Metabotropic glutamate receptor signaling is required for NMDA receptor-dependent ocular dominance plasticity and LTD in visual cortex

A feature of early postnatal neocortical development is a transient peak in signaling via metabotropic glutamate receptor 5 (mGluR5). In visual cortex, this change coincides with increased sensitivity of excitatory synapses to monocular deprivation (MD). However, loss of visual responsiveness after MD occurs via mechanisms revealed by the study of long-term depression (LTD) of synaptic transmission, which in layer 4 is induced by acute activation of NMDA receptors (NMDARs) rather than mGluR5. Here we report that chronic postnatal down-regulation of mGluR5 signaling produces coordinated impairments in both NMDAR-dependent LTD in vitro and ocular dominance plasticity in vivo. The data suggest that ongoing mGluR5 signaling during a critical period of postnatal development establishes the biochemical conditions that are permissive for activity-dependent sculpting of excitatory synapses via the mechanism of NMDAR-dependent LTD.Temporary monocular deprivation (MD) sets in motion synaptic changes in visual cortex that result in impaired vision through the deprived eye. The primary cause of visual impairment is depression of excitatory thalamocortical synaptic transmission in layer 4 of visual cortex (1–3). The study of long-term depression (LTD) of synapses, elicited in vitro by electrical or chemical stimulation, has revealed many of the mechanisms involved in deprived-eye depression (4). In slices of visual cortex, LTD in layer 4 is induced by NMDA receptor (NMDAR) activation and expressed by posttranslational modification and internalization of AMPA receptors (AMPARs) (5, 6). MD induces identical NMDAR-dependent changes in AMPARs, and synaptic depression induced by deprivation in vivo occludes LTD in visual cortex ex vivo (6–8). Manipulations of NMDARs and AMPAR trafficking that interfere with LTD also prevent the effects of MD (7, 9–11).Although NMDAR-dependent LTD is widely expressed in the brain (12, 13), it is now understood that different circuits use different mechanisms for long-term homosynaptic depression (14). For example, in the CA1 region of hippocampus, synaptic activation of either NMDARs or metabotropic glutamate receptor 5 (mGluR5) induces LTD. In both cases, depression is expressed postsynaptically as a reduction in AMPARs, but these forms of LTD are not mutually occluding and have distinct signaling requirements (15). A defining feature of mGluR5-dependent postsynaptic LTD in CA1 is a requirement for the immediate translation of synaptic mRNAs (16). In visual cortex, there is evidence that induction of LTD in layers 2–4 requires NMDAR activation, whereas induction of LTD in layer 6 requires activation of mGluR5 (17, 18).The hypothesis that mGluRs, in addition to NMDARs, play a key role in visual cortical plasticity can be traced back more than 25 y to observations that glutamate-stimulated phosphoinositide turnover, mediated in visual cortex by mGluR5 coupled to phospholipase C, is elevated during the postnatal period of heightened sensitivity to MD (19). Early attempts to test this hypothesis were inconclusive owing to the use of weak and nonselective orthosteric compounds (20–22); however, subsequent experiments did confirm that NMDAR-dependent LTD occurs normally in layers 2/3 of visual cortex in Grm5 knockout mice (23).The idea that mGluR5 is critically involved in visual cortical plasticity in vivo was rekindled with the finding that deprived-eye depression fails to occur in layer 4 of Grm5^+/− mutant mice (24). This finding was unexpected because, as reviewed above, a considerable body of evidence has implicated the mechanism of NMDAR-dependent LTD in deprived-eye depression. In the present study, we reexamined the role of mGluR5 in LTD and ocular dominance plasticity in layer 4, using the Grm5^+/− mouse and a highly specific negative allosteric modulator, 2-chloro-4-((2,5-dimethyl-1-(4-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)ethynyl)pyridine (CTEP), that has proven suitable for chronic inhibition of mGluR5 (25, 26). Our data show that NMDAR-dependent LTD and deprived-eye depression in layer 4 require mGluR5 signaling during postnatal development.     

Visual responses in adult cat visual cortex depend on N-methyl-D-aspartate receptors.

