in retinorecipient layers as shown by prelabeling from retina with FITC-coupled cholera toxin; (3) transmission delays appropriate for retinal afferents as established with the thick slice preparation; (4) patterns of labeled afferents resulting from applications of Dil crystals to slices fixed after recording; and (5) the similarity in transmitter pharmacology between thin and thick slice preparations. Pharmacological manipulations carried out with bath-applied antagonists indicated that glutamate is the principal retinotectal transmitter. The broadly active glutamate receptor blocker, kynurenic acid, reversibly eliminated the postsynaptic component of the field potential as confirmed with 0 Ca2+ saline. A complete block was also effected by the non-NMDA antagonists CNQX and DNQX. The specific NMDA antagonist, APS, caused a smaller and variable reduction in response amplitude. The GABA antagonist, bicuculline, caused a prolongation of the monosynaptic field epsp in retinorecipient layers and an enhancement of the long-latency, negative wave in cellular layers below, supporting a late, excitation-limiting role for this inhibitory transmitter.

We examined the pattern of NADPH-diaphorase (NADPH-d) staining in the lateral geniculate nucleus (LGN) of dorsal thalamus in fetal and newborn kittens, and adult cats. This staining visualizes the synthesizing enzyme of nitric oxide (NO), a neuromodulator associated with central nervous system (CNS) development and synaptic plasticity. In the adult, very few LGN cells stained for NADPH-d, and these were restricted to interlaminar zones and ventral C layers. NADPH-d labeled a dense network of fibers and axon terminals throughout the LGN and adjacent thalamic nuclei. The source of such labelling has been reported to be cholinergic neurons from the parabrachial region of the brain stem (Bickford et al., 1993). A very different pattern of staining was observed in prenatal and early postnatal kittens. Between embryonic (E) day 46–57, lightly stained cells appeared throughout the LGN. From this age, through about the first month of life, the number of stained cells in the LGN rose rapidly. The density (cells/ mm2) of labeled cells peaked at postnatal day (P) 28 (P28), and was about 150 times greater than the level measured in the adult LGN. After P28, cell staining declined rapidly, and fell to adult levels at P41. The reduction in cell staining that occurred between P35–41 was accompanied by the appearance of fine-caliber fiber staining, similar to that observed in the adult LGN. NADPH-d staining, which reveals the presence of nitric oxide synthase (NOS), and thus NO activity, may reflect two processes. In the adult LGN, the labeling of cholinergic axons arising from the brain-stem parabrachial region coupled with a paucity of the LGN cellular staining suggests that NO operates in an orthograde manner, being co-released with ACh to influence the gain and efficacy of retinogeniculate transmission. By contrast, in developing kitten, NADPH-d staining of LGN cells suggests that NO acts in a retrograde fashion, perhaps playing a role in maintaining associative processes underlying activity-dependent refinement of retinogeniculate connections.

Effects of extracellular calcium on signal transmission between photoreceptors and horizontal cells (HCs) are studied in superfused isolated retina of the larval tiger salamander. Horizontal cell light response is optimal when extracellular Ca2+ is maintained between 1–2 mM. Ca2+ levels beyond this range in either direction significantly reduce the HC light response amplitude. When extracellular Ca2+ is lowered from 2 mM to 0.5 mM, the rod input to HCs is reduced whereas the cone input is not affected. In comparison, the peak voltage responses of rods are not changed whereas the cone voltage responses are enhanced in 0.5 mM Ca2+. The selective suppression of rod input to HCs is probably due to the interplay of three factors: (1) the photocurrents, (2) voltage- and time-dependent membrane currents in photoreceptors, and (3) the Ca2-dependent synaptic gain between photoreceptors and HCs.

Retinal cones are depolarized in darkness, keeping voltage-gated Ca2+ channels open and sustaining exocytosis of synaptic vesicles. Light hyperpolarizes the membrane potential, closing Ca2+ channels and suppressing exocytosis. Here, we quantify the Ca2+ concentration in cone terminals, with Ca2+ indicator dyes. Two-photon ratiometric imaging of fura-2 shows that global Ca2+ averages ~360 nM in darkness and falls to ~190 nM in bright light. Depolarizing cones from their light to their dark membrane potential reveals hot spots of Ca2+ that co-label with a fluorescent probe for the synaptic ribbon protein ribeye, consistent with tight localization of Ca2+ channels near ribbons. Measurements with a low-affinity Ca2+ indicator show that the local Ca2+ concentration near the ribbon exceeds 4 μM in darkness. The high level of Ca2+ near the ribbon combined with previous estimates of the Ca2+ sensitivity of release leads to a predicted dark release rate that is much faster than observed, suggesting that the cone synapse operates in a maintained state of synaptic depression in darkness.

