Sensory modality-specific homeostatic plasticity in the developing optic tectum.

We found a previously unknown form of homeostatic synaptic plasticity in multisensory neurons in the optic tectum of Xenopus laevis tadpoles. Individual tectal neurons are known to receive converging inputs from multiple sensory modalities. We observed that long-term alterations in either visual or mechanosensory activity in vivo resulted in homeostatic changes specific to each sensory modality. In contrast with typical forms of homeostatic synaptic plasticity, such as synaptic scaling, we found that this type of plasticity occurred in a pathway-specific manner that is more reminiscent of hebbian-type plasticity.

Neurodevelopmental effects of chronic exposure to elevated levels of pro-inflammatory cytokines in a developing visual system.

BACKGROUND: Imbalances in the regulation of pro-inflammatory cytokines have been increasingly correlated with a number of severe and prevalent neurodevelopmental disorders, including autism spectrum disorder, schizophrenia and Down syndrome. Although several studies have shown that cytokines have potent effects on neural function, their role in neural development is still poorly understood. In this study, we investigated the link between abnormal cytokine levels and neural development using the Xenopus laevis tadpole visual system, a model frequently used to examine the anatomical and functional development of neural circuits. RESULTS: Using a test for a visually guided behavior that requires normal visual system development, we examined the long-term effects of prolonged developmental exposure to three pro-inflammatory cytokines with known neural functions: interleukin (IL)-1beta, IL-6 and tumor necrosis factor (TNF)-alpha. We found that all cytokines affected the development of normal visually guided behavior. Neuroanatomical imaging of the visual projection showed that none of the cytokines caused any gross abnormalities in the anatomical organization of this projection, suggesting that they may be acting at the level of neuronal microcircuits. We further tested the effects of TNF-alpha on the electrophysiological properties of the retinotectal circuit and found that long-term developmental exposure to TNF-alpha resulted in enhanced spontaneous excitatory synaptic transmission in tectal neurons, increased AMPA/NMDA ratios of retinotectal synapses, and a decrease in the number of immature synapses containing only NMDA receptors, consistent with premature maturation and stabilization of these synapses. Local interconnectivity within the tectum also appeared to remain widespread, as shown by increased recurrent polysynaptic activity, and was similar to what is seen in more immature, less refined tectal circuits. TNF-alpha treatment also enhanced the overall growth of tectal cell dendrites. Finally, we found that TNF-alpha-reared tadpoles had increased susceptibility to pentylenetetrazol-induced seizures. CONCLUSIONS: Taken together our data are consistent with a model in which TNF-alpha causes premature stabilization of developing synapses within the tectum, therefore preventing normal refinement and synapse elimination that occurs during development, leading to increased local connectivity and epilepsy. This experimental model also provides an integrative approach to understanding the effects of cytokines on the development of neural circuits and may provide novel insights into the etiology underlying some neurodevelopmental disorders.

Development of multisensory convergence in the Xenopus optic tectum.

The adult Xenopus optic tectum receives and integrates visual and nonvisual sensory information. Nonvisual inputs include mechanosensory inputs from the lateral line, auditory, somatosensory, and vestibular systems. While much is known about the development of visual inputs in this species, almost nothing is known about the development of mechanosensory inputs to the tectum. In this study, we investigated mechanosensory inputs to the tectum during critical developmental stages (stages 42-49) in which the retinotectal map is being established. Tract-tracing studies using lipophilic dyes revealed a large projection between the hindbrain and the tectum as early as stage 42; this projection carries information from the Vth, VIIth, and VIIIth nerves. By directly stimulating hindbrain and visual inputs using an isolated whole-brain preparation, we found that all tectal cells studied received both visual and hindbrain input during these early developmental stages. Pharmacological data indicated that the hindbrain-tectal projection is glutamatergic and that there are no direct inhibitory hindbrain-tectal ascending projections. We found that unlike visual inputs, hindbrain inputs do not show a decrease in paired-pulse facilitation over this developmental period. Interestingly, over this developmental period, hindbrain inputs show a transient increase followed by a significant decrease in the alpha-amino-3-hydroxyl-5-methyl-4-isoxazolepropionate (AMPA)/N-methyl-D-aspartate (NMDA) ratio and show no change in quantal size, both in contrast to visual inputs. Our data support a model by which fibers are added to the hindbrain-tectal projection across development. Nascent fibers form new synapses with tectal neurons and primarily activate NMDA receptors. At a time when retinal ganglion cells and their tectal synapses mature, hindbrain-tectal synapses are still undergoing a period of rapid synaptogenesis. This study supports the idea that immature tectal cells receive converging visual and mechanosensory information and indicates that the Xenopus tectum might be an ideal preparation to study the early development of potential multisensory interactions at the cellular level.

Synapse-specific homeostatic mechanisms in the hippocampus.

Homeostatic synaptic plasticity allows neural circuits to function stably despite fluctuations to their inputs. Previous work has shown that excitatory synaptic strength increases globally when neuronal inputs are chronically silenced. A recent paper by Kim and Tsien describes a new type of synapse-specific homeostatic plasticity in which input silencing causes simultaneous strengthening and weakening of different populations of excitatory synapses within a hippocampal network. These seemingly antagonistic homeostatic adaptations maintain synaptic gain and preserve overall network stability by limiting harmful reverberatory bursting, which may underlie epileptic seizures.

Developmental regulation of neuromodulator function in the stomatogastric ganglion of the lobster, Homarus americanus.

Neuromodulatory substances have profound effects on the two motor patterns generated by the adult crustacean stomatogastric ganglion (STG), the gastric mill rhythm and the pyloric rhythm. Developmentally regulated changes in the modulatory functions of neuromodulators could therefore play an important role in the maturation of the output from the developing STG. We compared the effects of neuromodulators on isolated embryonic and adult STG of the lobster, Homarus americanus. Bath application of Val(1)-SIFamide, a peptide whose expression is different in embryos and adults, activated different neuron classes in embryos and adults. Cancer borealis tachykinin-related peptide 1a, a peptide that does not appear in the terminals of modulatory neurons in the STG until after embryonic development, also produced different motor patterns in embryos and adults. In contrast, red pigment concentrating hormone, a peptide with a similar distribution in the STNS across development, produced similar motor patterns in embryonic and adult STG. Proctolin, serotonin, and allatostatin were also physiologically active on the isolated embryonic STG. Together, these results demonstrate that receptors to many neuromodulators are present and functional on STG neurons before the motor patterns of the stomatogastric nervous system are mature. Moreover, neuromodulator responses change during development, perhaps contributing to the maturation of the output from the stomatogastric nervous system.