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1.  Altered Hippocampal Synaptic Physiology in Aged Parkin-Deficient Mice 
Neuromolecular medicine  2010;12(3):270-276.
We examined synaptic function in the hippocampus of aged mice deficient for the Parkinson’s disease-linked protein, parkin. Surprisingly, heterozygous but not homozygous parkin-deficient mice exhibited impairments in basal excitatory synaptic strength. Similarly heterozygous mice exhibited broad deficits in paired-pulse facilitation, while homozygous parkin-deficient mice exhibited more restricted deficits. In contrast to the measurements of basal synaptic function, synaptic plasticity was not altered in aged heterozygous parkin-deficient mice, but was enhanced in aged homozygous parkin-deficient mice, due to an absence of age-related decline. These findings of differential synaptic phenotypes in heterozygous vs. homozygous parkin deficiency suggest compensatory responses to genetic abnormalities could play an important role during the development of pathology in response to parkin deficiency.
doi:10.1007/s12017-010-8113-y
PMCID: PMC4326226  PMID: 20232175
Parkin; PARK2; Hippocampus; LTP; Plasticity; EPSP; Mouse; Compensatory; Aging; CA1
2.  Dual leucine zipper kinase is required for excitotoxicity-induced neuronal degeneration 
The Journal of Experimental Medicine  2013;210(12):2553-2567.
Loss of dual leucine zipper kinase results in attenuated JNK/c-Jun stress response pathway activation and reduced neuronal degeneration after kainic acid–induced excitotoxic seizures.
Excessive glutamate signaling is thought to underlie neurodegeneration in multiple contexts, yet the pro-degenerative signaling pathways downstream of glutamate receptor activation are not well defined. We show that dual leucine zipper kinase (DLK) is essential for excitotoxicity-induced degeneration of neurons in vivo. In mature neurons, DLK is present in the synapse and interacts with multiple known postsynaptic density proteins including the scaffolding protein PSD-95. To examine DLK function in the adult, DLK-inducible knockout mice were generated through Tamoxifen-induced activation of Cre-ERT in mice containing a floxed DLK allele, which circumvents the neonatal lethality associated with germline deletion. DLK-inducible knockouts displayed a modest increase in basal synaptic transmission but had an attenuation of the JNK/c-Jun stress response pathway activation and significantly reduced neuronal degeneration after kainic acid–induced seizures. Together, these data demonstrate that DLK is a critical upstream regulator of JNK-mediated neurodegeneration downstream of glutamate receptor hyper-activation and represents an attractive target for the treatment of indications where excitotoxicity is a primary driver of neuronal loss.
doi:10.1084/jem.20122832
PMCID: PMC3832926  PMID: 24166713
3.  SAHA Enhances Synaptic Function and Plasticity In Vitro but Has Limited Brain Availability In Vivo and Does Not Impact Cognition 
PLoS ONE  2013;8(7):e69964.
Suberoylanilide hydroxamic acid (SAHA) is an inhibitor of histone deacetylases (HDACs) used for the treatment of cutaneous T cell lymphoma (CTCL) and under consideration for other indications. In vivo studies suggest reducing HDAC function can enhance synaptic function and memory, raising the possibility that SAHA treatment could have neurological benefits. We first examined the impacts of SAHA on synaptic function in vitro using rat organotypic hippocampal brain slices. Following several days of SAHA treatment, basal excitatory but not inhibitory synaptic function was enhanced. Presynaptic release probability and intrinsic neuronal excitability were unaffected suggesting SAHA treatment selectively enhanced postsynaptic excitatory function. In addition, long-term potentiation (LTP) of excitatory synapses was augmented, while long-term depression (LTD) was impaired in SAHA treated slices. Despite the in vitro synaptic enhancements, in vivo SAHA treatment did not rescue memory deficits in the Tg2576 mouse model of Alzheimer’s disease (AD). Along with the lack of behavioral impact, pharmacokinetic analysis indicated poor brain availability of SAHA. Broader assessment of in vivo SAHA treatment using high-content phenotypic characterization of C57Bl6 mice failed to demonstrate significant behavioral effects of up to 150 mg/kg SAHA following either acute or chronic injections. Potentially explaining the low brain exposure and lack of behavioral impacts, SAHA was found to be a substrate of the blood brain barrier (BBB) efflux transporters Pgp and Bcrp1. Thus while our in vitro data show that HDAC inhibition can enhance excitatory synaptic strength and potentiation, our in vivo data suggests limited brain availability may contribute to the lack of behavioral impact of SAHA following peripheral delivery. These results do not predict CNS effects of SAHA during clinical use and also emphasize the importance of analyzing brain drug levels when interpreting preclinical behavioral pharmacology.
doi:10.1371/journal.pone.0069964
PMCID: PMC3724849  PMID: 23922875
4.  GluN2B Antagonism Affects Interneurons and Leads to Immediate and Persistent Changes in Synaptic Plasticity, Oscillations, and Behavior 
Neuropsychopharmacology  2013;38(7):1221-1233.
