Biomedical subjects

Hey-Kyoung Lee

Publications and source records attributed to Hey-Kyoung Lee.

9 recordsLinked to original sources

PubMed2006

Synaptic plasticity and phosphorylation.

A number of neuronal functions, including synaptic plasticity, depend on proper regulation of synaptic proteins, many of which can be rapidly regulated by phosphorylation. Neuronal activity controls the function of these synaptic proteins by exquisitely regulating the balance of various protein kinase and protein phosphatase activity. Recent understanding of synaptic plasticity mechanisms underscores important roles that these synaptic phosphoproteins play in regulating both pre- and post-synaptic functions. This review will focus on key postsynaptic phosphoproteins that have been implicated to play a role in synaptic plasticity.

Animals↗

PubMed2006

Cross-modal regulation of synaptic AMPA receptors in primary sensory cortices by visual experience.

Lack of a sensory input not only alters the cortical circuitry subserving the deprived sense, but also produces compensatory changes in the functionality of other sensory modalities. Here we report that visual deprivation produces opposite changes in synaptic function in primary visual and somatosensory cortices in rats, which are rapidly reversed by visual experience. This type of bidirectional cross-modal plasticity is associated with changes in synaptic AMPA receptor subunit composition.

Animals↗

PubMed2005

BACE1, a major determinant of selective vulnerability of the brain to amyloid-beta amyloidogenesis, is essential for cognitive, emotional, and synaptic functions.

A transmembrane aspartyl protease termed beta-site APP cleavage enzyme 1 (BACE1) that cleaves the amyloid-beta precursor protein (APP), which is abundant in neurons, is required for the generation of amyloid-beta (Abeta) peptides implicated in the pathogenesis of Alzheimer's disease (AD). We now demonstrate that BACE1, enriched in neurons of the CNS, is a major determinant that predisposes the brain to Abeta amyloidogenesis. The physiologically high levels of BACE1 activity coupled with low levels of BACE2 and alpha-secretase anti-amyloidogenic activities in neurons is a major contributor to the accumulation of Abeta in the CNS, whereas other organs are spared. Significantly, deletion of BACE1 in APPswe;PS1DeltaE9 mice prevents both Abeta deposition and age-associated cognitive abnormalities that occur in this model of Abeta amyloidosis. Moreover, Abeta deposits are sensitive to BACE1 dosage and can be efficiently cleared from the CNS when BACE1 is silenced. However, BACE1 null mice manifest alterations in hippocampal synaptic plasticity as well as in performance on tests of cognition and emotion. Importantly, memory deficits but not emotional alterations in BACE1(-/-) mice are prevented by coexpressing APPswe;PS1DeltaE9 transgenes, indicating that other potential substrates of BACE1 may affect neural circuits related to emotion. Our results establish BACE1 and APP processing pathways as critical for cognitive, emotional, and synaptic functions, and future studies should be alert to potential mechanism-based side effects that may occur with BACE1 inhibitors designed to ameliorate Abeta amyloidosis in AD.

Amyloid Precursor Protein Secretases↗

PubMed2005

NMDA receptor-independent long-term depression correlates with successful aging in rats.

Some individuals maintain high cognitive functioning at older ages. Here we show that mechanisms for long-term depression differ in aged rodents that maintain cognitive performance compared to young adults. Our results imply that cognitive abilities may be sustained in aged individuals by a switch in synaptic plasticity mechanisms.

Adaptation, Physiological↗

PubMed2004

Altered cortical synaptic morphology and impaired memory consolidation in forebrain- specific dominant-negative PAK transgenic mice.

Molecular and cellular mechanisms for memory consolidation in the cortex are poorly known. To study the relationships between synaptic structure and function in the cortex and consolidation of long-term memory, we have generated transgenic mice in which catalytic activity of PAK, a critical regulator of actin remodeling, is inhibited in the postnatal forebrain. Cortical neurons in these mice displayed fewer dendritic spines and an increased proportion of larger synapses compared to wild-type controls. These alterations in basal synaptic morphology correlated with enhanced mean synaptic strength and impaired bidirectional synaptic modifiability (enhanced LTP and reduced LTD) in the cortex. By contrast, spine morphology and synaptic plasticity were normal in the hippocampus of these mice. Importantly, these mice exhibited specific deficits in the consolidation phase of hippocampus-dependent memory. Thus, our results provide evidence for critical relationships between synaptic morphology and bidirectional modifiability of synaptic strength in the cortex and consolidation of long-term memory.

Analysis of Variance↗

PubMed2003

Phosphorylation of the AMPA receptor GluR1 subunit is required for synaptic plasticity and retention of spatial memory.

