Targeting aberrant dendritic integration to treat cognitive comorbidities of epilepsy.

Memory deficits are a debilitating symptom of epilepsy, but little is known about mechanisms underlying cognitive deficits. Here, we describe a Na+ channel-dependent mechanism underlying altered hippocampal dendritic integration, degraded place coding and deficits in spatial memory. Two-photon glutamate uncaging experiments revealed a marked increase in the fraction of hippocampal first-order CA1 pyramidal cell dendrites capable of generating dendritic spikes in the kainate model of chronic epilepsy. Moreover, in epileptic mice dendritic spikes were generated with lower input synchrony, and with a lower threshold. The Nav1.3/1.1 selective Na+ channel blocker ICA-121431 reversed dendritic hyperexcitability in epileptic mice, while the Nav1.2/1.6 preferring anticonvulsant S-Lic did not. We used in vivo two-photon imaging to determine if aberrant dendritic excitability is associated with altered place-related firing of CA1 neurons. We show that ICA-121431 improves degraded hippocampal spatial representations in epileptic mice. Finally, behavioural experiments show that reversing aberrant dendritic excitability with ICA-121431 reverses hippocampal memory deficits. Thus, a dendritic channelopathy may underlie cognitive deficits in epilepsy and targeting it pharmacologically may constitute a new avenue to enhance cognition.

An astrocytic signaling loop for frequency-dependent control of dendritic integration and spatial learning.

Dendrites of hippocampal CA1 pyramidal cells amplify clustered glutamatergic input by activation of voltage-gated sodium channels and N-methyl-D-aspartate receptors (NMDARs). NMDAR activity depends on the presence of NMDAR co-agonists such as D-serine, but how co-agonists influence dendritic integration is not well understood. Using combinations of whole-cell patch clamp, iontophoretic glutamate application, two-photon excitation fluorescence microscopy and glutamate uncaging in acute rat and mouse brain slices we found that exogenous D-serine reduced the threshold of dendritic spikes and increased their amplitude. Triggering an astrocytic mechanism controlling endogenous D-serine supply via endocannabinoid receptors (CBRs) also increased dendritic spiking. Unexpectedly, this pathway was activated by pyramidal cell activity primarily in the theta range, which required HCN channels and astrocytic CB1Rs. Therefore, astrocytes close a positive and frequency-dependent feedback loop between pyramidal cell activity and their integration of dendritic input. Its disruption in mice led to an impairment of spatial memory, which demonstrated its behavioral relevance.

Unveiling the sensory and interneuronal pathways of the neuroendocrine connectome in Drosophila.

Neuroendocrine systems in animals maintain organismal homeostasis and regulate stress response. Although a great deal of work has been done on the neuropeptides and hormones that are released and act on target organs in the periphery, the synaptic inputs onto these neuroendocrine outputs in the brain are less well understood. Here, we use the transmission electron microscopy reconstruction of a whole central nervous system in the Drosophila larva to elucidate the sensory pathways and the interneurons that provide synaptic input to the neurosecretory cells projecting to the endocrine organs. Predicted by network modeling, we also identify a new carbon dioxide-responsive network that acts on a specific set of neurosecretory cells and that includes those expressing corazonin (Crz) and diuretic hormone 44 (Dh44) neuropeptides. Our analysis reveals a neuronal network architecture for combinatorial action based on sensory and interneuronal pathways that converge onto distinct combinations of neuroendocrine outputs.

Synchronous activity patterns in the dentate gyrus during immobility.

The hippocampal dentate gyrus is an important relay conveying sensory information from the entorhinal cortex to the hippocampus proper. During exploration, the dentate gyrus has been proposed to act as a pattern separator. However, the dentate gyrus also shows structured activity during immobility and sleep. The properties of these activity patterns at cellular resolution, and their role in hippocampal-dependent memory processes have remained unclear. Using dual-color in vivo two-photon Ca2+ imaging, we show that in immobile mice dentate granule cells generate sparse, synchronized activity patterns associated with entorhinal cortex activation. These population events are structured and modified by changes in the environment; and they incorporate place- and speed cells. Importantly, they are more similar than expected by chance to population patterns evoked during self-motion. Using optogenetic inhibition, we show that granule cell activity is not only required during exploration, but also during immobility in order to form dentate gyrus-dependent spatial memories.

Electric-Color Sensing in Weakly Electric Fish Suggests Color Perception as a Sensory Concept beyond Vision.

Many sighted animals use color as a salient and reliable cue [1] to identify conspecifics [2-4], predators, or food [5-7]. Similarly, nocturnal, weakly electric fish Gnathonemus petersii might rely on "electric colors" [8] for unambiguous, critical object recognitions. These fish identify nearby targets by emitting electric signals and by sensing the object-evoked signal modulations in amplitude and waveform with two types of epidermal electroreceptors (active electrolocation) [9-12]. Electrical capacitive objects (animals, plants) modulate both parameters; resistive targets (e.g., rocks) modulate only the signal's amplitude [11, 12]. Ambiguities of electrosensory inputs arise when object size, distance, or position vary. While previous reports suggest electrosensory disambiguations when both modulations are combined as electric colors [8, 13, 14], this concept has never been demonstrated in a natural, behaviorally relevant context. Here, we assessed electric-color perception (1) by recording object-evoked signal modulations and (2) by testing the fishes' behavioral responses to these objects during foraging. We found that modulations caused by aquatic animals or plants provided electric colors when combined as a ratio. Individual electric colors designated crucial targets (electric fish, prey insect larvae, or others) irrespective of their size, distance, or position. In behavioral tests, electrolocating fish reliably identified prey insect larvae of varying sizes from different distances and did not differentiate between artificial prey items generating similar electric colors. Our results indicate a color-like perceptual cue during active electrolocation, the computation [15], reliability, and use of which resemble those of color in vision. This suggests "color" perception as a sensory concept beyond vision and passive sensing.

Photosynthate accumulation in solar-powered sea slugs - starving slugs survive due to accumulated starch reserves.

BACKGROUND: Solar-powered sea slugs are famed for their ability to survive starvation due to incorporated algal chloroplasts. It is well established that algal-derived carbon can be traced in numerous slug-derived compounds, showing that slugs utilize the photosynthates produced by incorporated plastids. Recently, a new hypothesis suggests that the photosynthates produced are not continuously made available to the slug. Instead, at least some of the plastid's photosynthetic products are stored in the plastid itself and only later become available to the slug. The long-term plastid-retaining slug, Elysia timida and its sole food source, Acetabularia acetabulum were examined to determine whether or not starch, a combination of amylose and amylopectin and the main photosynthate produced by A. acetabulum, is produced by the stolen plastids and whether it accumulates within individual kleptoplasts, providing an energy larder, made available to the slug at a later time. RESULTS: Histological sections of Elysia timida throughout a starvation period were stained with Lugol's Iodine solution, a well-known stain for starch granules in plants. We present here for the first time, an increase in amylose concentration, within the slug's digestive gland cells during a starvation period, followed by a sharp decrease. Chemically blocking photosynthesis in these tissues resulted in no observable starch, indicating that the starch in untreated animals is a product of photosynthetic activity. CONCLUSION: This suggests that kleptoplasts function as both, a nutritive producer and storage device, holding onto the polysaccharides they produce for a certain time until they are finally available and used by the starving slug to withstand extended starvation periods.