Although antagonists to GluN2B-containing N-methyl-𝒟-aspartate receptors (NMDARs) have been widely considered to be neuroprotective under certain pathological conditions, their immediate and lasting impacts on synaptic, circuit, and cognitive functions are poorly understood. In hippocampal slices, we found that the GluN2B-selective antagonist Ro25-6981 (Ro25) reduced synaptic NMDAR responses and consequently neuronal output in a subpopulation of GABAergic interneurons, but not pyramidal neurons. Consistent with these effects, Ro25 reduced GABAergic responses in pyramidal neurons and hence could affect circuit functions by altering the excitation/inhibition balance in the brain. In slices from Ts65Dn mice, a Down syndrome model with excess inhibition and cognitive impairment, acutely applied Ro25-rescued long-term potentiation (LTP) and gamma oscillation deficits, whereas prolonged dosing induced persistent rescue of LTP. In contrast, Ro25 did not impact LTP in wild-type (wt) mice but reduced gamma oscillations both acutely and following prolonged treatment. Although acute Ro25 treatment impaired memory performance in wt mice, memory deficits in Ts65Dn mice were unchanged. Thus, GluN2B–NMDARs contribute to the excitation/inhibition balance via impacts on interneurons, and blocking GluN2B–NMDARs can alter functions that depend on this balance, including synaptic plasticity, gamma oscillations, and memory. That prolonged GluN2B antagonism leads to persistent changes in synaptic and circuit functions, and that the influence of GluN2B antagonism differs between wt and disease model mice, provide critical insight into the therapeutic potential and possible liabilities of GluN2B antagonists.
doi:10.1038/npp.2013.19
PMCID: PMC3656364  PMID: 23340518
GluN2B; interneuron; oscillation; LTP; memory; Down syndrome; glutamate; neurophysiology; GABA; learning & memory; GluN2B; Down syndrome; interneuron; LTP; oscillation
5.  Glutamate Receptor Subunit GluA1 is Necessary for Long-term Potentiation and Synapse Unsilencing, but not Long-term Depression in Mouse Hippocampus 
Brain Research  2011;1435:8-14.
Receptor subunit composition is believed to play a major role in the synaptic trafficking of AMPA receptors (AMPARs), and thus in activity-dependent synaptic plasticity. To isolate a physiological role of GluA1-containing AMPARs in area CA3 of the hippocampus, pair recordings were performed in organotypic hippocampal slices taken from genetically modified mice lacking the GluA1 subunit. We report here that long-term potentiation (LTP) is impaired not only at active but also at silent synapses when the GluA1 subunit is absent. The GluA1 knockout mice also exhibited reduced AMPAR-mediated evoked currents between pairs of CA3 pyramidal neurons under baseline conditions suggesting a significant role for GluA1-containing AMPARs in regulating basal synaptic transmission. In two independent measures, however, long-term depression (LTD) was unaffected in tissue from these mice. These data provide a further demonstration of the fundamental role that GluA1-containing AMPARs play in activity-dependent increases in synaptic strength but do not support a GluA1-dependent mechanism for reductions in synaptic strength.
doi:10.1016/j.brainres.2011.11.029
PMCID: PMC3268828  PMID: 22197030
Glutamate receptor; AMPA receptor; knockout; synaptic plasticity; silent synapse; long-term potentiation; long-term depression; hippocampus
6.  Dendritic sodium channels regulate network integration in globus pallidus neurons: A modeling study 
The globus pallidus (GP) predominantly contains GABAergic projection neurons that occupy a central position in the indirect pathway of the basal ganglia. They have long dendrites that can extend through half the diameter of the GP in rats, potentially enabling convergence and interaction between segregated basal ganglia circuits. Because of the length and fine diameter of GP dendrites, however, it is unclear how much influence distal synapses have on spiking activity. Dendritic expression of fast voltage-dependent Na+ channels (NaF channels) can enhance the importance of distal excitatory synapses by allowing for dendritic spike initiation and by subthreshold boosting of EPSPs. Antibody labeling has demonstrated the presence of NaF channel proteins in GP dendrites but the quantitative expression density of the channels remains unknown. We built a series of 9 GP neuron models that differed only in their dendritic NaF channel expression level to assess the functional impact of this parameter. The models were all similar in their basic electrophysiological features; however, higher expression levels of dendritic NaF channels increased the relative effectiveness of distal inputs for both excitatory and inhibitory synapses, broadening the effective extent of the dendritic tree. Higher dendritic NaF channel expression also made the neurons more resistant to tonic inhibition and highly sensitive to clustered synchronous excitation. The dendritic NaF channel expression pattern may therefore be a critical determinant of convergence for both the striatopallidal and subthalamopallidal projections, while also dictating which spatiotemporal input patterns are most effective at driving GP neuron output.
