Rat Visual Cortex Research Articles

Heterosynaptic Plasticity Prevents Runaway Synaptic Dynamics

Spike timing-dependent plasticity (STDP) and other conventional Hebbian-type plasticity rules are prone to produce runaway dynamics of synaptic weights. Once potentiated, a synapse would have higher probability to lead to spikes and thus to be further potentiated, but once depressed, a synapse would tend to be further depressed. The runaway synaptic dynamics can be prevented by precisely balancing STDP rules for potentiation and depression; however, experimental evidence shows a great variety of potentiation and depression windows and magnitudes. Here we show that modifications of synapses to layer 2/3 pyramidal neurons from rat visual and auditory cortices in slices can be induced by intracellular tetanization: bursts of postsynaptic spikes without presynaptic stimulation. Induction of these heterosynaptic changes depended on the rise of intracellular calcium, and their direction and magnitude correlated with initial state of release mechanisms. We suggest that this type of plasticity serves as a mechanism that stabilizes the distribution of synaptic weights and prevents their runaway dynamics. To test this hypothesis, we develop a cortical neuron model implementing both homosynaptic (STDP) and heterosynaptic plasticity with properties matching the experimental data. We find that heterosynaptic plasticity effectively prevented runaway dynamics for the tested range of STDP and input parameters. Synaptic weights, although shifted from the original, remained normally distributed and nonsaturated. Our study presents a biophysically constrained model of how the interaction of different forms of plasticity--Hebbian and heterosynaptic--may prevent runaway synaptic dynamics and keep synaptic weights unsaturated and thus capable of further plastic changes and formation of new memories.

P.3.c.004 A mechanism of antipsychotic treatment failure and its reversal

Among the GABAergic neocortical interneurons, parvalbumin-containing fast-spiking (FS) basket cells are essential mediators of feed-forward inhibition, network synchrony and oscillations, and timing of the critical period for sensory plasticity. The FS phenotype matures after birth. It depends on the expression of the voltage-gated potassium channels Kv3.1b/3.2 which mediate the fast membrane repolarization necessary for firing fast action potentials at high frequencies. We have now tested in rat visual cortex if visual deprivation affects the Kv3 expression. During normal development, Kv3.1b/3.2 mRNA and protein expression increased in rat visual cortex reaching adult levels around P20. Dark rearing from birth neither prevented nor delayed the upregulation. Rather unexpectedly, the expression of Kv3.1b protein and Kv3.2 mRNA and protein increased to higher levels from the third postnatal week onwards. Triple-labeling revealed that in dark-reared visual cortex Kv3.2 was upregulated in parvalbuminergic interneurons in supragranular layers which in normal animals rarely display Kv3.2 expression. Recovery from dark rearing normalized Kv3.2 expression. This showed that visual experience influences the Kv3 expression. The results suggest that an altered expression of Kv3 channels affects the functional properties of FS neurons, and may contribute to the deficits in inhibition observed in the sensory-deprived cortex.

Energy-efficient encoding by shifting spikes in neocortical neurons

The speed of computations in neocortical networks critically depends on the ability of populations of spiking neurons to rapidly detect subtle changes in the input and translate them into firing rate changes. However, high sensitivity to perturbations may lead to explosion of noise and increased energy consumption. Can neuronal networks reconcile the requirements for high sensitivity, operation in a low-noise regime, and constrained energy consumption? Using intracellular recordings in slices from the rat visual cortex, we show that layer 2/3 pyramidal neurons are highly sensitive to minor input perturbations. They can change their population firing rate in response to small artificial excitatory postsynaptic currents (aEPSCs) immersed in fluctuating noise very quickly, within 2-2.5ms. These quick responses were mediated by the generation of new, additional action potentials (APs), but also by shifting spikes into the response peak. In that latter case, the spike count increase during the peak and the decrease after the peak cancelled each other, thus producing quick responses without increases in total spike count and associated energy costs. The contribution of spikes from one or the other source depended on the aEPSCs timing relative to the waves of depolarization produced by ongoing activity. Neurons responded by shifting spikes to aEPSCs arriving at the beginning of a depolarization wave, but generated additional spikes in response to aEPSCs arriving towards the end of a wave. We conclude that neuronal networks can combine high sensitivity to perturbations and operation in a low-noise regime. Moreover, certain patterns of ongoing activity favor this combination and energy-efficient computations.