We have investigated the role of the N-methyl-D-aspartate (NMDA) receptor, a subtype of glutamate receptor, in the responses of cells in adult cat visual cortex. After intracortical infusion of the NMDA receptor antagonist DL-2-amino-5-phosphonovalerate (DL-APV) for one day, iontophoretic responses to NMDA, to kainate, and to quisqualate revealed a receptor blockade specific to NMDA receptors and extending several millimeters from the cannula. In this region, neuronal responses to visual stimulation were profoundly suppressed, in a manner strongly correlated with the degree of NMDA receptor blockade. Neither NMDA receptor blockade nor activity suppression was caused by the inactive stereoisomer L-APV. Hence, we conclude that NMDA receptors make a major contribution to normal excitatory transmission in adult visual cortex.     

Homeostatic plasticity mechanisms are required for juvenile, but not adult, ocular dominance plasticity

Ocular dominance (OD) plasticity in the visual cortex is a classic model system for understanding developmental plasticity, but the visual cortex also shows plasticity in adulthood. Whether the plasticity mechanisms are similar or different at the two ages is not clear. Several plasticity mechanisms operate during development, including homeostatic plasticity, which acts to maintain the total excitatory drive to a neuron. In agreement with this idea, we found that an often-studied substrain of C57BL/6 mice, C57BL/6JOlaHsd (6JOla), lacks both the homeostatic component of OD plasticity as assessed by intrinsic signal imaging and synaptic scaling of mEPSC amplitudes after a short period of dark exposure during the critical period, whereas another substrain, C57BL/6J (6J), exhibits both plasticity processes. However, in adult mice, OD plasticity was identical in the 6JOla and 6J substrains, suggesting that adult plasticity occurs by a different mechanism. Consistent with this interpretation, adult OD plasticity was normal in TNFα knockout mice, which are known to lack juvenile synaptic scaling and the homeostatic component of OD plasticity, but was absent in adult α-calcium/calmodulin-dependent protein kinase II;T286A (αCaMKII(T286A)) mice, which have a point mutation that prevents autophosphorylation of αCaMKII. We conclude that increased responsiveness to open-eye stimulation after monocular deprivation during the critical period is a homeostatic process that depends mechanistically on synaptic scaling during the critical period, whereas in adult mice it is mediated by a different mechanism that requires αCaMKII autophosphorylation. Thus, our study reveals a transition between homeostatic and long-term potentiation-like plasticity mechanisms with increasing age.     

Experience-dependent plasticity in adult rat barrel cortex.

This study tested the hypothesis that the receptive fields (RFs) of neurons in the adult sensory cortex are shaped by the recent history of sensory experience. Sensory experience was altered by a brief period of "whisker pairing": whiskers D2 and either D1 or D3 were left intact, while all other whiskers on the right side of the face were trimmed close to the fur. The animals were anesthetized 64-66 h later and the responses of single neurons in contralateral cortical barrel D2 to stimulation of whisker D2 (the center RF) and the four neighboring whiskers (D1, D3, C2, and E2; the excitatory surround RF) were measured. Data from 79 cells in four rats with whiskers paired were compared to data from 52 cells in four rats with untrimmed whiskers (control cases). During the period of whisker pairing, the RFs of cells in barrel D2 changed in three ways: (i) the response to the center RF, whisker D2, increased by 39%, (ii) the response to the paired surround RF whisker increased by 85-100%, and (iii) the response to all clipped (unpaired) surround RF whiskers decreased by 9-42%. In the control condition, the response of barrel D2 cells to the two neighboring whiskers, D1 and D3, was equal. After whisker pairing, the response to the paired neighbor of D2 was more than twice as large as the response to the cut neighbor of D2. These findings indicate that a brief change in the pattern of sensory activity can alter the configuration of cortical RFs, even in adult animals.     