doi:10.1523/JNEUROSCI.2662-10.2010
PMCID: PMC3022226  PMID: 21068320
globus pallidus; basal ganglia; sodium channel; synaptic; dendritic spike; synchrony; model; information theory
7.  Imbalanced pattern completion vs. separation in cognitive disease: network simulations of synaptic pathologies predict a personalized therapeutics strategy 
BMC Neuroscience  2010;11:96.
Background
Diverse Mouse genetic models of neurodevelopmental, neuropsychiatric, and neurodegenerative causes of impaired cognition exhibit at least four convergent points of synaptic malfunction: 1) Strength of long-term potentiation (LTP), 2) Strength of long-term depression (LTD), 3) Relative inhibition levels (Inhibition), and 4) Excitatory connectivity levels (Connectivity).
Results
To test the hypothesis that pathological increases or decreases in these synaptic properties could underlie imbalances at the level of basic neural network function, we explored each type of malfunction in a simulation of autoassociative memory. These network simulations revealed that one impact of impairments or excesses in each of these synaptic properties is to shift the trade-off between pattern separation and pattern completion performance during memory storage and recall. Each type of synaptic pathology either pushed the network balance towards intolerable error in pattern separation or intolerable error in pattern completion. Imbalances caused by pathological impairments or excesses in LTP, LTD, inhibition, or connectivity, could all be exacerbated, or rescued, by the simultaneous modulation of any of the other three synaptic properties.
Conclusions
Because appropriate modulation of any of the synaptic properties could help re-balance network function, regardless of the origins of the imbalance, we propose a new strategy of personalized cognitive therapeutics guided by assay of pattern completion vs. pattern separation function. Simulated examples and testable predictions of this theorized approach to cognitive therapeutics are presented.
doi:10.1186/1471-2202-11-96
PMCID: PMC2931521  PMID: 20704756
8.  Dynamin-dependent NMDAR endocytosis during LTD and its dependence on synaptic state 
BMC Neuroscience  2005;6:48.
Background
The N-methyl-D-aspartate (NMDA)-type glutamate receptor expressed at excitatory glutamatergic synapses is required for learning and memory and is critical for normal brain function. At a cellular level, this receptor plays a pivotal role in triggering and controlling synaptic plasticity. While it has been long recognized that this receptor plays a regulatory role, it was considered by many to be itself immune to synaptic activity-induced plasticity. More recently, we and others have shown that NMDA receptor-mediated synaptic responses can be subject to activity-dependent depression.
Results
Here we show that depression of synaptic transmission mediated by NMDA receptors displays a state-dependence in its plasticity; NMDA receptors are resistant to activity-induced changes at silent and recently-silent synapses. Once synapses transition to the active state however, NMDA receptors become fully 'plastic'. This state-dependence is identical to that shown by the α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor. Furthermore, the down-regulation of NMDAR-mediated responses during synaptic depression is prevented by disruption of dynamin-dependent endocytosis.
Conclusion
NMDA receptor-mediated synaptic responses are plastic in a state-dependent manner. Depending on the plasticity state in which a synapse currently resides, NMDA receptors will either be available or unavailable for down-regulation. The mechanism underlying the down-regulation of NMDA receptor-mediated synaptic responses is endocytosis of the NMDA receptor. Other potential mechanisms, such as receptor diffusion along the plane of the membrane, or changes in the activity of the channel are not supported. The mechanisms of AMPA receptor and NMDA receptor endocytosis appear to be tightly coupled, as both are either available or unavailable for endocytosis in the same synaptic states. Endocytosis of NMDA receptors would serve as a potent mechanism for metaplasticity. Such state-dependent regulation of NMDAR endocytosis will provide fundamental control over downstream NMDA receptor-dependent plasticity of neuronal circuitry.
doi:10.1186/1471-2202-6-48
PMCID: PMC1187896  PMID: 16042781

Results 1-8 (8)