A cortical circuit for gain control by behavioral state.

The brain's response to sensory input is strikingly modulated by behavioral state. Notably, the visual response of mouse primary visual cortex (V1) is enhanced by locomotion, a tractable and accessible example of a time-locked change in cortical state. The neural circuits that transmit behavioral state to sensory cortex to produce this modulation are unknown. In vivo calcium imaging of behaving animals revealed that locomotion activates vasoactive intestinal peptide (VIP)-positive neurons in mouse V1 independent of visual stimulation and largely through nicotinic inputs from basal forebrain. Optogenetic activation of VIP neurons increased V1 visual responses in stationary awake mice, artificially mimicking the effect of locomotion, and photolytic damage of VIP neurons abolished the enhancement of V1 responses by locomotion. These findings establish a cortical circuit for the enhancement of visual response by locomotion and provide a potential common circuit for the modulation of sensory processing by behavioral state.

Population encoding of stimulus features along the visual hierarchy.

The retina and primary visual cortex (V1) both exhibit diverse neural populations sensitive to diverse visual features. Yet it remains unclear how neural populations in each area partition stimulus space to span these features. One possibility is that neural populations are organized into discrete groups of neurons, with each group signaling a particular constellation of features. Alternatively, neurons could be continuously distributed across feature-encoding space. To distinguish these possibilities, we presented a battery of visual stimuli to the mouse retina and V1 while measuring neural responses with multi-electrode arrays. Using machine learning approaches, we developed a manifold embedding technique that captures how neural populations partition feature space and how visual responses correlate with physiological and anatomical properties of individual neurons. We show that retinal populations discretely encode features, while V1 populations provide a more continuous representation. Applying the same analysis approach to convolutional neural networks that model visual processing, we demonstrate that they partition features much more similarly to the retina, indicating they are more like big retinas than little brains.

The clustered gamma protocadherin PcdhγC4 isoform regulates cortical interneuron programmed cell death in the mouse cortex.

Cortical inhibitory interneurons (cINs) are born in the ventral forebrain and migrate into the cortex where they make connections with locally produced excitatory glutamatergic neurons. Cortical function critically depends on the number of cINs, which is also key to establishing the appropriate inhibitory/excitatory balance. The final number of cINs is determined during a postnatal period of programmed cell death (PCD) when ~40% of the young cINs are eliminated. Previous work shows that the loss of clustered gamma protocadherins (Pcdhgs), but not of genes in the Pcdha or Pcdhb clusters, dramatically increased BAX-dependent cIN PCD. Here, we show that PcdhγC4 is highly expressed in cINs of the mouse cortex and that this expression increases during PCD. The sole deletion of the PcdhγC4 isoform, but not of the other 21 isoforms in the Pcdhg gene cluster, increased cIN PCD. Viral expression of the PcdhγC4, in cIN lacking the function of the entire Pcdhg cluster, rescued most of these cells from cell death. We conclude that PcdhγC4 plays a critical role in regulating the survival of cINs during their normal period of PCD. This highlights how a single isoform of the Pcdhg cluster, which has been linked to human neurodevelopmental disorders, is essential to adjust cIN cell numbers during cortical development.

Production of brain-derived neurotrophic factor gates plasticity in developing visual cortex.

We have previously shown that recovery of visual responses to a deprived eye during the critical period in mouse primary visual cortex requires phosphorylation of the TrkB receptor for BDNF [M. Kaneko, J. L. Hanover, P. M. England, M. P. Stryker, Nat. Neurosci. 11, 497-504 (2008)]. We have now studied the temporal relationship between the production of mature BDNF and the recovery of visual responses under several different conditions. Visual cortical responses to an eye whose vision has been occluded for several days during the critical period and is then re-opened recover rapidly during binocular vision or much more slowly following reverse occlusion, when the previously intact fellow eye is occluded in a model of "patch therapy" for amblyopia. The time to recovery of visual responses differed by more than 18 h between these two procedures, but in each, the production of mature BDNF preceded the physiological recovery. These findings suggest that a spurt of BDNF production is permissive for the growth of connections serving the deprived eye to restore visual responses. Attenuation of recovery of deprived-eye responses by interference with TrkB receptor activation or reduction of BDNF production by interference with homeostatic synaptic scaling had effects consistent with this suggestion.

Aberrant cortical spine dynamics after concussive injury are reversed by integrated stress response inhibition.