Essential role for a long-term depression mechanism in ocular dominance plasticity

The classic example of experience-dependent cortical plasticity is the ocular dominance (OD) shift in visual cortex after monocular deprivation (MD). The experimental model of homosynaptic long-term depression (LTD) was originally introduced to study the mechanisms that could account for deprivation-induced loss of visual responsiveness. One established LTD mechanism is a loss of sensitivity to the neurotransmitter glutamate caused by internalization of postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs). Although it has been shown that MD similarly causes a loss of AMPARs from visual cortical synapses, the contribution of this change to the OD shift has not been established. Using an herpes simplex virus (HSV) vector, we expressed in visual cortical neurons a peptide (G2CT) designed to block AMPAR internalization by hindering the association of the C-terminal tail of the AMPAR GluR2 subunit with the AP2 clathrin adaptor complex. We found that G2CT expression interferes with NMDA receptor (NMDAR)-dependent AMPAR endocytosis and LTD, without affecting baseline synaptic transmission. When expressed in vivo, G2CT completely blocked the OD shift and depression of deprived-eye responses after MD without affecting baseline visual responsiveness or experience-dependent response potentiation in layer 4 of visual cortex. These data suggest that AMPAR internalization is essential for the loss of synaptic strength caused by sensory deprivation in visual cortex.     

Nerve growth factor-induced synaptogenesis and hypertrophy of cortical cholinergic terminals.

In this study light and EM quantitative analysis were used to examine whether exogenous nerve growth factor (NGF) could affect terminal fields and synaptic connections in the adult rat brain in vivo. Adult rats received, immediately after unilateral decortication, 2.5S NGF (12 micrograms/day) or vehicle intracerebroventricularly for 7 days. Thirty days after the lesion cholinergic fiber length was quantified, using image analysis, in the remaining cortical area adjacent to the lesion site in each animal. Rats that had received vehicle showed a significantly reduced cortical choline acetyl-transferase-immunoreactive fiber network in the remaining cortex when compared with control animals. By contrast, the network in lesioned rats that had received 2.5S NGF was not different from control animals. Furthermore, the number of cortical choline acetyltransferase-immunoreactive varicosities, which decreased in vehicle-treated lesioned rats, significantly increased above control in lesioned rats that had received 2.5S NGF. At the ultrastructural level, 30 days after the lesion, animals that had received vehicle showed shrunken cholinergic boutons in cortical layer V and fewer synapses compared with control animals. Exogenous NGF, administered to lesioned rats, increased to supernormal levels both size of cholinergic boutons and number of synaptic contacts. These parameters were unaltered in unlesioned rats treated with NGF. This study demonstrates that exogenous NGF can cause significant compensatory changes in terminal fields and synaptic connections in the adult fully differentiated central nervous system.     

Order-sensitive plasticity in adult primary auditory cortex

The neural response to a stimulus presented as part of a rapid sequence is often quite different from the response to the same stimulus presented in isolation. In primary auditory cortex (A1), although the most common effect of preceding stimuli is inhibitory, most neurons can also exhibit response facilitation if the appropriate spectral and temporal separation of sequence elements is presented. In this study, we investigated whether A1 neurons in adult animals can develop context-dependent facilitation to a novel acoustic sequence. After repeatedly pairing electrical stimulation of the basal forebrain with a three-element sequence (high frequency tone--low frequency tone-- noise burst), 25% of A1 neurons exhibited facilitation to the low tone when preceded by the high tone, compared with only 5% in controls. In contrast, there was no increase in the percent of sites that showed facilitation for the reversed tone order (low preceding high). Nearly 60% of sites exhibited a facilitated response to the noise burst when preceded by the two tones. Although facilitation was greatest in response to the paired sequence, facilitation also generalized to related sequences that were either temporally distorted or missing one of the tones. Pairing basal forebrain stimulation with the acoustic sequence also caused a decrease in the time to peak response and an increase in population discharge synchrony, which was not seen after pairing simple tones, tone trains, or broadband stimuli. These results indicate that context-dependent facilitation and response synchronization can be substantially altered in an experience-dependent fashion and provide a potential mechanism for learning spectrotemporal patterns.     

Mechanisms underlying rapid experience-dependent plasticity in the human visual cortex.

Visual deprivation induces a rapid increase in visual cortex excitability that may result in better consolidation of spatial memory in animals and in lower visual recognition thresholds in humans. gamma-Aminobutyric acid (GABA)ergic, N-methyl-d-aspartate (NMDA), and cholinergic receptors are thought to be involved in visual cortex plasticity in animal studies. Here, we used a pharmacological approach and found that lorazepam (which enhances GABA(A) receptor function by acting as a positive allosteric modulator), dextrometorphan (NMDA receptor antagonist), and scopolamine (muscarinic receptor antagonist) blocked rapid plastic changes associated with light deprivation. These findings suggest the involvement of GABA, NMDA, and cholinergic receptors in rapid experience-dependent plasticity in the human visual cortex.     