Wave propagation of cortical population activity under urethane anesthesia is state dependent

BackgroundPropagating waves of excitation have been observed extensively in the neocortex, during both spontaneous and sensory-evoked activity, and they play a critical role in spatially organizing information processing. However, the state-dependence of these spatiotemporal propagation patterns is largely unexplored. In this report, we use voltage-sensitive dye imaging in the rat visual cortex to study the propagation of spontaneous population activity in two discrete cortical states induced by urethane anesthesia.ResultsWhile laminar current source density patterns of spontaneous population events in these two states indicate a considerable degree of similarity in laminar networks, lateral propagation in the more active desynchronized state is approximately 20% faster than in the slower synchronized state. Furthermore, trajectories of wave propagation exhibit a strong anisotropy, but the preferred direction is different depending on cortical state.ConclusionsOur results show that horizontal wave propagation of spontaneous neural activity is largely dependent on the global activity states of local cortical circuits.

Alterations in membrane and firing properties of layer 2/3 pyramidal neurons following focal laser lesions in rat visual cortex

Focal cortical injuries are well known to cause changes in function and excitability of the surviving cortical areas but the cellular correlates of these physiological alterations are not fully understood. In the present study we employed a well established ex vivo–in vitro model of focal laser lesions in the rat visual cortex and we studied membrane and firing properties of the surviving layer 2/3 pyramidal neurons. Patch-clamp recordings, performed in the first week post-injury, revealed an increased input resistance, a depolarized spike threshold as well as alterations in the firing pattern of neurons in the cortex ipsilateral to the lesion. Notably, the reported lesion-induced alterations emerged or became more evident when an exciting perfusing solution, known as modified artificial cerebrospinal fluid, was used to increase the ongoing synaptic activity in cortical slices. Conversely, application of glutamatergic or GABAA receptor blockers reduced the observed alterations and GABAB receptor blockers abolished the differences completely. All together the present findings suggest that changes in synaptic receptors function, following focal cortical injuries, can modulate membrane and firing properties of layer 2/3 pyramidal neurons. This previously unknown functional interplay between synaptic and membrane properties may constitute a novel cellular mechanism to explain alterations in neuronal network function and excitability following focal cortical injuries.

Layer- and cell-type-specific tonic GABAergic inhibition of pyramidal neurons in the rat visual cortex

Tonic inhibition mediated by persistent activation of γ-aminobutyric acidA (GABAA) receptors by ambient GABA plays a crucial role in the regulation of network excitability and neuronal signal processing. Varying degrees in the strength of tonic inhibition were detected across different cell types throughout the brain. Since sensory information flows through cortical layers in a specific order, the characteristics of tonic inhibition in different cortical layers are of interest. Therefore, we examined the properties of tonic inhibition in pyramidal neurons (PyNs) throughout the rat visual cortex. Layer 2/3 PyNs and burst-spiking PyNs in layers 5 and 6 showed prominent tonic GABAA currents. Tonic GABAA currents in layer 4 star PyNs and regular-spiking PyNs in layers 5 and 6 were much weaker. The magnitude of tonic currents correlated well with the inhibition of spike generation. The amplitude of tonic GABAA currents measured with bicuculline and gabazine, the two different GABAA receptor blockers, did not differ. The differences in the expression levels of extrasynaptic GABAA receptors might be the major contributor to the differences in tonic GABAA currents among cell types. Furthermore, α5 subunits might contribute significantly to tonic currents in infragranular burst-spiking PyNs, especially in layer 5. These results suggest that ambient GABA might exert differential effects on the neuronal integration in a layer- and cell-type-specific manner and thus contribute to the processing of sensory properties by selectively tuning the signals flowing through the visual cortex.

