Standard Amblyopia Therapy in Adults with Longstanding Amblyopia Improves Visual Acuity and Contrast Sensitivity.

Purpose: Perceptual learning or dichoptic training may result in improved acuity in adult amblyopes. However, for amblyopic children (<18 years), most clinicians recommend standard part-time patching. The purpose of this study was to determine if standard amblyopia therapy results in an enhancement in vision in the amblyopic eye of adults.

Inhibitors of the Neutral Amino Acid Transporters ASCT1 and ASCT2 Are Effective in In Vivo Models of Schizophrenia and Visual Dysfunction.

The -methyl-d-aspartate receptor coagonist d-serine is a substrate for the neutral amino acid transporters ASCT1 and ASCT2, which may regulate its extracellular levels in the central nervous system (CNS). We tested inhibitors of ASCT1 and ASCT2 for their effects in rodent models of schizophrenia and visual dysfunction, which had previously been shown to be responsive to d-serine. L-4-fluorophenylglycine (L-4FPG), L-4-hydroxyPG (L-4OHPG), and L-4-chloroPG (L-4ClPG) all showed high plasma bioavailability when administered systemically to rats and mice.

Phenylglycine analogs are inhibitors of the neutral amino acid transporters ASCT1 and ASCT2 and enhance NMDA receptor-mediated LTP in rat visual cortex slices.

The N-methyl-d-aspartate receptor (NMDA) co-agonist d-serine is a substrate for the neutral amino acid transporters ASCT1 (SLC1A4) and ASCT2 (SLC1A5). We identified l-phenylglycine (PG) and its analogs as inhibitors of ASCT1 and ASCT2. PG analogs were shown to be non-substrate inhibitors of ASCT1 and ASCT2 with a range of activities relative to other amino acid transport systems, including sodium-dependent glutamate transporters, the sodium-independent d-serine transporter asc-1 and system L.

Restoration of visual performance by d-serine in models of inner and outer retinal dysfunction assessed using sweep VEP measurements in the conscious rat and rabbit.

The NMDA subtype of glutamate receptor and its co-agonist d-serine play a key role in synaptic function in the central nervous system (CNS), including visual cortex and retina. In retinal diseases such as glaucoma and macular degeneration, a loss of vision arises from malfunction of retinal cells, resulting in a glutamate hypofunctional state along the visual pathway in the affected parts of the visual field. An effective strategy to remedy this loss of function might be to increase extracellular levels of d-serine and thereby boost synaptic NMDA receptor-mediated visual transmission and/or plasticity to compensate for the impairment.

D-Serine Is a Substrate for Neutral Amino Acid Transporters ASCT1/SLC1A4 and ASCT2/SLC1A5, and Is Transported by Both Subtypes in Rat Hippocampal Astrocyte Cultures.

N-methyl-D-aspartate (NMDA) receptors play critical roles in synaptic transmission and plasticity. Activation of NMDA receptors by synaptically released L-glutamate also requires occupancy of co-agonist binding sites in the tetrameric receptor by either glycine or D-serine. Although D-serine appears to be the predominant co-agonist at synaptic NMDA receptors, the transport mechanisms involved in D-serine homeostasis in brain are poorly understood.

Activity of the enantiomers of erythro-3-hydroxyaspartate at glutamate transporters and NMDA receptors.

The enantiomers of erythro-3-hydroxyaspartate were tested for activity at glutamate transporters and NMDA receptors. Both enantiomers inhibited glutamate transporters in rat hippocampal crude synaptosomes and elicited substrate-like activity at excitatory amino acid transporter 1, 2, and 3 as measured by voltage clamp in the Xenopus oocyte expression system. The enantiomers had similar affinities, but the D-enantiomer showed a lower maximal effect at excitatory amino acid transporter 1, 2, and 3 than the L-enantiomer.

Effects of 3-aminoglutarate, a "silent" false transmitter for glutamate neurons, on synaptic transmission and epileptiform activity.

Pharmacological tools that interact with the mechanisms that regulate vesicular filling and release of the neurotransmitter L-glutamate would be of enormous value. In this study, we provide physiological evidence that the glutamate analog, 3-aminoglutarate (3-AG), acts as a false transmitter to reduce presynaptic glutamate release. 3-AG inhibits glutamate-mediated neurotransmission both in primary neuronal cultures and in brain slices with more intact neural circuits.

3-Aminoglutarate is a "silent" false transmitter for glutamate neurons.