Dynamic changes in receptive-field size in cat primary visual cortex.

Immediately after focal retinal lesions, receptive fields (RFs) in primary visual cortex expand considerably, even when the retinal damage is limited to the photoreceptor layer. The time course of these changes suggests that mere lack of stimulation in the vicinity of the RF accompanied by stimulation in the surrounding region causes the RF expansion. While recording from single cells in cat area 17, we simulated this pattern of stimulation with a pattern of moving lines in the visual field, masking out an area covering the RF of the recorded cell, thereby producing an "artificial scotoma." Over approximately 10 min this masking resulted in a 5-fold average expansion in RF area. Stimulating the RF center caused the field to collapse in size, returning to near its original extent; reconditioning with the masked stimulus led to RF reexpansion. Stimulation in the surrounding region was required for the RF expansion to occur--little expansion was seen during exposure to a blank screen. We propose that the expansion may account for visual illusions, such as perceptual fill-in of stabilized images and illusory contours and may constitute the prodrome of altered cortical topography after retinal lesions. These findings support the idea that even in adult animals RFs are dynamic, capable of being altered by the sensory context.     

Brief visual experience induces immediate early gene expression in the cat visual cortex.

Brief visual experience causes rapid physiological changes in the visual cortex during early postnatal development. A possible mediator of these effects is the immediate early genes whose protein products are involved in the rapid response of neurons to transsynaptic stimulation. Here we report evidence that the levels of immediate early gene mRNAs in the visual cortex can be altered by manipulating the visual environment. Specifically, we find that brief (1 h) visual experience in dark-reared cats causes dramatic transient inductions of egr1, c-fos, and junB mRNAs in the visual cortex but not in the frontal cortex. Levels of c-jun and c-myc mRNAs are unaffected. These results suggest that select combinatorial interactions of immediate early gene proteins are an important step in the cascade of events through which visually elicited activity controls visual cortical development.     

Lesion-induced plasticity in the second somatosensory cortex of adult macaques.

We have reported that elimination of the representation of any body part in the primary (i.e., postcentral) somatosensory cortex of the adult macaque selectively eliminates the representation of that same body part in the second somatosensory area SII. We now report that, although removal of the entire postcentral hand representation does indeed leave the SII hand representation unresponsive to somatic stimulation initially, 6-8 weeks later this cortex is no longer silent. Instead, most or all of the region that had been vacated by the hand representation is now found to be occupied by an expanded foot representation. This massive somatotopic reorganization, involving more than half the areal extent of SII, exceeds that previously observed in the postcentral cortex after peripheral nerve damage and may reflect a greater capacity for reorganizational changes in higher order than in primary sensory cortical areas.     

Stimulus-specific neuronal oscillations in orientation columns of cat visual cortex.

In areas 17 and 18 of the cat visual cortex the firing probability of neurons, in response to the presentation of optimally aligned light bars within their receptive field, oscillates with a peak frequency near 40 Hz. The neuronal firing pattern is tightly correlated with the phase and amplitude of an oscillatory local field potential recorded through the same electrode. The amplitude of the local field-potential oscillations are maximal in response to stimuli that match the orientation and direction preference of the local cluster of neurons. Single and multiunit recordings from the dorsal lateral geniculate nucleus of the thalamus showed no evidence of oscillations of the neuronal firing probability in the range of 20-70 Hz. The results demonstrate that local neuronal populations in the visual cortex engage in stimulus-specific synchronous oscillations resulting from an intracortical mechanism. The oscillatory responses may provide a general mechanism by which activity patterns in spatially separate regions of the cortex are temporally coordinated.     