A spontaneous state of weakly correlated synaptic excitation and inhibition in visual cortex

Cortical spontaneous activity reflects an animal’s behavioral state and affects neural responses to sensory stimuli. The correlation between excitatory and inhibitory synaptic input to single neurons is a key parameter in models of cortical circuitry. Recent measurements demonstrated highly correlated synaptic excitation and inhibition during spontaneous “up-and-down” states, during which excitation accounted for approximately 80% of inhibitory variance (Shu et al., 2003; Haider et al., 2006). Here we report in vivo whole-cell estimates of the correlation between excitation and inhibition in the rat visual cortex under pentobarbital anesthesia, during which up-and-down states are absent. Excitation and inhibition are weakly correlated, relative to the up-and-down state: excitation accounts for less than 40% of inhibitory variance. Although these correlations are lower than when the circuit cycles between up-and-down states, both behaviors may arise from the same circuitry. Our observations provide evidence that different correlational patterns of excitation and inhibition underlie different cortical states.

Expression of Perineuronal Nets, Parvalbumin and Protein Tyrosine Phosphatase σ in the Rat Visual Cortex During Development and After BFD

Purpose of the Study: Protein tyrosine phosphatase σ (PTPσ) acts as a neuronal receptor for chondroitin sulfate proteoglycans (CSPGs). CSPGs have inhibitory effects on experience-dependent plasticity and usually form lattice-like cell coatings that surround the parvalbumin (PV) interneurons in the visual cortex (VC). We investigated developmental changes and the effect of binocular form deprivation (BFD) on PTPσ, perineuronal nets (PNNs) and their tempo-spatial relationships with PV neurons in the VC.Materials and Methods: Double-immunostaining was used to observe the coexpression pattern of PNNs staining by biotinylated wisteria floribunda lectin (WFA) with PV neurons. The expression of PTPσ in the VC of Long Evans rats was detected by real-time quantitative PCR, immunohistochemistry and western blots. The changes in the number of PV/WFA/PTPσ labeled cells in layer IV of the VC and its proportion of PV neurons were examined during development and after BFD.Results: The expression of PV neurons wrapped by PNNs was increased, particularly in the first half of the critical period, and the ratio for PV neurons reached the highest level (over 75%) at adulthood, indicating that PNNs may play an important role in the maturation of PV neurons during the critical period. BFD decreased the density of PNNs and the percentage of PV neurons with PNNs. This result suggests that the number of PNNs surrounding PV neurons may be experience-dependent. Meanwhile, the CSPG receptor PTPσ was maintained at its lowest level during the critical period and could be modulated by BFD after the critical period. The percentage of PV/WFA/PTPσ-positive cells in PV population increased during development and reached its highest ratio at adulthood, which could also be reversed by BFD.Conclusions: The changes in the coexpression of PNNs, PV and PTPσ provide valuable insights into the connection between CSPGs and PV neurons.

Repetitive visual stimulation enhances recovery from severe amblyopia

Severe amblyopia, characterized by a significant reduction in visual acuity through the affected eye, is highly resistant to reversal in adulthood. We have previously shown that synaptic plasticity can be reactivated in the adult rat visual cortex by dark exposure, and the reactivated plasticity can be harnessed to promote the recovery from severe amblyopia. Here we show that deprived-eye visually evoked responses are rapidly strengthened in dark-exposed amblyopes by passive viewing of repetitive visual stimuli. Surprisingly, passive visual stimulation rapidly enhanced visually evoked responses to novel stimuli and enhanced the recovery from severe amblyopia driven by performance of active visual discriminations. Thus a series of simple, noninvasive manipulations of visual experience can be used in combination to significantly guide the recovery of visual response strength, selectivity, and spatial acuity in adult amblyopes.