Astrocytes were classically considered as simple supportive cells for neurons without a significant role in information processing by the nervous system. However, considerable amounts of evidence obtained by several groups during the past years demonstrated the existence of a bidirectional communication between astrocytes and neurons, which prompted a re-examination of the role of astrocytes in the physiology of the nervous system. While neurons base their excitability on electrical signals generated across the membrane, astrocytes base their cellular excitability on variations of the Ca2+ concentration in the cytosol. This article discusses our current knowledge of the properties of the synaptically evoked astrocyte Ca2+ signal, which reveals that astrocytes display integrative properties for synaptic information processing. Astrocytes respond selectively to different axon pathways, discriminate between the activity of different synapses and their Ca2+ signal is non-linearly modulated by the simultaneous activity of different synaptic inputs. Furthermore, this Ca2+ signal modulation depends on astrocyte cellular intrinsic properties and is bidirectionally regulated by the level of synaptic activity. Finally, astrocyte Ca2+ elevations can trigger the release of gliotransmitters, which modulate neuronal activity as well as synaptic transmission and plasticity, hence granting the bidirectional communication with neurons. Consequently, astrocytes can be considered as cellular elements involved in information processing by the nervous system.

The genetic locus for incomplete congenital stationary night blindness (CSNB2) has been identified as the CACNA1f gene, encoding the α1F calcium channel subunit, a member of the L-type family of calcium channels. The electroretinogram associated with CSNB2 implicates α1F in synaptic transmission between retinal photoreceptors and bipolar cells. Using a recently developed monoclonal antibody to α1F, we localize the channel to ribbon active zones in rod photoreceptor terminals of the mouse retina, supporting a role for α1F in mediating glutamate release from rods. Detergent extraction experiments indicate that α1F is part of a detergent-resistant active zone complex, which also includes the synaptic ribbons. Comparison of native mouse rod calcium currents with recombinant α1F currents reveals that the current–voltage relationship for the native current is shifted approximately 30 mV to more hyperpolarized potentials than for the recombinant α1F current, suggesting modulation of the native channel by intracellular factors. Lastly, we present evidence for L-type α1D calcium channel subunits in cone terminals of the mouse retina. The presence of α1D channels in cones may explain the residual visual abilities of individuals with CSNB2.

In the CNS, fine processes of astrocytes often wrap around dendrites, axons and synapses, which provides an interface where neurons and astrocytes might interact. We have reported previously that selective Ca2+ elevation in astrocytes, by photolysis of caged Ca2+ by o-nitrophenyl-EGTA (NP-EGTA), causes a kainite receptor-dependent increase in the frequency of spontaneous inhibitory post-synaptic potentials (sIPSCs) in neighboring interneurons in hippocampal slices. However, tetrodotoxin (TTX), which blocks action potentials, reduces the frequency of miniature IPSCs (mIPSCs) in interneurons during Ca2+ uncaging by an unknown presynaptic mechanism. In this study we investigate the mechanism underlying the presynaptic inhibition. We show that Ca2+ uncaging in astrocytes is accompanied by a decrease in the amplitude of evoked IPSCs (eIPSCs) in neighboring interneurons. The decreases in eIPSC amplitude and mIPSC frequency are prevented by CPPG, a group II/III metabotropic glutamate receptor (mGluR) antagonist, but not by the AMPA/kainate and NMDA receptor antagonists CNQX/CPP. Application of either the group II mGluR agonist DCG IV or the group III mGluR agonist L-AP4 decreased the amplitude of eIPSCs by a presynaptic mechanism, and both effects are blocked by CPPG. Thus, activation of mGluRs mediates the effects of Ca2+ uncaging on mIPSCs and eIPSCs. Our results indicate that Ca2+-dependent release of glutamate from astrocytes can activate distinct classes of glutamate receptors and differentially modulate inhibitory synaptic transmission in hippocampal interneurons.

Simultaneous recordings from relay cells in the lateral geniculate nucleus (LGN) and their retinal afferents were used to examine the rules governing the transmission of spikes across the retino-geniculate synapse. Retinal spikes that terminate short retinal interspike intervals are much more likely to be transmitted across the synapse than spikes terminating longer intervals. This facilitation can be observed for interspike intervals as long as 50 ms when retinal firing rates are low, but the range of effective intervals decreases exponentially as retinal firing rate increases. Contribution, the fraction of LGN spikes triggered by an individual retinal afferent, is typically much higher during visual stimulation than during maintained activity, and these differences are unrelated to presynaptic or postsynaptic firing rate. It is suggested that this effect is a manifestation of increased synchronization of spikes among retinal afferents to the geniculate cell during structured visual stimulation, and that this synchronization offers a means of enhancing signal-to-noise ratio at the retino-geniculate synapse. Cross-correlograms between geniculate burst spikes and retinal afferents often contain two distinct peaks; a short latency peak that results from direct coupling between burst spikes and retinal input spikes, and a longer latency peak that represents indirect coupling in which retinal spikes trigger the calcium spike underlying the burst. Direct coupling is most likely to occur for the later spikes in the burst, and is present regardless of whether the calcium spike underlying the burst is triggered by the same or a different retinal afferent. These results further illuminate the relationship between tonic and burst modes of retino-geniculate transmission and indicate that bursts in LGN relay cells can be viewed as a mechanism of signal amplification, producing signals whose timing is potentially related to the temporal structure of a stimulus, independent of presynaptic and postsynaptic firing rate. This mechanism also appears to capitalize on the synchronization that is present among parallel retinal afferents to a geniculate cell.