Kara G. Pratt

Homeostatic Regulation of Intrinsic Excitability and Synaptic Transmission in a Developing Visual Circuit

One of the major challenges faced by the developing visual system is how to stably process visual information, yet at the same time remain flexible enough to accommodate growth and plasticity induced by visual experience. We find that in the Xenopus retinotectal circuit, during a period in development when the retinotectal map undergoes activity-dependent refinement and visual inputs strengthen, tectal neurons adapt their intrinsic excitability such that a stable relationship between the total level of synaptic input and tectal neuron spike output is conserved. This homeostatic balance between synaptic and intrinsic properties is maintained, in part, via regulation of voltage-gated Na+ currents, resulting in a stable neuronal input–output function. We experimentally manipulated intrinsic excitability or synapse strengthening in developing tectal neurons in vivo by electroporation of a leak K+ channel gene or a peptide that interferes with normal AMPA receptor trafficking. Both manipulations resulted in a compensatory increase in voltage-gated Na+ currents. This suggests that intrinsic neuronal properties are actively regulated as a function of the total level of neuronal activity experienced during development. We conclude that the coordinated changes between synaptic and intrinsic properties allow developing optic tectal neurons to remain within a stable dynamic range, even as the pattern and strength of visual inputs changes over development, suggesting that homeostatic regulation of intrinsic properties plays a central role in the functional development of neural circuits.

Activity-dependent remodeling of presynaptic inputs by postsynaptic expression of activated CaMKII.

Competitive synaptic remodeling is an important feature of developmental plasticity, but the molecular mechanisms remain largely unknown. Calcium/calmodulin-dependent protein kinase II (CaMKII) can induce postsynaptic changes in synaptic strength. We show that postsynaptic CaMKII also generates structural synaptic rearrangements between cultured cortical neurons. Postsynaptic expression of activated CaMKII (T286D) increased the strength of transmission between pairs of pyramidal neuron by a factor of 4, through a modest increase in quantal amplitude and a larger increase in the number of synaptic contacts. Concurrently, T286D reduced overall excitatory synaptic density and increased the proportion of unconnected pairs. This suggests that connectivity from some synaptic partners was increased while other partners were eliminated. The enhancement of connectivity required activity and NMDA receptor activation, while the elimination did not. These data suggest that postsynaptic activation of CaMKII induces a structural remodeling of presynaptic inputs that favors the retention of active presynaptic partners.

Development and spike timing-dependent plasticity of recurrent excitation in the Xenopus optic tectum.

Much of the information processing in the brain occurs at the level of local circuits; however, the mechanisms underlying their initial development are poorly understood. We sought to examine the early development and plasticity of local excitatory circuits in the optic tectum of Xenopus laevis tadpoles. We found that retinal input recruits persistent, recurrent intratectal synaptic excitation that becomes more temporally compact and less variable over development, thus increasing the temporal coherence and precision of tectal cell spiking. We also saw that patterned retinal input can sculpt recurrent activity according to a spike timing–dependent plasticity rule, and that impairing this plasticity during development results in abnormal refinement of the temporal characteristics of recurrent circuits. This plasticity is a previously unknown mechanism by which patterned retinal activity allows intratectal circuitry to self-organize, optimizing the temporal response properties of the tectal network, and provides a substrate for rapid modulation of tectal neuron receptive-field properties.

Visual Avoidance in Xenopus Tadpoles Is Correlated With the Maturation of Visual Responses in the Optic Tectum

The optic tectum is central for transforming incoming visual input into orienting behavior. Yet it is not well understood how this behavior is organized early in development and how it relates to the response properties of the developing visual system. We designed a novel behavioral assay to study the development of visually guided behavior in Xenopus laevis tadpoles. We found that, during early development, visual avoidance-an innate, tectally mediated behavior-is tuned to a specific stimulus size and is sensitive to changes in contrast. Using in vivo recordings we found that developmental changes in the spatial tuning of visual avoidance are mirrored by changes in tectal receptive field sharpness and the temporal properties of subthreshold visual responses, whereas contrast sensitivity is affected by the gain of the visual response. We also show that long- and short-term perturbations of visual response properties predictably alter behavioral output. We conclude that our assay for visual avoidance is a useful functional measure of the developmental state of the tectal circuitry. We use this assay to show that the developing visual system is tuned to facilitate behavioral output and that the system can be modulated by neural activity, allowing it to adapt to environmental changes it encounters during development.

Presenilin 1 regulates homeostatic synaptic scaling through Akt signaling

Neurons adapt to long-lasting changes in network activity, both in vivo and in vitro, by adjusting their synaptic strengths to stabilize firing rates. We found that homeostatic scaling of excitatory synapses was impaired in hippocampal neurons derived from mice lacking presenilin 1 (Psen1−/− mice) or expressing a familial Alzheimers disease–linked Psen1 mutation (Psen1M146V). These findings suggest that deficits in synaptic homeostasis may contribute to brain dysfunction in Alzheimers disease.