Perineuronal nets increase inhibitory GABAergic currents during the critical period in rats.

To investigate inhibitory γ-aminobutyric acid (GABA) ergic postsynaptic currents (IPSCs) and postsynaptic currents (PSCs) in layer IV of the rat visual cortex during the critical period and when plasticity was extended through dissolution of the perineuronal nets (PNNs). We employed 24 normal Long-Evans rats to study GABAA-PSC characteristics of neurons within layer IV of the visual cortex during development. The animals were divided into six groups of four rats according to ages at recording: PW3 (P21-23d), PW4 (P28-30d), PW5 (P35-37d), PW6 (P42-44d), PW7 (P49-51d), and PW8 (56-58d). An additional 24 chondroitin sulfate proteoglycan (CSPG) degradation rats (also Long-Evans) were generated by making a pattern of injections of chondroitinase ABC (chABC) into the visual cortex 1 week prior to recording at PW3, PW4, PW5, PW6, PW7, and PW8. Immunohistochemistry was used to identify the effect of chABC injection on CSPGs. PSCs were detected with whole-cell patch recordings, and GABAA receptor-mediated IPSCs were pharmacologically isolated. IPSC peak current showed a strong rise in the age-matched control group, peaked at PW5 and were maintained at a roughly constant value thereafter. Although there was a small increase in peak current for the chABC group with age, the peak currents continued to decrease with the delayed highest value at PW6, resulting in significantly different week-by-week comparison with normal development. IPSC decay time continued to increase until PW7 in the control group, while those in the chABC group were maintained at a stable level after an initial increase at PW4. Compared with normal rats, the decay times recorded in the chABC rats were always shorter, which differed significantly at each age. We did not observe any differences in IPSC properties between the age-matched control and penicillinase (P-ase) group. However, the change in IPSCs after chABC treatment was not reflected in the total PSCs or in basic membrane properties in layer IV of the rat visual cortex. Our results demonstrate that rather than rapidly increasing during the critical period for neuronal plasticity, IPSCs in layer IV of rat visual cortex are maintained at an immature level when PNNs are removed by chABC. This suggests that GABA receptor maturation involves the conformation of the CSPGs in PNNs.

VEGF reverts the cognitive impairment induced by a focal traumatic brain injury during the development of rats raised under environmental enrichment

The role of VEGF in the nervous system is extensive; apart from its angiogenic effect, VEGF has been described as a neuroprotective, neurotrophic and neurogenic molecule. Similar effects have been described for enriched environment (EE). Moreover, both VEGF and EE have been related to improved spatial memory. Our aim was to investigate the neurovascular and cognitive effects of intracerebrally-administered VEGF and enriched environment during the critical period of the rat visual cortex development. Results showed that VEGF infusion as well as enriched environment induced neurovascular and cognitive effects in developing rats. VEGF administration produced an enhancement during the learning process of enriched animals and acted as an angiogenic factor both in primary visual cortex (V1) and dentate gyrus (DG) in order to counteract minipump implantation-induced damage. This fact revealed that DG vascularization is critical for normal learning. In contrast to this enriched environment acted on the neuronal density of the DG and V1 cortex, and results showed learning enhancement only in non-operated rats. In conclusion, VEGF administration only has effects if damage is observed due to injury. Once control values were reached, no further effects appeared, showing a ceiling effect. Our results strongly support that in addition to neurogenesis, vascularization plays a pivotal role for learning and memory.

