Critical periods for experience-dependent synaptic scaling in visual cortex

The mechanisms underlying experience-dependent plasticity and refinement of central circuits are not yet fully understood. A non-Hebbian form of synaptic plasticity, which scales synaptic strengths up or down to stabilize firing rates, has recently been discovered in cultured neuronal networks. Here we demonstrate the existence of a similar mechanism in the intact rodent visual cortex. The frequency of miniature excitatory postsynaptic currents (mEPSCs) in principal neurons increased steeply between post-natal days 12 and 23. There was a concomitant decrease in mEPSC amplitude, which was prevented by rearing rats in complete darkness from 12 days of age. In addition, as little as two days of monocular deprivation scaled up mEPSC amplitude in a layer- and age-dependent manner. These data indicate that mEPSC amplitudes can be globally scaled up or down as a function of development and sensory experience, and suggest that synaptic scaling may be involved in the activity-dependent refinement of cortical connectivity.     

Developmental switch in the polarity of experience-dependent synaptic changes in layer 6 of mouse visual cortex

Layer 6 (L6) of primary sensory cortices is distinct from other layers in that it provides a major cortical input to primary sensory thalamic nuclei. L6 pyramidal neurons in the primary visual cortex (V1) send projections to the lateral geniculate nucleus (LGN), as well as to the thalamic reticular nucleus and higher order thalamic nuclei. Although L6 neurons are proposed to modulate the activity of thalamic relay neurons, how sensory experience regulates L6 neurons is largely unknown. Several days of visual deprivation homeostatically adjusts excitatory synapses in L4 and L2/3 of V1 depending on the developmental age. For instance, L4 exhibits an early critical period during which visual deprivation homeostatically scales up excitatory synaptic transmission. On the other hand, homeostatic changes in L2/3 excitatory synapses are delayed and persist into adulthood. In the present study we examined how visual deprivation affects excitatory synapses on L6 pyramidal neurons. We found that L6 pyramidal neurons homeostatically increase the strength of excitatory synapses following 2 days of dark exposure (DE), which was readily reversed by 1 day of light exposure. This effect was restricted to an early critical period, similar to that reported for L4 neurons. However, at a later developmental age, a longer duration of DE (1 wk) decreased the strength of excitatory synapses, which reversed to normal levels with light exposure. These changes are opposite to what is predicted from the homeostatic plasticity theory. Our results suggest that L6 neurons differentially adjust their excitatory synaptic strength to visual deprivation depending on the age of the animals.     

Role of NMDA and non-NMDA receptors in synaptic transmission in rat piriform cortex

Summary The pharmacology of synaptic transmission was studied in slices of rat piriform cortex using the selective non-NMDA glutamate receptor antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX) and the selective NMDA receptor antagonist D-2-amino-5-phosphonopentanoate (D-AP5). DNQX produced a dose-dependent blockade of synaptic transmission at both lateral olfactory tract and associational system synapses with half-maximal effects at about 2.5 M. D-AP5 had no significant effects on field potentials recorded in medium containing 2.5 mM Mg⁺⁺. However in low Mg⁺⁺ (100–200 M) medium, D-AP5 did reduce a slow component of postsynaptic responses in both synaptic systems. In Mg⁺⁺-free medium, 20 M DNQX did not completely block transmission; the remaining response components were blocked by D-AP5. These results suggest that normal synaptic transmission in the two main inputs to the superficial layers of piriform cortex is mediated by non-NMDA receptors but that NMDA receptors can also participate under conditions where the Mg⁺⁺ block of the NMDA channel is alleviated.     

Activity-dependent synaptic plasticity of NMDA receptors

Activity-dependent, bidirectional control of synaptic efficacy is thought to contribute to many forms of experience-dependent plasticity, including learning and memory. Although most excitatory synapses contain both AMPA and N -methyl- d -aspartate receptors (AMPARs and NMDARs), most studies have focused on the plasticity of synaptic AMPARs, and on the pivotal role of NMDA receptors for its induction. Here we review evidence that synaptic NMDARs themselves are subject to long-term activity-dependent changes by mechanisms that may differ from that of synaptic AMPARs. The bidirectional modulation of NMDAR-mediated synaptic responses is likely to have important functional implications for NMDAR-dependent forms of synaptic plasticity.     

