AC-1 and synaptic development.

<p>Across many developing brain structures, axons initially grow toward, and synapse exuberantly with, target neurons before the later removal of excess inputs. In many cases, this input pruning leads to a remarkable specificity, where a single target is innervated by only one axon. This phenomenon has been observed at the neuromuscular junction, the climbing fibre to Purkinje cell synapse in the cerebellum, and also at relay synapses in the thalamus.</p

The many layers of specification and plasticity in the neocortex.

<p>In this issue of Neuron, Li et al. (2013) show that transgenically eliminating thalamocortical neurotransmission disrupts the formation of barrel columns in the somatosensory cortex and cortical lamination, providing evidence for the importance of extrinsic activity-dependent factors in cortical development.</p

Synaptic lability after experience-dependent plasticity is not mediated by calcium-permeable AMPARs.

Activity- or experience-dependent plasticity has been associated with the trafficking of calcium-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (CP-AMPARs) in a number of experimental systems. In some cases it has been shown that CP-AMPARs are only transiently present and can be removed in an activity-dependent manner. Here we test the hypothesis that the presence of CP-AMPARs confers instability onto recently potentiated synapses. Previously we have shown that altered sensory input (single-whisker experience; SWE) strengthens layer 4-2/3 excitatory synapses in mouse primary somatosensory cortex, in part by the trafficking of CP-AMPARs. Both in vivo and in vitro, this potentiation is labile, and can be depressed by N-Methyl-D-aspartate receptor (NMDAR)-activation. In the present study, the role of CP-AMPARs in conferring this synaptic instability after in vivo potentiation was evaluated. We develop an assay to depress the strength of individual layer 4-2/3 excitatory synapses after SWE, using a strontium (Sr(++))-replaced artificial cerebrospinal fluid (ACSF) solution (Sr-depression). This method allows disambiguation of changes in quantal amplitude (a post-synaptic measure) from changes in event frequency (typically a presynaptic phenomenon). Presynaptic stimulation paired with post-synaptic depolarization in Sr(++) lead to a rapid and significant reduction in EPSC amplitude with no change in event frequency. Sr-depression at recently potentiated synapses required NMDARs, but could still occur when CP-AMPARs were not present. As a further dissociation between the presence of CP-AMPARs and Sr-depression, CP-AMPARs could be detected in some cells from control, whisker-intact animals, although Sr-depression was never observed. Taken together, our findings suggest that CP-AMPARs are neither sufficient nor necessary for synaptic depression after in vivo plasticity in somatosensory cortex. This article is part of a Special Issue entitled "Calcium permeable AMPARs in synaptic plasticity and disease."</p

Pathway-specific trafficking of native AMPARs by in vivo experience.

An accumulating body of evidence supports the notion that trafficking of AMPA receptors (AMPARs) underlies strengthening of glutamatergic synapses and, in turn, learning and memory in the behaving animal. However, without exception, these experiments have been performed using artificial stimulation protocols, cultured neurons, or viral-overexpression systems that can significantly alter the normal function of AMPARs. Using a single-whisker experience protocol that significantly enhances neuronal responses in vivo, we have targeted neurons in and around the spared whisker column of fosGFP transgenic mice for whole-cell recording. Here we show that in vivo experience induces the pathway-specific strengthening of neocortical excitatory synapses. By assaying AMPARs for rectification and sensitivity to joro spider toxin, we find that in vivo experience induces the delivery of native GluR2-lacking receptors at spared, but not deprived, inputs. These data demonstrate that pathway-specific trafficking of GluR2-lacking AMPARs is a normal feature of synaptic strengthening that underlies experience-dependent plasticity in the behaving animal.</p

The barista on the bus: cellular and synaptic mechanisms for visual recognition memory.

Our ability to recognize that something is familiar, often referred to as visual recognition memory, has been correlated with a reduction in neural activity in the perirhinal cortex. In this issue of Neuron, Griffiths et al. now provide evidence that this form of memory requires AMPA receptor endocytosis and long-term depression of excitatory synapses in this brain area.</p

Experimental evidence for sparse firing in the neocortex.