Serotonergic modulation of LTP at excitatory and inhibitory synapses in the developing rat visual cortex

The stability and efficacy of neuronal circuits are achieved through a detailed balance between pyramidal cell and interneuron activities. Interestingly, the neocortical excitatory–inhibitory (E–I) balance is actively maintained at the soma of Layer 5 pyramidal neurons which receive 20% of excitation and 80% of inhibition after dendritic integration, and this is not affected by changes in synaptic strength. To infer the role of serotonergic neuromodulation on the activity-dependent maintenance of the E–I balance, we performed continuous voltage clamp measurements of stimulation-locked conductance dynamics in Layer 5 pyramidal neurons before and after long-term potentiation (LTP) induction, together with chronic or acute manipulation of serotonin function. When a theta-burst stimulation was applied in Layer 2/3 of 5-HT depleted cortical slices (after in vivo treatment with the tryptophan hydroxylase inhibitor p-chlorophenylalanine (pCPA)), or after in vitro perfusion of the potent 5-HT1A receptor antagonist WAY-100,635, we observed a persistent shift of the ratio between excitation and inhibition toward more inhibition. This was due to a strong LTP of inhibition co-aligned with a weak LTP of excitation, whereas the same protocol caused a similar potentiation of excitatory and inhibitory inputs when applied in control slices. In contrast, neither excitatory nor inhibitory postsynaptic currents were potentiated when LTP protocols were delivered in the presence of either the selective serotonin reuptake inhibitor citalopram or the 5-HT1A receptor agonist 8-OH-DPAT. This is the first demonstration that serotonergic neuromodulation is crucial for the maintenance of the neocortical E–I balance during high-frequency regimes.

Evidence That Primary Visual Cortex Is Required for Image, Orientation, and Motion Discrimination by Rats

The pigmented Long-Evans rat has proven to be an excellent subject for studying visually guided behavior including quantitative visual psychophysics. This observation, together with its experimental accessibility and its close homology to the mouse, has made it an attractive model system in which to dissect the thalamic and cortical circuits underlying visual perception. Given that visually guided behavior in the absence of primary visual cortex has been described in the literature, however, it is an empirical question whether specific visual behaviors will depend on primary visual cortex in the rat. Here we tested the effects of cortical lesions on performance of two-alternative forced-choice visual discriminations by Long-Evans rats. We present data from one highly informative subject that learned several visual tasks and then received a bilateral lesion ablating >90% of primary visual cortex. After the lesion, this subject had a profound and persistent deficit in complex image discrimination, orientation discrimination, and full-field optic flow motion discrimination, compared with both pre-lesion performance and sham-lesion controls. Performance was intact, however, on another visual two-alternative forced-choice task that required approaching a salient visual target. A second highly informative subject learned several visual tasks prior to receiving a lesion ablating >90% of medial extrastriate cortex. This subject showed no impairment on any of the four task categories. Taken together, our data provide evidence that these image, orientation, and motion discrimination tasks require primary visual cortex in the Long-Evans rat, whereas approaching a salient visual target does not.

Membrane Insertion of New AMPA Receptors and LTP Induced by Glycine is Prevented by Blocking NR2A-Containing NMDA Receptors in the Rat Visual Cortex In Vitro

N-methyl-D-aspartate receptors (NMDA-Rs) activation has been implicated in various forms of synaptic plasticity depending on the receptor subtypes involved. However, the contribution of NR2A and NR2B subunits in glycine-induced long-term potentiation (LTP) of miniature excitatory postsynaptic currents (mEPSCs) in layer II/III pyramidal neurons of the rat visual cortex remains unclear. The present study used whole-cell patch-clamp recordings in vitro to investigate the role of NR2A-containing and NR2B-containing NMDA-Rs in glycine-induced LTP in visual cortical slices from 13-15 day old rats. We found that glycine-induced LTP of mEPSCs was readily induced in layer II/III pyramidal neurons of the rat visual cortex with glycine. D-APV, a selective NMDA-R antagonist, blocked the glycineinduced LTP. Moreover, the selective NR2B-containing NMDA-R antagonists (Ro 25-6981) displayed no influence on the glycine-induced LTP. However, Zn2+, a voltage-independent NR2A-containing NMDA-R antagonist, prevented glycine-induced LTP. These results suggest that the glycine-induced LTP in layer II/III pyramidal neurons of the rat visual cortex is NMDA-R-dependent and requires NR2A-containing NMDA-Rs, not NR2B-containing NMDA-Rs.