Modeling human neurodevelopmental disorders in the Xenopus tadpole: from mechanisms to therapeutic targets

The Xenopus tadpole model offers many advantages for studying the molecular, cellular and network mechanisms underlying neurodevelopmental disorders. Essentially every stage of normal neural circuit development, from axon outgrowth and guidance to activity-dependent homeostasis and refinement, has been studied in the frog tadpole, making it an ideal model to determine what happens when any of these stages are compromised. Recently, the tadpole model has been used to explore the mechanisms of epilepsy and autism, and there is mounting evidence to suggest that diseases of the nervous system involve deficits in the most fundamental aspects of nervous system function and development. In this Review, we provide an update on how tadpole models are being used to study three distinct types of neurodevelopmental disorders: diseases caused by exposure to environmental toxicants, epilepsy and seizure disorders, and autism.

Multisensory Integration in Mesencephalic Trigeminal Neurons in Xenopus Tadpoles

Mesencephalic trigeminal (M-V) neurons are primary somatosensory neurons with somata located within the CNS, instead of in peripheral sensory ganglia. In amphibians, these unipolar cells are found within the optic tectum and have a single axon that runs along the mandibular branch of the trigeminal nerve. The axon has collaterals in the brain stem and is believed to make synaptic contact with neurons in the trigeminal motor nucleus, forming part of a sensorimotor loop. The number of M-V neurons is known to increase until metamorphosis and then decrease, suggesting that at least some M-V neurons may play a transient role during tadpole development. It is not known whether their location in the optic tectum allows them to process both visual and somatosensory information. Here we compare the anatomical and electrophysiological properties of M-V neurons in the Xenopus tadpole to principal tectal neurons. We find that, unlike principal tectal cells, M-V neurons can sustain repetitive spiking when depolarized and express a significant H-type current. M-V neurons could also be driven synaptically by visual input both in vitro and in vivo, but visual responses were smaller and longer-lasting than those seen in principal tectal neurons. We also found that the axon of M-V neurons appears to directly innervate a tentacle found in the corner of the mouth of premetamorphic tadpoles. Electrical stimulation of this transient sensory organ results in antidromic spiking in M-V neurons in the tectum. Thus M-V neurons may play an integrative multisensory role during tadpole development.

There's More Than One Way to Scale a Synapse

TNFalpha has been proposed to underlie synaptic scaling, but the mechanism and functional significance of this remain unclear. In this issue of Neuron, Cingolani et al. demonstrate that TNFalpha can mediate scaling through the regulation of beta3 integrins. Kaneko et al. show that TNFalpha-dependent synaptic scaling plays an important role in visual cortical plasticity.

An Evolutionarily Conserved Mechanism for Activity-Dependent Visual Circuit Development.

Neural circuit development is an activity-dependent process. This activity can be spontaneous, such as the retinal waves that course across the mammalian embryonic retina, or it can be sensory-driven, such as the activation of retinal ganglion cells (RGCs) by visual stimuli. Whichever the source, neural activity provides essential instruction to the developing circuit. Indeed, experimentally altering activity has been shown to impact circuit development and function in many different ways and in many different model systems. In this review, we contemplate the idea that retinal waves in amniotes, the animals that develop either in ovo or utero (namely reptiles, birds and mammals) could be an evolutionary adaptation to life on land, and that the anamniotes, animals whose development is entirely external (namely the aquatic amphibians and fish), do not display retinal waves, most likely because they simply don’t need them. We then review what is known about the function of both retinal waves and visual stimuli on their respective downstream targets, and predict that the experience-dependent development of the tadpole visual system is a blueprint of what will be found in future studies of the effects of spontaneous retinal waves on instructing development of retinorecipient targets such as the superior colliculus (SC) and the lateral geniculate nucleus.

Region-specific regulation of voltage-gated intrinsic currents in the developing optic tectum of the Xenopus tadpole

Across the rostrocaudal (RC) axis of the Xenopus tadpole optic tectum exists a developmental gradient. This gradient has served as a useful model to study many aspects of synapse and dendrite maturation. To compliment these studies, we characterized how the intrinsic excitability, the ease in which a neuron can fire action potentials, might also be changing across the same axis. Whole-cell recordings from tectal neurons at different points along the RC axis revealed a graded increase in intrinsic excitability: compared with neurons at the caudal end of the tectum, neurons at the rostral end fired more action potentials in response to current injection and expressed greater peak Na⁺ and K⁺ currents, the major intrinsic currents in these neurons that underlie the action potential. We also observed, along the same axis and in the same direction, a previously described increase in the amount of synaptic drive received by individual neurons (Wu GY, Malinow R, Cline HT. Science 274: 972-976, 1996). Thus as synaptic activity ramps up across the RC axis, so does intrinsic excitability. The reduction of overall circuit activity induced a compensatory scaling up of peak Na⁺ and K⁺ currents only in the caudal portion of the tectum, suggesting a region-specific, compensatory form of plasticity.