Astrocytic control of synaptic NMDA receptors

Astrocytes express a wide range of G-protein coupled receptors that trigger release of intracellular Ca²⁺, including P2Y, bradykinin and protease activated receptors (PARs). By using the highly sensitive sniffer-patch technique, we demonstrate that the activation of P2Y receptors, bradykinin receptors and protease activated receptors all stimulate glutamate release from cultured or acutely dissociated astrocytes. Of these receptors, we have utilized PAR1 as a model system because of favourable pharmacological and molecular tools, its prominent expression in astrocytes and its high relevance to neuropathological processes. Astrocytic PAR1-mediated glutamate release in vitro is Ca²⁺ dependent and activates NMDA receptors on adjacent neurones in culture. Activation of astrocytic PAR1 in hippocampal slices induces an APV-sensitive inward current in CA1 neurones and causes APV-sensitive neuronal depolarization in CA1 neurones, consistent with release of glutamate from astrocytes. PAR1 activation enhances the NMDA receptor-mediated component of synaptic miniature EPSCs, evoked EPSCs and evoked EPSPs in a Mg²⁺-dependent manner, which may reflect spine head depolarization and consequent reduction of NMDA receptor Mg²⁺ block during subsequent synaptic currents. The release of glutamate from astrocytes following PAR1 activation may also lead to glutamate occupancy of some perisynaptic NMDA receptors, which pass current following relief of tonic Mg²⁺ block during synaptic depolarization. These results suggest that astrocytic G-protein coupled receptors that increase intracellular Ca²⁺ can tune synaptic NMDA receptor responses.     

Reversible blockade of experience-dependent plasticity by calcineurin in mouse visual cortex

Numerous protein kinases have been implicated in visual cortex plasticity, but the role of serine/threonine protein phosphatases has not yet been established. Calcineurin, the only known Ca2+/calmodulin-activated protein phosphatase in the brain, has been identified as a molecular constraint on synaptic plasticity in the hippocampus and on memory. Using transgenic mice overexpressing calcineurin inducibly in forebrain neurons, we now provide evidence that calcineurin is also involved in ocular dominance plasticity. A transient increase in calcineurin activity is found to prevent the shift of responsiveness in the visual cortex following monocular deprivation, and this effect is reversible. These results imply that the balance between protein kinases and phosphatases is critical for visual cortex plasticity.     

miR-132, an experience-dependent microRNA, is essential for visual cortex plasticity

Using quantitative analyses, we identified microRNAs (miRNAs) that were abundantly expressed in visual cortex and that responded to dark rearing and/or monocular deprivation. The most substantially altered miRNA, miR-132, was rapidly upregulated after eye opening and was delayed by dark rearing. In vivo inhibition of miR-132 in mice prevented ocular dominance plasticity in identified neurons following monocular deprivation and affected the maturation of dendritic spines, demonstrating its critical role in the plasticity of visual cortex circuits.     

Recruiting extrasynaptic NMDA receptors augments synaptic signaling

N-Methyl-d-aspartate receptor (NMDAR) activation may promote cell survival or initiate cell death, with the outcome dependent on whether synaptic or extrasynaptic receptors are activated. Similarly, this differential activation has been proposed to govern the direction of plasticity. However, the physiological parameters necessary to activate extrasynaptic NMDARs in brain slices remain unknown. Using the irreversible use-dependent NMDAR antagonist MK-801 to isolate extrasynaptic NMDARs, we have tested the ability of short-stimulation trains from 5 to 400 Hz to activate these receptors on CA1 hippocampal slice pyramidal neurons. Frequencies as low as 25 Hz engage extrasynaptic NMDARs, with maximal activation at frequencies between 100 and 200 Hz. Since similar bursts of synaptic input occur during exploratory behavior in rats, our results demonstrate that "extrasynaptic" NMDARs regularly participate in synaptic transmission. Further, 175-Hz-stimulation trains activate all available synaptic and extrasynaptic dendritic NMDARs, suggesting these NMDARs act as synaptic receptors as needed, transiently increasing synaptic strength. Thus extrasynaptic NMDARs play a vital role in synaptic physiology, calling into question their status as "extrasynaptic."     