C-Fos activity mapping reveals differential effects of noradrenaline and serotonin depletion on the regulation of ocular dominance plasticity in rats

The roles of the central noradrenergic and serotonergic system in the activity-dependent regulation of ocular dominance plasticity have been a contentious issue. Using c-Fos activity mapping, we have developed a new, straightforward method to measure the strength of ocular dominance plasticity: the number of c-Fos-immunopositive cells in layer IV of rat visual cortex (Oc1B), ipsilateral to the stimulated eye, is a sensitive and reliable measure of the effects of monocular deprivation. Applying this new method, here we studied the unique modification of the degree of c-Fos expression induced in the visual cortex, in that endogenous noradrenaline (NA) and serotonin (5HT) in the cortex were significantly reduced, respectively by specific pharmacological agents. Intraperitoneal injections of N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) and p-chlorophenylalanine (pCPA) selectively impair NA- and 5HT-containing nerve terminals and fibers, respectively. In the visual cortex with strongly reduced NA, the number of c-Fos-immunopositive cells was found remaining significantly decreased in response to stimulation of the deprived eye, while by open eye stimulation the expected increase in c-Fos-immunoreactivity was strongly suppressed, showing values not different from those obtained by monocular stimulation in the normal rats. In contrast, in the visual cortex with strongly reduced 5HT no expected decrease was found in response to stimulation of the deprived eye, while, as is usually the case for the normal animals, a significant increase was still induced in response to open eye stimulation. These findings suggest that the noradrenergic and serotonergic system regulate ocular dominance (OD) plasticity differently: in the NA-depleted cortex the expected increase in c-Fos expression by open eye stimulation was not seen due to strong suppression, whereas in 5HT-depletion, the expected decrease in c-Fos expression was not materialized due to strong suppression. The present findings with c-Fos activity mapping method indicated a novel possibility of the differential regulation of OD plasticity by two types of common monoaminergic systems.

Effect of protein tyrosine phosphatase σ on the reactivation of ocular dominance plasticity in the visual cortex of adult rats

