Yupeng Yang

Requirement for the RIIβ Isoform of PKA, But Not Calcium-Stimulated Adenylyl Cyclase, in Visual Cortical Plasticity

The cAMP-dependent protein kinase (PKA) signaling pathway plays a key role in visual cortical plasticity. Inhibitors that block activation of all PKA regulatory subunits (RIα,RIβ, RIIα, RIIβ) abolish long-term potentiation (LTP) and long-term depression (LTD) in vitro and ocular dominance plasticity (ODP) in vivo. The details of this signaling cascade, however, including the source of PKA signals and which PKA subunits are involved, are unknown. To investigate these issues we have examined LTP, LTD, and ODP in knock-out mice lacking either the two cortically expressed Ca2+-stimulated adenylyl cyclases (AC1 and AC8) or the predominant neocortical subunit of PKA (RIIβ). Here we show that plasticity remains intact in AC1/AC8-/- mice, whereas ODP and LTD, but not LTP, are absent in RIIβ-/- mice. We conclude that (1) plasticity in the visual cortex does not require the activity of known Ca2+-stimulated adenylyl cyclases, (2) the PKA dependence of ODP and LTD, but not LTP, is mediated by RIIβ-PKA, and (3) multiple isoforms of PKA contribute to LTD.

Reduced ocular dominance plasticity and long-term potentiation in the developing visual cortex of protein kinase A RIIα mutant mice

The cAMP‐dependent protein kinase (PKA) signalling pathway has been shown to play an important role in long‐term potentiation (LTP) and depression (LTD), and ocular dominance plasticity in the visual cortex. In order to investigate further the involvement of individual PKA subunits in visual cortical plasticity, LTP and LTD in vitro and ocular dominance plasticity in vivo in the developing visual cortex were examined in mice lacking the RIIα subunit of PKA. Here we show that LTP in layers II/III was decreased in RIIα knockout mice, but LTD was almost unaffected, and the ocular dominance shift induced by monocular deprivation was also partially blocked. These data provide evidence that RIIα is involved in LTP and ocular dominance plasticity, and further suggest that different afferent inputs could selectively activate particular subunits of PKA and thereby direct specific aspects of visual cortical plasticity.

Impaired In Vivo Synaptic Plasticity in Dentate Gyrus and Spatial Memory in Juvenile Rats Induced by Prenatal Morphine Exposure

Prenatal morphine exposure induces neurobiological changes, including deficits in learning and memory, in juvenile rat offspring. However the effects of this exposure on hippocampal plasticity, which is critical for learning and memory processes, are not well understood. The present study investigates the alterations of spatial memory and in vivo hippocampal synaptic plasticity in juvenile rats prenatally exposed to morphine. On gestation days 11–18, pregnant rats were randomly chosen to be injected twice daily with morphine or saline. Each juvenile offspring (postnatal day 22–31) performed one two‐trial Y‐maze task to evaluate spatial memory. Afterwards, the in vivo field excitatory postsynaptic potential (fEPSP) and population spike (PS) were recorded in the perforant path dentate gyrus (DG) pathway in the hippocampus. Prenatal morphine exposure reduced depotentiation (DP), but not long‐term potentiation (LTP), of the EPSP slope. However, both LTP and DP of the EPSP slope were depressed in prenatal morphine‐exposed juvenile offspring. The morphine group also showed poorer performance for the Y‐maze task than the control group. Depressed PS LTP, but not EPSP LTP, in the morphine group suggested that prenatal morphine exposure changed GABAergic inhibition, which mediates EPSP‐spike potentiation. Then a loss of GABA‐containing neurons in the DG area of the morphine group was observed using immunohistochemistry. Taken together, our results suggest that prenatal morphine exposure impairs the juvenile offsprings dentate synaptic plasticity and spatial memory, and that decreased GABAergic inhibition may play a role in these effects. These findings might contribute to an explanation for the cognitive deficits in children whose mothers abuse opiates during pregnancy.

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.