Induction of NMDA receptor-dependent long-term depression in visual cortex does not require metabotropic glutamate receptors

We tested the role of group I mGluRs in the induction of long-term depression (LTD) in the visual cortex, using the novel mGluR antagonist LY341495 and mice lacking mGluR5, the predominant phosphoinositide (PI)-linked mGluR in the visual cortex. We find that LY341495 is a potent blocker of glutamate-stimulated PI hydrolysis in visual cortical synaptoneurosomes, and that it effectively antagonizes the actions of the mGluR agonist 1S, 3R-aminocyclopentane-1,3-dicarboxylic acid (ACPD) on synaptic transmission in visual cortical slices. However, LY341495 has no effect on the induction of LTD by low-frequency stimulation. Furthermore, mice lacking mGluR5 show normal NMDA receptor-dependent LTD. These results indicate that group I mGluR activation is not required for the induction of NMDA receptor-dependent LTD in the visual cortex.     

Differential regulation of synaptic and extra-synaptic NMDA receptors

A variety of processes limit NMDA (N-methyl-D-aspartate) receptor (NMDAR) activity in response to agonist exposure, including rundown--the decline of peak current with repeated, sustained agonist application. Here we report that calcium and tyrosine phosphorylation differentially regulate rundown of synaptic versus extrasynaptic NMDAR-mediated current in rat hippocampal pyramidal neurons.     

Dynamic,experience-dependent modulation of synaptic zinc within the excitatory synapses of the mouse barrel cortex

Increasing evidence suggests that synaptic zinc, found within the axon terminals of a subset of glutamatergic neurons in the cerebral cortex, is intricately involved in cortical plasticity. Using the vibrissae/barrel cortex model of cortical plasticity, we have previously shown manipulations of sensory input leads to rapid changes in synaptic zinc levels within the corresponding regions of the somatotopic map in the cortex. Here, using electron microscopy, we show how some of these changes are mediated at the synaptic level. We found that the density of zincergic synapses increased significantly in layers II/III, IV, and V. In layers IV and V, this change occurred in the absence of a significant increase in excitatory synapse density, which seems to indicate that excitatory synapses, which previously did not contain synaptic zinc, begin to newly house zinc within its synaptic vesicles. Our results show that excitatory neurons can dynamically change the phenotype of the vesicular content of their synapses in response to changes in sensory input. Given the range of modulatory effects zinc can have on neurotransmission, such a change in the complement of vesicular contents presumably allow these neurons to utilize synaptic zinc to facilitate plasticity. Thus, our results further support the role of zinc as an active participant in the processes contributing to experience-dependent cortical plasticity.     

猫视皮层N-甲基-D-天门冬氨酸受体的基因表达

目的　检测 5种NMDAR亚基的mRNA在猫视皮层的表达情况 ,为NMDAR的功能多样性提供分子基础。方法　 3月龄猫 6只 ,采用地高辛标记的寡核苷酸探针 ,对猫视皮层切片进行原位杂交。结果　NR1的mRNA在视皮层的所有层均有强表达 ,NR2A在Ⅲ、Ⅳ层表达较高 ,而Ⅱ、Ⅴ层呈中等水平 ;NR2B的表达信号较弱 ,主要表达于Ⅰ、Ⅲ和Ⅴ层 ;NR2CmRNA的信号很弱 ,表达Ⅲ、Ⅴ和Ⅵ层 ;NR2DmRNA在视皮层各层呈中等表达 ,以Ⅴ和Ⅵ层的信号最强。结论　NMDAR各亚基在猫视皮层中的基因表达具有多样性 ,这可能构成了不同NR通道具有功能差异的分子基础     

Thalamic NMDA receptors and nociceptive sensory synaptic transmission

The responses of single thalamic neurones to noxious thermal stimulation were recorded in anaesthetized rats. The selective (NMDA) receptor antagonist, 3-((±)-2-carboxypiperazin-4-yl)propyl-1-phosphonate (CPP), antagonised nociceptive responses when ejected iontophoretically with currents which produced selective antagonism at NMDA receptors. In contrast, the non-NMDA excitatory amino acid receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) had little or no effect on nociceptive responses, although it was able to reduce responses to non-nociceptive mechanoreceptor input. These results show that there is substantial NMDA receptor involvement in thalamic nociceptive responses, and that the contribution of CNQX-sensitive non-NMDA receptors to these responses is not extensive. Furthermore, it appears that nociceptive and non-nociceptive input to the thalamus have distinct synaptic pharmacologies.     