Background Chondroitin sulphate proteoglycans (CSPGs) can cause the termination of ocular dominance plasticity in the visual cortex.Recently,protein tyrosine phosphatase σ (PTPσ) has been identified as a receptor that inhibits CSPGs.However,whether PTPσ and its downstream molecules participate in the reactivation of ocular dominance plasticity in adult visual cortex has not been studied.Objective The present study was to investigate the changes in the expression of the PTPσ,probabilistic neural networks (PNNs),and molecules downstream of PNN,such as N-cadherin/β-catenin,after the reactivation of adult visual cortical plasticity.Methods Fifty-four SPF Long Evans rats were grouped according to different postnatal week (PW) as the PW1 (6 rats),PW3 (6 rats),PW5 (6 rats),PW7 (24 rats),and PW9 (12 rats) groups,and the upper and lower eyelids were sutured in the 12 rats from the PW7 group for 14 days to establish the binocular plasticity reactivation models.Expression of PTPσ and PNNs in the rat visual cortex was detected using immunochemistry,and changes of PTPσ mRNA,N-cadherin mRNA and β-catenin mRNA expression in the rat visual cortex with plasticity reactivation were assessed by real-time fluorescence quantitative PCR (RT Q-PCR).The use of animals followed the Regulations for the Administration of Affairs Concerning Experimental Animals by State Science and Technology Commission.Results The expression level of PTPσ mRNA was significantly higher in the PW9 group than that of the binocular plasticity reactivation models and the PW7 group (t =1.965,3.526,P＜0.01).The staining of the rat visual cortex for PTPσwas localized to the cellular membrane,cytoplasm and axon.Cell densities of the PW9 group in the Ⅱ-Ⅲ layer,Ⅳ layer and Ⅴ-Ⅵ layer of the visual cortex were elevated in the PW9 rats compared with the PW7 rats (t =24.593,23.444,13.556,P＜0.01) and rats from the binocular plasticity reactivation model (t =44.111,43.000,16.556,P＜0.01).Cell densities for PNNs in the Ⅳ and Ⅴ-Ⅵ layers were significantly increased in the PW9 rats in comparison with the PW7 rats (t=1.926,P＜0.01 ;t=1.370,P＜0.05),but the cell density in the Ⅱ-Ⅱ layer has no statistical significance (t=0.889,P＞0.05).However,cell densities for PNNs in the Ⅱ-Ⅲ and Ⅳ layers in the binocular plasticity reactivation models were lower than those of the PW9 rats (t =2.556,4.585,P＜0.01).Compared with PW1 rats,the expression levels of the N-cadherin mRNA in the PW3,PW5,PW7,PW9 rats were lower (t =28.932,28.988,27.083,28.908,P＜0.01),but those in the PW7 rats were enhanced in comparison with the PW3 rats,PW5 rats and PW9 rats (t =1.848,1.904,1.825,P＜0.01).No significant difference was seen in the expression of the N-cadherin mRNA between the PW9 rats and rats from the binocular plasticity reactivation model (t =0.072,P＞0.05).A statistically significant increase was found in the β-catenin mRNA expression in the PW1 rats compared with the PW3,PW5,PW7 and PW9 rats (t =3.918,3.534,2.645,4.652,P＜ 0.0 1),as well as between rats from the binocular plasticity reactivation model and the PW9 rats (t =0.570,P＜0.01).Conclusions PTPr,PNNs and β-catenin are involved in the reactivation of ocular dominance plasticity in the adult visual cortex. Key words: Visual cortex; Protein tyrosine phosphatase σ; Plasticity; Binocular form-deprivation

Effects of Digesting Chondroitin Sulfate Proteoglycans on Plasticity in Cat Primary Visual Cortex

Monocular deprivation (MD) during a critical period of postnatal development produces significant changes in the anatomy and physiology of the visual cortex, and the deprived eye becomes amblyopic. Extracellular matrix molecules have a major role in restricting plasticity such that the ability to recover from MD decreases with age. Chondroitin sulfate proteoglycans (CSPGs) act as barriers to cell migration and axon growth. Previous studies showing that degradation of CSPGs by the bacterial enzyme chondroitinase can restore plasticity in the adult rat visual cortex suggest a potential treatment for amblyopia. Here MD was imposed in cats from the start of the critical period until 3.5 months of age. The deprived eye was reopened, the functional architecture of the visual cortex was assessed by optical imaging of intrinsic signals, and chondroitinase was injected into one hemisphere. Imaging was repeated 1 and 2 weeks postinjection, and visually evoked potentials (VEPs) and single-cell activity were recorded. Immunohistochemistry showed that digestion of CSPGs had been successful. After 2 weeks of binocular exposure, some recovery of deprived-eye responses occurred when chondroitinase had been injected into the hemisphere contralateral to that eye; when injected into the ipsilateral hemisphere, no recovery was seen. Deprived-eye VEPs were no larger in the injected hemisphere than in the opposite hemisphere. The small number of neurons dominated by the deprived eye exhibited poor tuning characteristics. These results suggest that despite structural effects of chondroitinase in adult cat V1, plasticity was not sufficiently restored to enable significant functional recovery of the deprived eye.