Environmental enrichment extends ocular dominance plasticity into adulthood and protects from stroke-induced impairments of plasticity

Ocular dominance (OD) plasticity in mouse primary visual cortex (V1) declines during postnatal development and is absent beyond postnatal day 110 if mice are raised in standard cages (SCs). An enriched environment (EE) promotes OD plasticity in adult rats. Here, we explored cellular mechanisms of EE in mouse V1 and the therapeutic potential of EE to prevent impairments of plasticity after a cortical stroke. Using in vivo optical imaging, we observed that monocular deprivation in adult EE mice (i) caused a very strong OD plasticity previously only observed in 4-wk-old animals, (ii) restored already lost OD plasticity in adult SC-raised mice, and (iii) preserved OD plasticity after a stroke in the primary somatosensory cortex. Using patch-clamp electrophysiology in vitro, we also show that (iv) local inhibition was significantly reduced in V1 slices of adult EE mice and (v) the GABA/AMPA ratio was like that in 4-wk-old SC-raised animals. These observations were corroborated by in vivo analyses showing that diazepam treatment significantly reduced the OD shift of EE mice after monocular deprivation. Taken together, EE extended the sensitive phase for OD plasticity into late adulthood, rejuvenated V1 after 4 mo of SC-rearing, and protected adult mice from stroke-induced impairments of cortical plasticity. The EE effect was mediated most likely by preserving low juvenile levels of inhibition into adulthood, which potentially promoted adaptive changes in cortical circuits.Ocular dominance (OD) plasticity induced by monocular deprivation (MD) is one of the best studied models of experience-dependent plasticity in the mammalian cortex (1, 2). OD plasticity in primary visual cortex (V1) of C57BL/6J mice is maximal at 4 wk of age, declines after 2–3 mo, and is absent beyond postnatal day 110 (PD110) if animals are raised in standard cages (SCs) (3–6). In 4-wk-old mice, 4 d of MD are sufficient to induce an OD shift to the open eye; therefore, neurons in the binocular V1, which are usually dominated by the contralateral eye in rodents (3, 7), become activated more equally by both eyes (5, 8). This juvenile OD shift is predominantly mediated by a decrease in the visual cortical responses to the deprived eye (1, 9–11), whereas significant OD shifts in older animals up to PD110 need 7 d of MD and are mediated primarily by increased open-eye responses in V1. Raising animals in an enriched environment (EE) gives them the opportunity of enhanced physical, social, and cognitive stimulation and influences brain physiology and behavior in many ways (12, 13). It has been shown previously that EE enhances visual system development in rats (14) and mice (15–17), increases levels of the brain-derived neurotrophic factor and serotonin (18), reduces both extracellular GABA levels (18, 19) and the density of ECM perineuronal nets (PNNs) (19), and promotes OD plasticity in adult and aging rats (18–21). Here, we explored cellular mechanisms of EE in V1 of mice and the therapeutic potential of EE to prevent impairments of plasticity after a cortical stroke. Furthermore, we studied whether EE would prolong the sensitive phase for OD plasticity into adulthood and also restore this form of plasticity in mice that were raised in SC until PD110 (i.e., in animals that were already beyond their sensitive phase for OD plasticity). Despite pharmacological detection of in vivo GABA levels, suggesting that EE reduces intracortical inhibition, direct electrophysiological evidence is still missing. We therefore recorded GABA, AMPA, and NMDA currents in slices from EE- and SC-raised mice and also tested the efficacy of diazepam injections to abolish OD plasticity of EE mice in vivo. Finally, we studied whether raising mice in EE would protect them from lesion-induced impairments of OD plasticity. Our results show that raising mice in EE preserved OD plasticity into late adulthood rejuvenated the brain after 3 mo of SC-rearing, and protected adult mice from stroke-induced impairments of cortical plasticity. Our electrophysiological measurements and diazepam treatment indicate that the plasticity-promoting effect of EE was primarily mediated by reduced intracortical inhibition compared with SC-raised mice. These results suggest EE as a preventive intervention to enhance and preserve plasticity in adulthood and after a cortical lesion.     

Delayed plasticity of inhibitory neurons in developing visual cortex

During postnatal development, altered sensory experience triggers the rapid reorganization of neuronal responses and connections in sensory neocortex. This experience-dependent plasticity is disrupted by reductions of intracortical inhibition. Little is known about how the responses of inhibitory cells themselves change during plasticity. We investigated the time course of inhibitory cell plasticity in mouse primary visual cortex by using functional two-photon microscopy with single-cell resolution and genetic identification of cell type. Initially, local inhibitory and excitatory cells had similar binocular visual response properties, both favoring the contralateral eye. After 2 days of monocular visual deprivation, excitatory cell responses shifted to favor the open eye, whereas inhibitory cells continued to respond more strongly to the deprived eye. By 4 days of deprivation, inhibitory cell responses shifted to match the faster changes in their excitatory counterparts. These findings reveal a dramatic delay in inhibitory cell plasticity. A minimal linear model reveals that the delay in inhibitory cell plasticity potently accelerates Hebbian plasticity in neighboring excitatory neurons. These findings offer a network-level explanation as to how inhibition regulates the experience-dependent plasticity of neocortex.     

