No abstract

AMPA and NMDA receptors are coexpressed at many central synapses, but the factors that control the ratio of these two receptors are not well understood. We recorded mixed miniature or evoked synaptic currents arising from coactivation of AMPA and NMDA receptors and found that long-lasting changes in activity scaled both currents up and down proportionally through changes in the number of postsynaptic receptors. The ratio of NMDA to AMPA current was similar at different synapses onto the same neuron, and this relationship was preserved following activity-dependent synaptic scaling. These data show that AMPA and NMDA receptors are tightly coregulated by activity at synapses at which they are both expressed and suggest that a mechanism exists to actively maintain a constant receptor ratio across a neuron's synapses.

Spike-timing-dependent plasticity (STDP) offers a powerful means of forming and modifying neural circuits. Experimental and theoretical studies have demonstrated its potential usefulness for functions as varied as cortical map development, sharpening of sensory receptive fields, working memory, and associative learning. Even so, it is unlikely that STDP works alone. Unless changes in synaptic strength are coordinated across multiple synapses and with other neuronal properties, it is difficult to maintain the stability and functionality of neural circuits. Moreover, there are certain features of early postnatal development (e.g., rapid changes in sensory input) that threaten neural circuit stability in ways that STDP may not be well placed to counter. These considerations have led researchers to investigate additional types of plasticity, complementary to STDP, that may serve to constrain synaptic weights and/or neuronal firing. These are collectively known as “homeostatic plasticity” and include schemes that control the total synaptic strength of a neuron, that modulate its intrinsic excitability as a function of average activity, or that make the ability of synapses to undergo Hebbian modification depend upon their history of use. In this article, we will review the experimental evidence for homeostatic forms of plasticity and consider how they might interact with STDP during development, and learning and memory.

Correlated network activity plays a critical role in the development of many neural circuits. Purkinje cells are among the first neurons to populate the cerebellar cortex, where they sprout exuberant axon collaterals. Here we use multiple patch-clamp recordings targeted with two-photon microscopy to characterize monosynaptic connections between Purkinje cells of juvenile mice. We show that Purkinje cell axon collaterals project asymmetrically in the sagittal plane, directed away from the lobule apex. Based on our anatomical and physiological characterization of this connection, we construct a network model that robustly generates waves of activity traveling along chains of connected Purkinje cells. Consistent with the model, we observe traveling waves of activity in Purkinje cells in sagittal slices from young mice that require GABAA receptor-mediated transmission and intact Purkinje cell axon collaterals. These traveling waves are absent in adult animals, suggesting they play a developmental role in wiring the cerebellar cortical microcircuit.