LTP and LTD vary with layer in rodent visual cortex

Mechanisms of plasticity in the visual cortex have been studied with long-term potentiation (LTP), long-term depression (LTD) and ocular dominance plasticity (ODP). It is now possible to compare results from these three forms of plasticity using knockout mice, and also by pharmacological manipulations. A review of the literature shows that if both LTP and LTD are completely abolished, then ODP will also be abolished. In other situations, there is little correlation. We hypothesize that this lack of correlation occurs because the mechanisms for LTP and LTD vary with layer in the visual cortex, and results show that they do.

Identification of two functionally distinct endosomal recycling pathways for dopamine d2 receptor.

Dopamine D2 receptor (DRD2) is important for normal function of the brain reward circuit. Lower DRD2 function in the brain increases the risk for substance abuse, obesity, attention deficit/hyperactivity disorder, and depression. Moreover, DRD2 is the target of most antipsychotics currently in use. It is well known that dopamine-induced DRD2 endocytosis is important for its desensitization. However, it remains controversial whether DRD2 is recycled back to the plasma membrane or targeted for degradation following dopamine stimulation. Here, we used total internal reflection fluorescent microscopy (TIRFM) to image DRD2 with a superecliptic pHluorin tagged to its N terminus. With these technical advances, we were able to directly visualize vesicular insertion events of DRD2 in cultured mouse striatal medium spiny neurons. We showed that insertion of DRD2 occurs on neuronal somatic and dendritic surfaces. Lateral diffusion of DRD2 was observed following its insertion. Most importantly, using our new approach, we uncovered two functionally distinct recycling pathways for DRD2: a constitutive recycling pathway and a dopamine activity-dependent recycling pathway. We further demonstrated that Rab4 plays an important role in constitutive DRD2 recycling, while Rab11 is required for dopamine activity-dependent DRD2 recycling. Finally, we demonstrated that the two DRD2 recycling pathways play distinct roles in determining DRD2 function: the Rab4-sensitive constitutive DRD2 recycling pathway determines steady-state surface expression levels of DRD2, whereas the Rab11-sensitive dopamine activity-dependent DRD2 recycling pathway is important for functional resensitization of DRD2. Our findings underscore the significance of endosomal recycling in regulation of DRD2 function.

GABAA and GABAB receptors mediated inhibition affect the pattern adaptation of relay cells in the dorsal lateral geniculate nucleus (LGNd) of cats

Pattern adaptation is very important for visual function, while the mechanisms that mediate pattern adaptation, especially in the dorsal lateral geniculate nucleus (LGNd), are still unclear. Iontophoresis of the antagonists and agonists of GABA receptors were employed to separately investigate the contribution of GABA(A) and GABA(B) receptors to pattern adaptation of LGNd cells. When GABA(A) receptors were blocked by bicuculline both the response amplitude of LGNd cells and the degree of adaptation increased significantly. Many neurons showing no pattern adaptation under the normal condition became adapted to a prolonged stimulus. Moreover, the proportion of cells showing adaptation doubled (from 40 to 88%). The mean adaptation index (AI, adapted response amplitude/original response amplitude) was 0.82 during bicuculline application, compared with 0.92 under the control condition. In additional, iontophoresis of baclofen, a selective GABA(B) receptor agonist, decreased the mean response amplitude to grating stimuli to 53% of normal. Nearly half of the neurons increased their adaptation index following baclofen administration and the mean AI increased from 0.89 to 1.01. Iontophoresis of GABA(B) receptor antagonist (CGP35348) could abolish this effect, though it had no significant effect on visual response amplitude and pattern adaptation itself. Iontophoresis of another GABA(B) receptor antagonist, 2-OH-saclofen, also had no significant effect on visual response amplitude and pattern adaptation. These results suggest that both GABA(A) receptors and GABA(B) receptors modulate the pattern adaptation of LGNd cells and are involved in synaptic plasticity.