Traumatic brain injury (TBI) is a leading cause of long-term neurological disability in the world and the strongest environmental risk factor for the development of dementia. Even mild TBI (resulting from concussive injuries) is associated with a greater than twofold increase in the risk of dementia onset. Little is known about the cellular mechanisms responsible for the progression of long-lasting cognitive deficits. The integrated stress response (ISR), a phylogenetically conserved pathway involved in the cellular response to stress, is activated after TBI, and inhibition of the ISR-even weeks after injury-can reverse behavioral and cognitive deficits. However, the cellular mechanisms by which ISR inhibition restores cognition are unknown. Here, we used longitudinal two-photon imaging in vivo after concussive injury in mice to study dendritic spine dynamics in the parietal cortex, a brain region involved in working memory. Concussive injury profoundly altered spine dynamics measured up to a month after injury. Strikingly, brief pharmacological treatment with the drug-like small-molecule ISR inhibitor ISRIB entirely reversed structural changes measured in the parietal cortex and the associated working memory deficits. Thus, both neural and cognitive consequences of concussive injury are mediated in part by activation of the ISR and can be corrected by its inhibition. These findings suggest that targeting ISR activation could serve as a promising approach to the clinical treatment of chronic cognitive deficits after TBI.

Stimulus-specific enhancement in mouse visual cortex requires GABA but not VIP-peptide release from VIP interneurons.

When adult mice are repeatedly exposed to a particular visual stimulus for as little as 1 h per day for several days while their visual cortex (V1) is in the high-gain state produced by locomotion, that specific stimulus elicits much stronger responses in V1 neurons for the following several weeks, even when measured in anesthetized animals. Such stimulus-specific enhancement (SSE) is not seen if locomotion is prevented. The effect of locomotion on cortical responses is mediated by vasoactive intestinal peptide (VIP) positive interneurons, which can release both the peptide and the inhibitory neurotransmitter GABA. Previous studies have examined the role of VIP-ergic interneurons, but none have distinguished the individual roles of peptide from GABA release. Here, we used genetic ablation to determine which of those molecules secreted by VIP-ergic neurons is responsible for SSE. SSE was not impaired by VIP deletion but was prevented by compromising release of GABA from VIP cells. This finding suggests that SSE may result from Hebbian mechanisms that remain present in adult V1.NEW & NOTEWORTHY Many neurons package and release a peptide along with a conventional neurotransmitter. The conventional view is that such peptides exert late, slow effects on plasticity. We studied a form of cortical plasticity that depends on the activity of neurons that express both vasoactive intestinal peptide (VIP) and the inhibitory neurotransmitter GABA. GABA release accounted for their action on plasticity, with no effect of deleting the peptide on this phenomenon.

Retinal input instructs alignment of visual topographic maps.

Sensory information is represented in the brain in the form of topographic maps, in which neighboring neurons respond to adjacent external stimuli. In the visual system, the superior colliculus receives topographic projections from the retina and primary visual cortex (V1) that are aligned. Alignment may be achieved through the use of a gradient of shared axon guidance molecules, or through a retinal-matching mechanism in which axons that monitor identical regions of visual space align. To distinguish between these possibilities, we take advantage of genetically engineered mice that we show have a duplicated functional retinocollicular map but only a single map in V1. Anatomical tracing revealed that the corticocollicular projection bifurcates to align with the duplicated retinocollicular map in a manner dependent on the normal pattern of spontaneous activity during development. These data suggest a general model in which convergent maps use coincident activity patterns to achieve alignment.

Experience-dependent structural plasticity at pre- and postsynaptic sites of layer 2/3 cells in developing visual cortex.

The developing brain can respond quickly to altered sensory experience by circuit reorganization. During a critical period in early life, neurons in the primary visual cortex rapidly lose responsiveness to an occluded eye and come to respond better to the open eye. While physiological and some of the molecular mechanisms of this process have been characterized, its structural basis, except for the well-known changes in the thalamocortical projection, remains obscure. To elucidate the relationship between synaptic remodeling and functional changes during this experience-dependent process, we used 2-photon microscopy to image synaptic structures of sparsely labeled layer 2/3 neurons in the binocular zone of mouse primary visual cortex. Anatomical changes at presynaptic and postsynaptic sites in mice undergoing monocular visual deprivation (MD) were compared to those in control mice with normal visual experience. We found that postsynaptic spines remodeled quickly in response to MD, with neurons more strongly dominated by the deprived eye losing more spines. These postsynaptic changes parallel changes in visual responses during MD and their recovery after restoration of binocular vision. In control animals with normal visual experience, the formation of presynaptic boutons increased during the critical period and then declined. MD affected bouton formation, but with a delay, blocking it after 3 d. These findings reveal intracortical anatomical changes in cellular layers of the cortex that can account for rapid activity-dependent plasticity.