Plasticity of the nervous system is dependent on mechanisms that regulate the strength of synaptic transmission. Excitatory synapses in the brain undergo long-term potentiation (LTP) and long-term depression (LTD), cellular models of learning and memory. Protein phosphorylation is required for the induction of many forms of synaptic plasticity, including LTP and LTD. However, the critical kinase substrates that mediate plasticity have not been identified. We previously reported that phosphorylation of the GluR1 subunit of AMPA receptors, which mediate rapid excitatory transmission in the brain, is modulated during LTP and LTD. To test if GluR1 phosphorylation is necessary for plasticity and learning and memory, we generated mice with knockin mutations in the GluR1 phosphorylation sites. The phosphomutant mice show deficits in LTD and LTP and have memory defects in spatial learning tasks. These results demonstrate that phosphorylation of GluR1 is critical for LTD and LTP expression and the retention of memories.

Animals↗

PubMed2003

The role of synaptic GTPase-activating protein in neuronal development and synaptic plasticity.

Synaptic GTPase-activating protein (SynGAP) is a neuronal RasGAP (Ras GTPase-activating protein) that is selectively expressed in brain and highly enriched at excitatory synapses, where it negatively regulates Ras activity and its downstream signaling pathways. To investigate the physiological role of SynGAP in the brain, we have generated mutant mice lacking the SynGAP protein. These mice exhibit postnatal lethality, indicating that SynGAP plays a critical role during neuronal development. In addition, cell biological experiments show that neuronal cultures from mutant mice have more synaptic AMPA receptor clusters, suggesting that SynGAP regulates glutamate receptor synaptic targeting. Moreover, electrophysiological studies demonstrated that heterozygous mutant mice have a specific defect in hippocampal long-term potentiation (LTP). These studies show that the regulation of synaptic Ras signaling by SynGAP is important for proper neuronal development and glutamate receptor trafficking and is critical for the induction of LTP.

Animals↗

PubMed2002

Absence of long-term depression in the visual cortex of glutamic Acid decarboxylase-65 knock-out mice.

Long-term depression (LTD) is widely considered a mechanism for experience-induced synaptic weakening in the brain. Recent in vivo studies on glutamic acid decarboxylase [GAD 65 (-/-)] knock-out mice indicates that GABAergic synaptic inhibition is also required for the normal weakening of deprived inputs in the visual cortex. To better understand how GABAergic inhibition might control plasticity, we assessed the status of synaptic inhibition and LTD in visual cortical slices of GAD 65 knock-out mice. We found the following: (1) the efficacy of GABAergic synapses during repetitive activation is reduced in GAD 65 (-/-) mice; (2) the induction of LTD is impaired in the visual cortex of GAD 65 (-/-) mice; and (3) chronic, but not acute, treatment with the benzodiazepine agonist diazepam restores LTD in GAD 65 (-/-) mice. These results suggest that a certain inhibitory tone is required for the induction of LTD in visual cortex. We propose that the lack of visual cortical LTD in GAD 65 (-/-) may account for the lack of experience-dependent plasticity in these mice.

Animals↗

PubMed2002

D(1) dopamine receptor stimulation increases GluR1 phosphorylation in postnatal nucleus accumbens cultures.

Postsynaptic interactions between dopamine and glutamate receptors in the nucleus accumbens are critical for acute responses to drugs of abuse and for neuroadaptations resulting from their chronic administration. We tested the hypothesis that D(1) dopamine receptor stimulation increases phosphorylation of the AMPA receptor subunit GluR1 at the protein kinase A phosphorylation site (Ser845). Nucleus accumbens cell cultures were prepared from postnatal day 1 rats. After 14 days in culture, GluR1 phosphorylation was measured by western blotting using phosphorylation site-specific antibodies. The D(1) receptor agonist SKF 81297 increased Ser845 phosphorylation in a concentration- dependent manner, with marked increases occurring within 5 min. This was prevented by the D(1) receptor antagonist SCH 23390 and the protein kinase A inhibitor H89, and reproduced by forskolin. The D(2) receptor agonist quinpirole attenuated the response to D(1) receptor stimulation. Neither D(1) nor D(2) receptor agonists altered GluR1 phosphorylation at Ser831, the site phosphorylated by protein kinase C and calcium/calmodulin-dependent protein kinase II. In other systems, phosphorylation of GluR1 at Ser845 is associated with enhancement of AMPA receptor currents. Thus, the present results suggest that AMPA receptor transmission in the nucleus accumbens may be augmented by concurrent D(1) receptor stimulation.

Animals↗