Amblyopia induced by anisometropia without shrinkage of ocular dominance columns in human striate cortex.

Amblyopia can be induced by opacity of the ocular media (e.g., cataract), misalignment of the ocular axes (strabismus), or unequal refractive error in the eyes (anisometropia). Experiments in monkeys have shown that early monocular eyelid suture, a model of amblyopia caused by cataract, results in shrinkage of the eye's ocular dominance columns in striate cortex. This reduction of the geniculocortical projection from the deprived eye has been thought to explain in part the mechanism of amblyopia. We labeled the ocular dominance columns in monkeys with amblyopia by using cytochrome oxidase histochemistry. In animals rendered amblyopic by early unilateral eyelid suture, no pattern of cytochrome oxidase activity appeared in layer IVc. Outside layer IVc, alternating rows of light and dark patches were present; the pale patches fit in register with the shrunken ocular dominance columns of the deprived eye, which were labeled by autoradiography. Subsequent removal of one eye caused a striking cytochrome oxidase pattern to emerge in layer IVc that correlated precisely with the shrunken (deprived eye) and expanded (normal eye) ocular dominance columns. This correlation was shown by injecting one eye with [3H]proline. It has remained unsettled whether other forms of amblyopia are accompanied by shrinkage of ocular dominance columns. To address this issue, in an analogous clinical case, we examined the pattern of cytochrome oxidase activity in a human subject with a history of anisometropic amblyopia who suffered a lesion of one optic nerve shortly before death. The ocular dominance columns were normal in width, indicating that some forms of amblyopia occur without shrinkage of ocular dominance columns.     

Relation between oscillatory activity and long-range synchronization in cat visual cortex.

Recent theoretical studies have suggested that oscillatory firing patterns with frequencies in the gamma band (30-70 Hz) may be instrumental for the establishment of synchrony among widely distributed neurons if synchrony is to be achieved by reciprocal connections. We have now investigated the relationship between synchrony and oscillations in cat visual cortex. Our results show that when synchronization of neuronal activity occurs over distances of > 2 mm in primary visual cortex, or occurs between the two hemispheres, it is almost always associated with oscillatory firing patterns, whereas synchronization over short distances occurs also in the absence of oscillations. Furthermore, our results indicate that short-range interactions affect both the firing rate of the respective neurons and the timing of their discharges, whereas only the latter is influenced by long-range interactions. These data support the hypothesis that oscillatory activity can contribute to the establishment of long-range synchrony in a network of reciprocally coupled neurons.     

All-or-none disconnection of pyramidal inputs onto parvalbumin-positive interneurons gates ocular dominance plasticity

Disinhibition is an obligatory initial step in the remodeling of cortical circuits by sensory experience. Our investigation on disinhibitory mechanisms in the classical model of ocular dominance plasticity uncovered an unexpected form of experience-dependent circuit plasticity. In the layer 2/3 of mouse visual cortex, monocular deprivation triggers a complete, “all-or-none,” elimination of connections from pyramidal cells onto nearby parvalbumin-positive interneurons (Pyr→PV). This binary form of circuit plasticity is unique, as it is transient, local, and discrete. It lasts only 1 d, and it does not manifest as widespread changes in synaptic strength; rather, only about half of local connections are lost, and the remaining ones are not affected in strength. Mechanistically, the deprivation-induced loss of Pyr→PV is contingent on a reduction of the protein neuropentraxin2. Functionally, the loss of Pyr→PV is absolutely necessary for ocular dominance plasticity, a canonical model of deprivation-induced model of cortical remodeling. We surmise, therefore, that this all-or-none loss of local Pyr→PV circuitry gates experience-dependent cortical plasticity.

