Mechanisms of response homeostasis during retinocollicular map formation.

The mechanisms of Hebbian synaptic plasticity have been widely hypothesized to play a role in the activity-dependent development of neural circuits. However, these mechanisms are inherently unstable and would lead to the runaway excitation or depression of circuits if left unchecked. In the last decade, a number of elegant studies have demonstrated that homeostatic plasticity mechanisms exist to stabilize neural networks and maintain the constancy of neuronal output in response to changes in activity levels. These include synaptic scaling, sliding threshold models of synaptic plasticity, dynamic regulation of the number and strength of synapses, and bidirectional control of intrinsic excitability. Recently, we showed that the total synaptic input onto individual neurons of the mouse superior colliculus is preserved regardless of the size of their visual receptive fields, a phenomenon we term 'response homeostasis'. Here, we argue that regulating the capacity for synaptic plasticity and controlling the number and strength of retinocollicular inputs can preserve collicular neuron output, and we present evidence that changes in intrinsic excitability are not associated with response homeostasis. We also review findings from a number of different mutant mice and discuss whether and how different cellular mechanisms may underlie response homeostasis. Combined with other studies, our work reveals an important role for homeostatic mechanisms in regulating functional connectivity during the construction of receptive fields and the refinement of topographic maps.

Retinocollicular synapse maturation and plasticity are regulated by correlated retinal waves.

During development, spontaneous retinal waves are thought to provide an instructive signal for retinotopic map formation in the superior colliculus. In mice lacking the beta2 subunit of nicotinic ACh receptors (beta2-/-), correlated retinal waves are absent during the first postnatal week, but return during the second postnatal week. In control retinocollicular synapses, in vitro analysis reveals that AMPA/NMDA ratios and AMPA quantal amplitudes increase during the first postnatal week while the prevalence of silent synapses decreases. In age-matched beta2-/- mice, however, these parameters remain unchanged through the first postnatal week in the absence of retinal waves, but quickly mature to control levels by the end of the second week, suggesting that the delayed onset of correlated waves is able to drive synapse maturation. To examine whether such a mechanistic relationship exists, we applied a "burst-based" plasticity protocol that mimics coincident activity during retinal waves. We find that this pattern of activation is indeed capable of inducing synaptic strengthening [long-term potentiation (LTP)] on average across genotypes early in the first postnatal week [postnatal day 3 (P3) to P4] and, interestingly, that the capacity for LTP at the end of the first week (P6-P7) is significantly greater in immature beta2-/- synapses than in mature control synapses. Together, our results suggest that retinal waves drive retinocollicular synapse maturation through a learning rule that is physiologically relevant to natural wave statistics and that these synaptic changes may serve an instructive role during retinotopic map refinement.

Developmental homeostasis of mouse retinocollicular synapses.

Spontaneous retinal waves during development are thought to provide an instructive signal for precise retinotopic mapping by correlating the activity of neighboring retinal ganglion cells. In mutant mice (beta2-/-) that lack correlated waves, retinocollicular map refinement is impaired. In vivo recordings reveal that neurons in the superior colliculus of beta2-/- mice have large receptive fields and low peak visual responses, resulting in a conservation of total integrated response. We find that this "response homeostasis" is maintained on a cell-by-cell basis, and argue that it does not depend on regulation from the visual cortex during adulthood. Instead, in vitro recordings show that homeostasis arises from the conservation of total synaptic input from the retina, and that it is maintained via different mechanisms over development. In the absence of correlated retinal waves, beta2-/- neurons sample a larger number of weaker retinal inputs relative to controls after the first postnatal week. Once retinal waves are restored, developmental learning rules and homeostasis drive refinement so that fewer, stronger synapses are retained, as in wild-type mice, but from a larger retinal area. Homeostasis in neurons has been shown previously to regulate the gain of synaptic transmission in response to perturbations of activity. Our results suggest that during the development of sensory maps, a unique consequence of homeostatic mechanisms is the precise shaping of neuronal receptive fields in conjunction with activity-dependent competition.

Estrogen-induced changes in the microtubular system correlate with a decreased susceptibility of aging neurons to beta amyloid neurotoxicity.

A growing body of evidence suggests that estrogen has beneficial effects on Alzheimer's disease. However, the mechanisms underlying estrogen's neuroprotective effects are not completely understood. In the present study, we analyzed first whether estrogen protects mature hippocampal neurons against fibrillar Abeta-induced neurotoxicity. 17alpha-Estradiol and 17beta-estradiol partially prevented neuronal death induced by fibrillar Abeta. Estrogen-induced neuroprotection correlated with the formation of a more dynamic microtubular system, including an increase in the pool of unstable microtubules and the expression of juvenile microtubule-associated proteins MAP2c and MAP1b. These results provide further evidence that experimental conditions capable of increasing the pool of unstable microtubules might render mature hippocampal neurons resistant to the degeneration caused by fibrillar Abeta deposits.

Membrane topology of a metabotropic glutamate receptor.

The metabotropic glutamate receptors (mGluRs) have been predicted to have a classical seven transmembrane domain structure similar to that seen for members of the G-protein-coupled receptor (GPCR) superfamily. However, the mGluRs (and other members of the family C GPCRs) show no sequence homology to the rhodopsin-like GPCRs, for which this seven transmembrane domain structure has been experimentally confirmed. Furthermore, several transmembrane domain prediction algorithms suggest that the mGluRs have a topology that is distinct from these receptors. In the present study, we set out to test whether mGluR5 has seven true transmembrane domains. Using a variety of approaches in both prokaryotic and eukaryotic systems, our data provide strong support for the proposed seven transmembrane domain model of mGluR5. We propose that this membrane topology can be extended to all members of the family C GPCRs.