Flow stimuli reveal ecologically appropriate responses in mouse visual cortex.

Assessments of the mouse visual system based on spatial-frequency analysis imply that its visual capacity is low, with few neurons responding to spatial frequencies greater than 0.5 cycles per degree. However, visually mediated behaviors, such as prey capture, suggest that the mouse visual system is more precise. We introduce a stimulus class-visual flow patterns-that is more like what the mouse would encounter in the natural world than are sine-wave gratings but is more tractable for analysis than are natural images. We used 128-site silicon microelectrodes to measure the simultaneous responses of single neurons in the primary visual cortex (V1) of alert mice. While holding temporal-frequency content fixed, we explored a class of drifting patterns of black or white dots that have energy only at higher spatial frequencies. These flow stimuli evoke strong visually mediated responses well beyond those predicted by spatial-frequency analysis. Flow responses predominate in higher spatial-frequency ranges (0.15-1.6 cycles per degree), many are orientation or direction selective, and flow responses of many neurons depend strongly on sign of contrast. Many cells exhibit distributed responses across our stimulus ensemble. Together, these results challenge conventional linear approaches to visual processing and expand our understanding of the mouse's visual capacity to behaviorally relevant ranges.

Transplanted Cells Are Essential for the Induction But Not the Expression of Cortical Plasticity.

Transplantation of even a small number of embryonic inhibitory neurons from the medial ganglionic eminence (MGE) into postnatal visual cortex makes it lose responsiveness to an eye deprived of vision when the transplanted neurons reach the age of the normal critical period of activity-dependent ocular dominance (OD) plasticity. The transplant might induce OD plasticity in the host circuitry or might instead construct a parallel circuit of its own to suppress cortical responses to the deprived eye. We transplanted MGE neurons expressing either archaerhodopsin or channelrhodopsin into the visual cortex of both male and female mice, closed one eyelid for 4-5 d, and, as expected, observed transplant-induced OD plasticity. This plasticity was evident even when the activity of the transplanted cells was suppressed or enhanced optogenetically, demonstrating that the plasticity was produced by changes in the host visual cortex.SIGNIFICANCE STATEMENT Interneuron transplantation into mouse V1 creates a window of heightened plasticity that is quantitatively and qualitatively similar to the normal critical period; that is, short-term occlusion of either eye markedly changes ocular dominance (OD). The underlying mechanism of this process is not known. Transplanted interneurons might either form a separate circuit to maintain the OD shift or might instead trigger changes in the host circuity. We designed experiments to distinguish the two hypotheses. Our findings suggest that while inhibition produced by the transplanted cells triggers this form of plasticity, the host circuity is entirely responsible for maintaining the OD shift.

Vesicular GABA Transporter Is Necessary for Transplant-Induced Critical Period Plasticity in Mouse Visual Cortex.

The maturation of GABAergic inhibitory circuits is necessary for the onset of the critical period for ocular dominance plasticity (ODP) in the postnatal visual cortex (Hensch, 2005; Espinosa and Stryker, 2012). When it is deficient, the critical period does not start. When inhibitory maturation or signaling is precocious, it induces a precocious critical period. Heterochronic transplantation of GABAergic interneuron precursors derived from the medial ganglionic eminence (MGE) can induce a second period of functional plasticity in the visual cortex (Southwell et al., 2010). Although the timing of MGE transplantation-induced plasticity is dictated by the maturation of the transplanted cells, its mechanisms remain largely unknown. Here, we sought to test the effect of blocking vesicular GABA loading and subsequent release by transplanted interneurons on the ability to migrate, integrate, and induce plasticity in the host circuitry. We show that MGE cells taken from male and female donors that lack vesicular GABA transporter (Vgat) expression disperse and differentiate into somatostatin- and parvalbumin-expressing interneurons upon heterochronic transplantation in the postnatal mouse cortex. Although transplanted Vgat mutant interneurons come to express mature interneuron markers and display electrophysiological properties similar to those of control cells, their morphology is significantly more complex. Significantly, Vgat mutant MGE transplants fail to induce ODP, demonstrating the pivotal role of vesicular GABAergic transmission for MGE transplantation-induced plasticity in the postnatal mouse visual cortex.SIGNIFICANCE STATEMENT Embryonic inhibitory neurons thrive when transplanted into postnatal brains, migrating and differentiating in the host as they would have done if left in the donor. Once integrated into the host, these new neurons can have profound effects. For example, in the visual cortex, such neurons induce a second critical period of activity-dependent plasticity when they reach the appropriate stage of development. The cellular mechanism by which these transplanted GABAergic interneurons induce plasticity is unknown. Here, we show that transplanted interneurons that are unable to fill synaptic vesicles with GABA migrate and integrate into the host circuit, but they do not induce a second period of plasticity. These data suggest a role for the vesicular GABA transporter in transplantation-mediated plasticity.