Understanding the storage and release of the excitatory neurotransmitter, L-glutamate by synaptic vesicles has lagged behind receptor characterizations due to a lack of pharmacological agents. We report that the glutamate analog, 3-aminoglutarate (3-AG) is a "silent" false transmitter for glutamate neurons that may be a useful tool to study storage and release mechanisms. Like L-glutamate itself, 3-AG is a high-affinity substrate for both the plasma membrane (EAATs) and vesicular (vGLUT) glutamate transporters.

Spike timing in CA3 pyramidal cells during behavior: implications for synaptic transmission.

Spike timing is thought to be an important mechanism for transmitting information in the CNS. Recent studies have emphasized millisecond precision in spike timing to allow temporal summation of rapid synaptic signals. However, spike timing over slower time scales could also be important, through mechanisms including activity-dependent synaptic plasticity or temporal summation of slow postsynaptic potentials (PSPs) such as those mediated by kainate receptors.

GABA(B) receptor-mediated presynaptic inhibition has history-dependent effects on synaptic transmission during physiologically relevant spike trains.

Presynaptic inhibition is a form of neuromodulation that interacts with activity-dependent short-term plasticity so that the magnitude, and sometimes even the polarity, of that activity-dependent short-term plasticity is changed. However, the functional consequences of this interaction during physiologically relevant spike trains are poorly understood. We examined the effects of presynaptic inhibition on excitatory synaptic transmission during physiologically relevant spike trains, using the GABA(B) receptor (GABA(B)R) agonist baclofen to engage presynaptic inhibition and field EPSPs (fEPSPs) in hippocampal slices to monitor synaptic output.

Presynaptic kainate receptors play different physiological roles in mossy fiber and associational-commissural synapses in CA3 of hippocampus from adult rats.

Mossy fiber (MF) and Associational-commissural (Assoc-com) synaptic responses were recorded simultaneously in CA3 from the same hippocampal slice. Low concentrations of Kainate (KA) (50 and 100 nM) reversibly increased the synaptic response and decreased the paired-pulse facilitation (PPF) in the MF synapse, while reversibly decreasing the synaptic response and increasing the PPF in the Assoc-com synapse. The same concentration of KA had no effect on synaptic transmission or the induction and expression of long-term potentiation (LTP) in area CA1.

Arg3.1/Arc mRNA induction by Ca2+ and cAMP requires protein kinase A and mitogen-activated protein kinase/extracellular regulated kinase activation.

Long-term potentiation (LTP) is a cellular model for persistent synaptic plasticity in the mammalian brain. Like several forms of memory, long-lasting LTP requires cAMP-mediated activation of protein kinase A (PKA) and is dependent on gene transcription. Consequently, activity-dependent genes such as c-fos that contain cAMP response elements (CREs) in their 5' regulatory region have been studied intensely.

Recognition memory correlates of hippocampal theta cells.

Investigations of hippocampal theta cell activity have typically involved behavioral tasks with modest cognitive demands. Recordings in rats locomoting through space or engaged in simple stimulus discrimination or conditioning have revealed some place specificity and S(+)/S(-) selectivity in addition to the hippocampal EEG theta-related behavioral/motor correlates. However, little data exist regarding theta cell activity during performance of more cognitively demanding, hippocampal-dependent recognition memory tasks.

Dynamic filtering of recognition memory codes in the hippocampus.

Principal cells of the dentate gyrus (DG), CA3, and CA1 subfields of the hippocampus were recorded in rat during performance of an odor-guided delayed nonmatch-to-sample task with distinct sample and test phases. The hippocampus was found to possess multiple encoding modes. In the sample phase, odor-selective activity was restricted primarily to CA1 and, to a lesser extent, CA3.

The polo-like protein kinases Fnk and Snk associate with a Ca(2+)- and integrin-binding protein and are regulated dynamically with synaptic plasticity.

In order to stabilize changes in synaptic strength, neurons activate a program of gene expression that results in alterations of their molecular composition and structure. Here we demonstrate that Fnk and Snk, two members of the polo family of cell cycle associated kinases, are co-opted by the brain to serve in this program. Stimuli that produce synaptic plasticity, including those that evoke long-term potentiation (LTP), dramatically increase levels of both kinase mRNAs.

Time-dependent reversal of long-term potentiation in area CA1 of the freely moving rat induced by theta pulse stimulation.

Previous studies in slices have shown that low-frequency stimulation at 5 Hz, i.e., theta pulse stimulation (TPS), completely reverses long-term potentiation (LTP) in area CA1 when delivered within 1-2 min after induction but produces progressively less depotentiation at longer delays, until it has no longer any impact at 30 min after induction.

Pim kinase expression is induced by LTP stimulation and required for the consolidation of enduring LTP.