Laminar analysis of the role of GluR1 in experience-dependent and synaptic depression in barrel cortex

Several synaptic depression mechanisms have been described for the hippocampus, cerebellum and neocortex in vitro, but little is known about which, if any, are engaged during experience-dependent depression (EDD). We found that EDD in the mouse barrel cortex depends on the AMPA subunit GluR1 in layers II/III and IV, but not in layer V, and that long-term depression is also GluR1 dependent in the IV-II/III, but not II/III-V, pathway.     

Mechanisms underlying dedepression of synaptic NMDA receptors in the hippocampus

N-Methyl-D-aspartate receptor (NMDAR)-mediated synaptic responses in hippocampal CA1 pyramidal cells are depressed during NMDAR-dependent long-term depression (LTD) due to mechanisms, in part, distinct from those underlying LTD of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated synaptic responses. The mechanisms underlying dedepression of synaptic NMDARs, however, are not known. We find that dedepression of NMDAR-mediated synaptic responses in the CA1 region of the rat hippocampus is input specific and does not require synaptic stimulation to be maintained. The induction of dedepression does not require activation of metabotropic glutamate receptors, L-type Ca(2+) channels, or release of Ca(2+) from intracellular stores. It does, however, rely on activation of NMDARs. In contrast to the dedepression of AMPAR-mediated synaptic responses, dedepression of NMDAR-mediated synaptic responses does not depend on activation of calcium/calmodulin-dependent protein kinase II, protein kinase C, cAMP-dependent protein kinase, or Src kinases. However, dedepression of synaptic NMDARs is significantly impaired by inhibitors of mitogen-activated protein kinase signaling. Specifically, inhibitors of extracellular signal-regulated kinase 1/2 prevented normal dedepression of synaptic NMDARs by a mechanism that did not require protein synthesis. These results provide further evidence that synaptic NMDARs can be bidirectionally modified by activity but by mechanisms distinct from those responsible for the activity-dependent, bidirectional modulation of synaptic AMPARs.     

NMDA receptor-dependent long-term synaptic depression in the entorhinal cortex in vitro

Kourrich, Saïd andC. Andrew Chapman.NMDA Receptor-Dependent Long-Term Synaptic Depression in theEntorhinal Cortex In Vitro. J. Neurophysiol. 89: 2112-2119, 2003. The entorhinal cortex receives a largeprojection from the piriform (primary olfactory) cortex and, in turn,provides the hippocampal formation with most of its cortical sensoryinput. Synaptic plasticity in this pathway may therefore affect theprocessing of olfactory information and memory encoding. We haverecently found that long-term synaptic depression (LTD) can be induced in this pathway in vivo by repetitive paired-pulse stimulation but notby low-frequency (1 Hz) stimulation with single pulses. Here, we haveused field potential recordings to investigate the stimulationparameters and transmitter receptors required for the induction of LTDin the rat entorhinal cortex in vitro. The effectiveness oflow-frequency stimulation (900 pulses at 1 or 5 Hz) and repeateddelivery of pairs of stimulation pulses (30-ms interpulse interval) wasassessed. Only repeated paired-pulse stimulation resulted in lastingLTD, and a low-intensity paired-pulse stimulation protocol that inducesLTD in vivo was only effective in the presence of theGABA_A receptor antagonist bicuculline (50 µM).LTD could also be induced in normal ACSF, however, by increasing thenumber of pulse-pairs delivered and by increasing the stimulation intensity during LTD induction. The induction of LTD was blocked byconstant bath application of theN-methyl-D-aspartate (NMDA) glutamate receptorantagonist D-2-amino-5-phosphonovalerate (50 µM),indicating that LTD is dependent on NMDA receptor activation. However,LTD was not blocked by the group I/II mGluR antagonist (RS)--ethyl-4-carboxyphenylglycine (500 µM) or by bicuculline (50 µM). The induction of LTD in the entorhinal cortex in vitro istherefore dependent on intense stimulation that recruits activation ofNMDA receptors, but does not require concurrent activation of mGluRs orinhibitory synaptic inputs.