Locomotion Enhances Neural Encoding of Visual Stimuli in Mouse V1.

Neurons in mouse primary visual cortex (V1) are selective for particular properties of visual stimuli. Locomotion causes a change in cortical state that leaves their selectivity unchanged but strengthens their responses. Both locomotion and the change in cortical state are thought to be initiated by projections from the mesencephalic locomotor region, the latter through a disinhibitory circuit in V1. By recording simultaneously from a large number of single neurons in alert mice viewing moving gratings, we investigated the relationship between locomotion and the information contained within the neural population. We found that locomotion improved encoding of visual stimuli in V1 by two mechanisms. First, locomotion-induced increases in firing rates enhanced the mutual information between visual stimuli and single neuron responses over a fixed window of time. Second, stimulus discriminability was improved, even for fixed population firing rates, because of a decrease in noise correlations across the population. These two mechanisms contributed differently to improvements in discriminability across cortical layers, with changes in firing rates most important in the upper layers and changes in noise correlations most important in layer V. Together, these changes resulted in a threefold to fivefold reduction in the time needed to precisely encode grating direction and orientation. These results support the hypothesis that cortical state shifts during locomotion to accommodate an increased load on the visual system when mice are moving.SIGNIFICANCE STATEMENT This paper contains three novel findings about the representation of information in neurons within the primary visual cortex of the mouse. First, we show that locomotion reduces by at least a factor of 3 the time needed for information to accumulate in the visual cortex that allows the distinction of different visual stimuli. Second, we show that the effect of locomotion is to increase information in cells of all layers of the visual cortex. Third, we show that the means by which information is enhanced by locomotion differs between the upper layers, where the major effect is the increasing of firing rates, and in layer V, where the major effect is the reduction in noise correlations.

Locomotion Induces Stimulus-Specific Response Enhancement in Adult Visual Cortex.

The responses of neurons in the visual cortex (V1) of adult mammals have long been thought to be stable over long periods. Here, we investigated whether repeated exposure to specific stimuli would enhance V1 visual responses in mice using intrinsic signal imaging through the intact skull and two-photon imaging of calcium signals in single neurons. Mice ran on Styrofoam balls floating on air while viewing one of three different, high-contrast visual stimuli. V1 responses to the stimuli that were viewed by the animal were specifically enhanced, while responses to other stimuli were unaffected. Similar exposure in stationary mice or in mice in which NMDA receptors were partially blocked did not significantly enhance responses. These findings indicate that stimulus-specific plasticity in the adult visual cortex depends on concurrent locomotion, presumably as a result of the high-gain state of the visual cortex induced by locomotion.SIGNIFICANCE STATEMENT We report a rapid and persistent increase in visual cortical responses to visual stimuli presented during locomotion in intact mice. We first used a method that is completely noninvasive to image intrinsic signals through the intact skull. We then measured the same effects on single neurons using two-photon calcium imaging and found that the increase in response to a particular stimulus produced by locomotion depends on how well the neuron is initially driven by the stimulus. To our knowledge, this is the first time such enhancement has been described in single neurons or using noninvasive measurements.

Amblyopia: New molecular/pharmacological and environmental approaches.