In animals and several cellular models of synaptic plasticity, long-lasting changes in synaptic strength are dependent on gene transcription and translation. Here we demonstrate that Pim-1, a serine/threonine kinase closely related to Pim-2 and Pim-3, is induced in hippocampus in response to stimuli that evoke long-term potentiation (LTP). Mice deficient for Pim-1 show normal synaptic transmission and short-term plasticity.

GABAB receptor antagonism: facilitatory effects on memory parallel those on LTP induced by TBS but not HFS.

The present experiments used CGP 35348, a selective GABAB receptor antagonist with a significantly higher affinity for post- versus presynaptic receptors, to dissociate the role of antagonist concentration versus stimulation mode in determining whether GABAB receptor blockade facilitates or suppresses long-term potentiation (LTP). The antagonist was applied by pressure ejection to one of two recording sites in area CA1 of hippocampal slices before LTP was induced at both sites with either theta burst or high-frequency stimulation (TBS or HFS). TBS produced a dose-dependent facilitation of potentiation that turned into depression at the highest concentration tested, a result reflecting the dose-dependent balance between the drug's postsynaptic disinhibitory effect and its action on presynaptic autoreceptors regulating the release of GABA.

Unilateral hippocampal ablation at birth causes a reduction in contralateral LTP.

Subcortical damage in neonates often has more severe consequences than in adults. Unilateral electrolytic hippocampal lesions in adult rats typically result in transient memory deficits, whereas neonatal lesions cause lasting memory impairments. We hypothesized that unilateral lesions made at birth may affect synaptic physiology in the contralateral hippocampus.

Time-dependent reversal of long-term potentiation by an integrin antagonist.

The integrin antagonist Gly-Arg-Gly-Asp-Ser-Pro (GRGDSP) was applied by local ejection to one of two recording sites in hippocampal slices at various times before and after long-term potentiation (LTP) was induced at both sites with theta burst stimulation. Applications 10 min before, immediately after, and 10 min after induction caused LTP at the experimental site to decay steadily relative to that at the within-slice control site. However, application at 25 min or more after induction had no detectable effect on potentiation.

Fear conditioning induces associative long-term potentiation in the amygdala.

Long-term potentiation (LTP) is an experience-dependent form of neural plasticity believed to involve mechanisms that underlie memory formation. LTP has been studied most extensively in the hippocampus, but the relation between hippocampal LTP and memory has been difficult to establish. Here we explore the relation between LTP and memory in fear conditioning, an amygdala-dependent form of learning in which an innocuous conditioned stimulus (CS) elicits fear responses after being associatively paired with an aversive unconditioned stimulus (US).

Neonatal vs. adult unilateral hippocampal lesions: differential alterations in contralateral hippocampal theta rhythm.

Subcortical damage often has more severe consequences in neonates than in adults. For example, unilateral hippocampal lesions in adult rats typically lead to transient memory deficits, whereas neonatal lesions cause lasting learning impairment. We hypothesized that the defects triggered by unilateral damage may include synaptic dysfunction in the contralateral hippocampus.

AMPA receptor facilitation accelerates fear learning without altering the level of conditioned fear acquired.

Rats treated with the AMPA receptor-facilitating drug 1-(quinoxolin-6-ylcarbonyl)piperidine (BDP-12) during training acquired fear conditioning to a tone faster than vehicle-treated controls. The effect on acquisition was dependent on the dose given. BDP-12-treated rats and vehicle-treated controls reached the same level of conditioned fear and extinguished at the same rate.

Studies on long-term depression in area CA1 of the anesthetized and freely moving rat.

Homosynaptic long-term depression (LTD) is reported to occur in field CA1 of hippocampal slices collected from immature brains. Because the effect has been postulated to be a memory storage mechanism, it is of interest to test for its presence in adult, awake animals. Unfortunately, not only has hippocampal LTD proved difficult to obtain reliably in vivo, but the few successful studies vary with respect to protocols and evidence that the depression is input-specific.

Arg-Gly-Asp-Ser-selective adhesion and the stabilization of long-term potentiation: pharmacological studies and the characterization of a candidate matrix receptor.

Peptides known to block the extracellular interactions of adhesion receptors belonging to a subclass of the integrin family were tested for their effects on the stabilization of long-term potentiation (LTP) in hippocampal slices. Theta burst stimulation delivered after infusions of Gly-Ala-Val-Ser-Thr-Ala (GAVSTA) resulted in a potentiation effect that decayed steadily over a period of 40 min; LTP elicited in the presence of inactive control peptides remained stable over this time period. GAVSTA had no detectible influence on baseline responses, induction processes, or the initial degree of potentiation.