Comparing development of synaptic proteins in rat visual, somatosensory, and frontal cortex

Two theories have influenced our understanding of cortical development: the integrated network theory, where synaptic development is coordinated across areas; and the cascade theory, where the cortex develops in a wave-like manner from sensory to non-sensory areas. These different views on cortical development raise challenges for current studies aimed at comparing detailed maturation of the connectome among cortical areas. We have taken a different approach to compare synaptic development in rat visual, somatosensory, and frontal cortex by measuring expression of pre-synaptic (synapsin and synaptophysin) proteins that regulate vesicle cycling, and post-synaptic density (PSD-95 and Gephyrin) proteins that anchor excitatory or inhibitory (E-I) receptors. We also compared development of the balances between the pairs of pre- or post-synaptic proteins, and the overall pre- to post-synaptic balance, to address functional maturation and emergence of the E-I balance. We found that development of the individual proteins and the post-synaptic index overlapped among the three cortical areas, but the pre-synaptic index matured later in frontal cortex. Finally, we applied a neuroinformatics approach using principal component analysis and found that three components captured development of the synaptic proteins. The first component accounted for 64% of the variance in protein expression and reflected total protein expression, which overlapped among the three cortical areas. The second component was gephyrin and the E-I balance, it emerged as sequential waves starting in somatosensory, then frontal, and finally visual cortex. The third component was the balance between pre- and post-synaptic proteins, and this followed a different developmental trajectory in somatosensory cortex. Together, these results give the most support to an integrated network of synaptic development, but also highlight more complex patterns of development that vary in timing and end point among the cortical areas.

Gene Expression Patterns Underlying the Reinstatement of Plasticity in the Adult Visual System

The nervous system is highly sensitive to experience during early postnatal life, but this phase of heightened plasticity decreases with age. Recent studies have demonstrated that developmental-like plasticity can be reactivated in the visual cortex of adult animals through environmental or pharmacological manipulations. These findings provide a unique opportunity to study the cellular and molecular mechanisms of adult plasticity. Here we used the monocular deprivation paradigm to investigate large-scale gene expression patterns underlying the reinstatement of plasticity produced by fluoxetine in the adult rat visual cortex. We found changes, confirmed with RT-PCRs, in gene expression in different biological themes, such as chromatin structure remodelling, transcription factors, molecules involved in synaptic plasticity, extracellular matrix, and excitatory and inhibitory neurotransmission. Our findings reveal a key role for several molecules such as the metalloproteases Mmp2 and Mmp9 or the glycoprotein Reelin and open up new insights into the mechanisms underlying the reopening of the critical periods in the adult brain.

Membrane Insertion of New AMPA Receptors and LTP Induced by Glycine is Prevented by Blocking NR2A-Containing NMDA Receptors in the Rat Visual Cortex In Vitro

N-methyl-D-aspartate receptors (NMDA-Rs) activation has been implicated in various forms of synaptic plasticity depending on the receptor subtypes involved. However, the contribution of NR2A and NR2B subunits in glycine-induced long-term potentiation (LTP) of miniature excitatory postsynaptic currents (mEPSCs) in layer II/III pyramidal neurons of the rat visual cortex remains unclear. The present study used whole-cell patch-clamp recordings in vitro to investigate the role of NR2A-containing and NR2B-containing NMDA-Rs in glycine-induced LTP in visual cortical slices from 13-15 day old rats. We found that glycine-induced LTP of mEPSCs was readily induced in layer II/III pyramidal neurons of the rat visual cortex with glycine. D-APV, a selective NMDA-R antagonist, blocked the glycineinduced LTP. Moreover, the selective NR2B-containing NMDA-R antagonists (Ro 25-6981) displayed no influence on the glycine-induced LTP. However, Zn2+, a voltage-independent NR2A-containing NMDA-R antagonist, prevented glycine-induced LTP. These results suggest that the glycine-induced LTP in layer II/III pyramidal neurons of the rat visual cortex is NMDA-R-dependent and requires NR2A-containing NMDA-Rs, not NR2B-containing NMDA-Rs.