Emerging technologies are now giving us unprecedented access to manipulate brain circuits, shedding new light on treatments for amblyopia. This research is identifying key circuit elements that control brain plasticity and highlight potential therapeutic targets to promote rewiring in the visual system during and beyond early life. Here, we explore how such recent advancements may guide future pharmacological, genetic, and behavioral approaches to treat amblyopia. We will discuss how animal research, which allows us to probe and tap into the underlying circuit and synaptic mechanisms, should best be used to guide therapeutic strategies. Uncovering cellular and molecular pathways that can be safely targeted to promote recovery may pave the way for effective new amblyopia treatments across the lifespan.

Development and long-term integration of MGE-lineage cortical interneurons in the heterochronic environment.

Interneuron precursors transplanted into visual cortex induce network plasticity during their heterochronic maturation. Such plasticity can have a significant impact on the function of the animal and is normally present only during a brief critical period in early postnatal development. Elucidating the synaptic and physiological properties of interneuron precursors as they mature is key to understanding how long-term circuit changes are induced by transplants. We studied the development of transplant-derived interneurons and compared it to endogenously developing interneurons (those that are born and develop in the same animal) at parallel developmental time points, using patch-clamp recordings in acute cortical slices. We found that transplant-derived interneurons develop into fast-spiking and non-fast-spiking neurons characteristic of the medial ganglionic eminence (MGE) lineage. Transplant-derived interneurons matured more rapidly than endogenously developing interneurons, as shown by more hyperpolarized membrane potentials, smaller input resistances, and narrower action potentials at a juvenile age. In addition, transplant-derived fast-spiking interneurons have more quickly saturating input-output relationships and lower maximal firing rates in adulthood, indicating a possible divergence in function. Transplant-derived interneurons both form inhibitory synapses onto host excitatory neurons and receive excitatory synapses from host pyramidal cells. Unitary connection properties are similar to those of host interneurons. These transplant-derived interneurons, however, were less densely functionally connected onto host pyramidal cells than were host interneurons and received fewer spontaneous excitatory inputs from host cells. These findings suggest that many physiological characteristics of interneurons are autonomously determined, while some factors impacting their circuit function may be influenced by the environment in which they develop.NEW & NOTEWORTHY Transplanting embryonic interneurons into older brains induces a period of plasticity in the recipient animal. We find that these interneurons develop typical fast-spiking and non-fast-spiking phenotypes by the end of adolescence. However, the input-output characteristics of transplant-derived neurons diverged from endogenously developing interneurons during adulthood, and they showed lower connection rates to local pyramidal cells at all time points. This suggests a unique and ongoing role of transplant-derived interneurons in host circuits, enabling interneuron transplant therapies.

Cortical plasticity induced by transplantation of embryonic somatostatin or parvalbumin interneurons.

GABAergic inhibition has been shown to play an important role in the opening of critical periods of brain plasticity. We recently have shown that transplantation of GABAergic precursors from the embryonic medial ganglionic eminence (MGE), the source of neocortical parvalbumin- (PV(+)) and somatostatin-expressing (SST(+)) interneurons, can induce a new period of ocular dominance plasticity (ODP) after the endogenous period has closed. Among the diverse subtypes of GABAergic interneurons PV(+) cells have been thought to play the crucial role in ODP. Here we have used MGE transplantation carrying a conditional allele of diphtheria toxin alpha subunit and cell-specific expression of Cre recombinase to deplete PV(+) or SST(+) interneurons selectively and to investigate the contributions of each of these types of interneurons to ODP. As expected, robust plasticity was observed in transplants containing PV(+) cells but in which the majority of SST(+) interneurons were depleted. Surprisingly, transplants in which the majority of PV(+) cells were depleted induced plasticity as effectively as those containing PV(+) cells. In contrast, depleting both cell types blocked induction of plasticity. These findings reveal that PV(+) cells do not play an exclusive role in ODP; SST(+) interneurons also can drive cortical plasticity and contribute to the reshaping of neural networks. The ability of both PV(+) and SST(+) interneurons to induce de novo cortical plasticity could help develop new therapeutic approaches for brain repair.

Activity-dependent recruitment of inhibition and excitation in the awake mammalian cortex during electrical stimulation.