Experience during a postnatal, critical period is essential to properly shape the functional connectivity of cortical circuits. A canonical model of cortical plasticity is the shift in ocular dominance following monocular deprivation (MD), which biases responses toward the nondeprived (ND) eye. Prior research established that MD-induced changes result from the reorganization of excitatory glutamatergic synapses onto excitatory pyramidal neurons (Pyr), which is, in turn, regulated by an inhibitory GABAergic network composed of parvalbumin-positive inhibitory interneurons (PVs). The current consensus is that a reduced, permissive level of inhibition from PV circuits in cortical layer 2/3 is required for plasticity at downstream excitatory synapses and that inhibition above or below the permissive range constrains the response to MD (1–3). Although the notion that rapid cortical disinhibition precedes and initiates the plasticity of glutamatergic connectivity is well established (4, 5), and decades old (6–8), the underlying cellular mechanisms remain unclear.Disinhibition of excitatory cortical neurons could be achieved indirectly, for example by suppressing PV activity via enhancing inhibition from other interneurons through cholinergic neuromodulation (9, 10) but more directly, and likely more effectively, by reducing the excitatory input onto PVs (4, 11–13). Our current investigation uncovered a unique form of experience-dependent plasticity that regulates the connectivity between pyramidal neurons and PVs. We found that the initial response to MD is the functional and structural elimination of ∼50% of these connections. In contrast to the outcome of known mechanisms of synaptic plasticity that manifest in widespread graded changes in synaptic strength, the loss of pyramidal–PV connectivity occurs in a discrete, “all-or-none,” fashion: whereas a subset of connections become completely eliminated, the persistent connections have normal strength. This disconnection is not only rapid but it is transient, affects only very local pyramidal–PV pairs, and, importantly, manipulations that promote/prevent this disconnection also promote/prevent shifts in ocular dominance. We surmise, therefore, that the rapid and transient disconnection of discrete subsets of PV circuits enables the subsequent Hebbian and homeostatic modification of glutamatergic circuitry.     

Nerve growth factor-induced phenotypic switch in guinea pig airway sensory neurons

Immunohistochemistry was combined with retrograde tracing techniques to characterize the effect of nerve growth factor (NGF) on substance P (SP) producing vagal neurons innervating the guinea pig trachea. Fast blue dye instilled into the trachea retrogradely labeled nerve cell bodies located in the nodose and jugular ganglia. In untreated guinea pigs > 99% of the SP-containing neurons labeled with fast blue were located in the jugular ganglia. The SP-positive neurons were small in diameter (23 +/- 1 microm) and were negative for neurofilament immunoreactivity. The fast-blue-positive neurons in the nodose ganglia, by contrast, were large in diameter (40 +/- 3 microm) and were negative for SP immunoreactivity and positive for neurofilament immunoreactivity. After NGF-beta injections into the tracheal wall, approximately 10% of the large-diameter nodose neurofilament-positive neurons projecting fibers to the trachea became SP-positive (p < 0.05). We previously demonstrated that nodose nerve endings supplying the trachea are exquisitely mechanically sensitive, but capsaicin- and bradykinin-insensitive. These results suggest that NGF not only increases SP expression in airway neurons, but changes the neuronal phenotype such that large, capsaicin-insensitive nodose neurons with fast-conducting "Adelta" fibers provide a component of the tachykinergic innervation.     

A rich environmental experience reactivates visual cortex plasticity in aged rats

Brain aging is characterized by functional deterioration across multiple systems, associated to a progressive decay of neural plasticity. Here, we explored environmental enrichment (EE), a condition of enhanced sensory-motor and cognitive stimulation, as a strategy to restore plasticity processes in the old brain. Visual system is one of the paradigmatic models for studying experience-dependent plasticity. While reducing input from one eye through monocular deprivation induces a marked ocular dominance (OD) shift of neurons in the primary visual cortex during development, the same manipulation is totally ineffective after the closure of the critical period. We show that EE is able to reactivate OD plasticity in the visual cortex of aging rats, as assessed with both visual-evoked potentials and single-unit recordings. A marked reduction in intracortical GABAergic inhibition and a remodeling of extracellular matrix accompany this effect. The non-invasive nature of EE makes this paradigm eligible for human application.