Contrast adaptation in cat lateral geniculate nucleus and influence of corticothalamic feedback

Contrast adaptation is a basic property of visual information processing. However, important questions about contrast adaptation in the lateral geniculate nucleus (LGN) remain. For example, it is unclear whether the different information channels have the same or distinct contrast adaptation properties and mechanisms. It has been recognized that the visual system is not a one‐way ascending pathway, but also contains descending feedback projections. Although studies have explored the role of this feedback system, it is unclear whether corticothalamic feedback contributes to adaptation in the LGN. To investigate these questions, we studied contrast adaptation of LGN neurons in anesthetized and paralysed cats by measuring electrophysiological responses to visual test stimuli before and after adaptation induced by prolonged visual stimulation. After adaptation, contrast response functions were usually shifted towards higher contrasts, indicating decreased contrast gain, and the maximum response decreased. Also, contrast adaptation effects were stronger in Y‐cells than in X‐cells. Furthermore, adaptation effects were still observed in the LGN when the corticothalamic feedback was inactivated. Changes in the contrast gain of Y‐cells were diminished in the absence of feedback, while contrast gain was largely unchanged in X‐cells. Our observations confirm that contrast adaptation occurs in LGN neurons and furthermore demonstrate that Y‐cells show stronger adaptation effects than X‐cells. These results also provide an example of how corticothalamic feedback modulates contrast information processing distinctly in different information channels.

Non-dominant eye responses in the dorsal lateral geniculate nucleus of the cat: an intracellular study

UNLABELLED While binocularity has been established as an important characteristic of cat visual cortical neurons, neurons in the dorsal lateral geniculate nucleus (LGNd) are commonly believed to be monocular. To test whether binocularity exists at the level of the LGNd, postsynaptic potentials (PSPs) of 101 cells were intracellularly recorded in eight normal and eight monocularly deprived cats while presenting stimuli to either the dominant or non-dominant eyes. The results showed that: (1) About 92% of neurons (45 out of 49) responded to a flashing spot presented to the non-dominant eye. In contrast to the dominant eye responses, the non-dominant eye PSPs usually exhibited the same polarization tendency (hyperpolarization or depolarization) to flashing spot stimuli of light increment or decrement, and most of them were inhibitory (hyperpolarization, 35 out of 45, 78%). (2) The response field (RF) of the non-dominant eye overlapped that of the dominant eye. (3) For most binocular cells, peak-to-peak amplitudes of non-dominant eye PSPs were about half the size (46%) of those of the dominant eye. The peak latencies and half-peak latencies of non-dominant eye PSPs were significantly longer than those of the dominant eye (mean differences were 5.4 ms and 5.6 ms respectively). (4) Most of the binocular cells responded well to contrast reversing gratings presented to the non-dominant eye, and the responses were clearly spatial-frequency tuned. No null phase could be found for non-dominant eye PSPs, no matter the neuron was classified as X or Y type according to dominant eye elicited responses. Some of the cells responded well to drifting gratings presented to the non-dominant eye. (5) We also recorded 52 cells in monocularly deprived cats, and found that 49 cells (94%) showed significant responses to flashing spots presented to the non-dominant eye, a similar percentage to that found in normal cats (92%). CONCLUSION as strongly monocular neurons, most of LGNd cells could also be driven by the non-dominant eye. The responses evoked by non-dominant eye stimulation differ greatly from those evoked by dominant eye stimulation, and remain intact even without visual experience. These observations suggest an important role of the perigeniculate nucleus in providing binocular inputs to LGNd cells.

The Topographical Arrangement of Cutoff Spatial Frequencies across Lower and Upper Visual Fields in Mouse V1

The visual response to spatial frequency (SF), a characteristic of spatial structure across position in space, is of particular importance for animal survival. A natural challenge for rodents is to detect predators as early as possible while foraging. Whether neurons in mouse primary visual cortex (V1) are functionally organized to meet this challenge remains unclear. Combining intrinsic signal optical imaging and single-unit recording, we found that the cutoff SF was much greater for neurons whose receptive fields were located above the mouse. Specifically, we discovered that the cutoff SF increased in a gradient that was positively correlated with the elevation in the visual field. This organization was present at eye opening and persisted through adulthood. Dark rearing delayed the maturation of the cutoff SF globally, but had little impact on the topographical organization of the cutoff SF, suggesting that this regional distribution is innately determined. This form of cortical organization of different SFs may benefit the mouse for detection of airborne threats in the natural environment.