Electrical stimulation is an effective tool for mapping and altering brain connectivity, with applications ranging from treating pharmacology-resistant neurological disorders to providing sensory feedback for neural prostheses. Paramount to the success of these applications is the ability to manipulate electrical currents to precisely control evoked neural activity patterns. However, little is known about stimulation-evoked responses in inhibitory neurons nor how stimulation-evoked activity patterns depend on ongoing neural activity. In this study, we used 2-photon imaging and cell-type specific labeling to measure single-cell responses of excitatory and inhibitory neurons to electrical stimuli in the visual cortex of awake mice. Our data revealed strong interactions between electrical stimulation and pre-stimulus activity of single neurons in awake animals and distinct recruitment and response patterns for excitatory and inhibitory neurons. This work demonstrates the importance of cell-type-specific labeling of neurons in future studies.

Dendritic BDNF synthesis is required for late-phase spine maturation and recovery of cortical responses following sensory deprivation.

Sensory experience in early postnatal life shapes neuronal connections in the brain. Here we report that the local synthesis of brain-derived neurotrophic factor (BDNF) in dendrites plays an important role in this process. We found that dendritic spines of layer 2/3 pyramidal neurons of the visual cortex in mutant mice lacking dendritic Bdnf mRNA and thus local BDNF synthesis were normal at 3 weeks of age, but thinner, longer, and more closely spaced (morphological features of immaturity) at 4 months of age than in wild-type (WT) littermates. Layer 2/3 of the visual cortex in these mutant animals also had fewer GABAergic presynaptic terminals at both ages. The overall size and shape of dendritic arbors were, however, similar in mutant and WT mice at both ages. By using optical imaging of intrinsic signals and single-unit recordings, we found that mutant animals failed to recover cortical responsiveness following monocular deprivation (MD) during the critical period, although they displayed normally the competitive loss of responsiveness to an eye briefly deprived of vision. Furthermore, MD still induced a loss of responsiveness to the closed eye in adult mutant mice, but not in adult WT mice. These results indicate that dendritic BDNF synthesis is required for spine pruning, late-phase spine maturation, and recovery of cortical responsiveness following sensory deprivation. They also suggest that maturation of dendritic spines is required for the maintenance of cortical responsiveness following sensory deprivation in adulthood.

Genomic imprinting of experience-dependent cortical plasticity by the ubiquitin ligase gene Ube3a.

A defect in the maternal copy of a ubiqutin ligase gene Ube3a can produce a neurodevelopmental defect in human children known as Angelman syndrome. We investigated the role of the maternally expressed Ube3a gene in experience-dependent development and plasticity of the mouse visual system. As demonstrated by optical imaging, rapid ocular dominance (OD) plasticity after brief monocular deprivation (MD) was severely impaired during the critical period (CP) in the visual cortex (VC) of Ube3a maternal-deficient (m-/p+) mice. Prolonged MD elicited significant plasticity in m-/p+ mice that never matched the level seen in control animals. In older animals after the CP, 7-day MD elicited mild OD shifts in both control and m-/p+ mice; however, the OD shifts in m-/p+ mice lacked the strengthening of visual responses to the two eyes characteristic of normal adult plasticity. Anatomic effects of the maternal deficiency include reduced spine density on basal, but not apical, dendrites of pyramidal neurons in the binocular region of the VC. Imprinting of Ube3a expression was not fully established in the early postnatal period, consistent with the normal development of cortical retinotopy and visual acuity that we observed in m-/p+ mice, but was fully established by the onset of the CP. These results demonstrate that paternal and maternal genomes are not functionally equivalent for cortical plasticity, and that maternally expressed Ube3a is required for normal experience-dependent modification of cortical circuits during and after the CP.

Constitutively active H-ras accelerates multiple forms of plasticity in developing visual cortex.

Experience-dependent cortical plasticity has been studied by using loss-of-function methods. Here, we take the complementary approach of using a genetic gain-of-function that enhances plasticity. We show that a constitutively active form of H-ras (H-ras(G12V)), expressed presynaptically at excitatory synapses in mice, accelerates and enhances multiple, mechanistically distinct forms of plasticity in the developing visual cortex. In vivo, H-ras(G12V) not only increased the rate of ocular dominance change in response to monocular deprivation (MD), but also accelerated recovery from deprivation by reverse occlusion. In vitro, H-ras(G12V) expression decreased baseline presynaptic release probability and enhanced presynaptically expressed long-term potentiation (LTP). H-ras(G12V) expression also accelerated the increase following MD in the frequency of miniature excitatory potentials, mirroring accelerated plasticity in vivo. These findings demonstrate accelerated neocortical plasticity, which offers an avenue toward future therapies for many neurological and neuropsychiatric disorders.