<p>The advent of unbiased recording and imaging techniques to evaluate firing activity across neocortical neurons has revealed substantial heterogeneity in response properties in vivo, and that a minority of neurons are responsible for the majority of spikes. Despite the computational advantages to sparsely firing populations, experimental data defining the fraction of responsive neurons and the range of firing rates have not been synthesized. Here we review data about the distribution of activity across neuronal populations in primary sensory cortex. Overall, the firing output of granular and infragranular layers is highest. Although subthreshold activity across supragranular neurons is decidedly non-sparse, spikes are much less frequent and some cells are silent. Superficial layers of the cortex may employ specific cell and circuit mechanisms to increase sparseness.</p

A seizure-induced gain-of-function in BK channels is associated with elevated firing activity in neocortical pyramidal neurons.

A heritable gain-of-function in BK channel activity has been associated with spontaneous seizures in both rodents and humans. We find that chemoconvulsant-induced seizures induce a gain-of-function in BK channel current that is associated with abnormal, elevated network excitability. Action potential half-width, evoked firing rate, and spontaneous network activity in vitro were all altered 24 h following picrotoxin-induced seizures in layer 2/3 pyramidal cells in the neocortex of young mice (P13-P16). Action potential half-width and firing output could be normalized to control values by application of BK channel antagonists in vitro. Thus, both inherited and acquired BK channel gain-of-functions are linked to abnormal excitability. Because BK channel antagonists can reduce elevated firing activity in neocortical neurons, BK channels might serve as a new target for anticonvulsant therapy.</p

Ongoing in vivo experience triggers synaptic metaplasticity in the neocortex.

In vivo experience can occlude subsequent induction of long-term potentiation and enhance long-term depression of synaptic responses. Although a reduced capacity for synaptic strengthening may function to prevent excessive excitation, such an effect paradoxically implies that continued experience or training should not improve and may even degrade neural representations. In mice, we examined the effect of ongoing whisker stimulation on synaptic strengthening at layer 4-2/3 synapses in the barrel cortex. Although N-methyl-d-aspartate receptors were required to initiate strengthening, they subsequently suppressed further potentiation at these synapses in vitro and in vivo. Despite this transition, synaptic strengthening continued with additional sensory activity but instead required the activation of metabotropic glutamate receptors, suggesting a mechanism by which continued experience can result in increasing synaptic strength over time.</p

A comparative genomics approach to identifying the plasticity transcriptome.

BACKGROUND: Neuronal activity regulates gene expression to control learning and memory, homeostasis of neuronal function, and pathological disease states such as epilepsy. A great deal of experimental evidence supports the involvement of two particular transcription factors in shaping the genomic response to neuronal activity and mediating plasticity: CREB and zif268 (egr-1, krox24, NGFI-A). The gene targets of these two transcription factors are of considerable interest, since they may help develop hypotheses about how neural activity is coupled to changes in neural function. RESULTS: We have developed a computational approach for identifying binding sites for these transcription factors within the promoter regions of annotated genes in the mouse, rat, and human genomes. By combining a robust search algorithm to identify discrete binding sites, a comparison of targets across species, and an analysis of binding site locations within promoter regions, we have defined a group of candidate genes that are strong CREB- or zif268 targets and are thus regulated by neural activity. Our analysis revealed that CREB and zif268 share a disproportionate number of targets in common and that these common targets are dominated by transcription factors. CONCLUSION: These observations may enable a more detailed understanding of the regulatory networks that are induced by neural activity and contribute to the plasticity transcriptome. The target genes identified in this study will be a valuable resource for investigators who hope to define the functions of specific genes that underlie activity-dependent changes in neuronal properties.</p

Ipsilateral whiskers suppress experience-dependent plasticity in the barrel cortex.

Each cerebral hemisphere processes sensory input from both sides of the body, but the impact of this convergence on shaping and modifying receptive field properties remains controversial. Here we investigated the effect of chronic deprivation of ipsilateral sensory whiskers on receptive field plasticity in primary somatosensory cortex. In the absence of ipsilateral whiskers, cortical receptive fields were significantly larger than control after 1 week. Removal of all but a single whisker from one side of the face [single-whisker experience (SWE)] has been shown to result in the expansion of the cortical area responding to the spared whisker. We compared the effects of SWE in the presence (SWE-unilateral) and absence (SWE-bilateral) of ipsilateral whiskers. SWE-bilateral deprivation results in a significant increase in neuronal responses to spared whisker stimulation both in its cognate barrel column and in adjacent, surrounding barrel columns compared with control and SWE-unilateral deprived animals. Surround receptive fields in deprived columns were maintained in SWE-bilateral treated animals but depressed in SWE-unilateral animals. The increase in spared whisker responses was progressive with longer deprivation periods. These data show that ipsilateral whiskers can constrain receptive field size in the barrel cortex.</p