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1.  Developmentally Altered Inhibition in Ts65Dn, a mouse model of Down syndrome 
Brain research  2012;1440:1-8.
We studied the development of GABA-mediated synaptic inhibition in the CA1 region of the hippocampus in Ts65Dn mice, a model system for Down syndrome (DS). While there was no significant difference in the amplitude of stimulus-evoked monosynaptic inhibitory postsynaptic potentials (IPSPs) between acute hippocampal slices from Ts65Dn mice and diploid (2N) wild-type littermates at the end of the first and third postnatal week, the Ts65Dn animals showed significantly larger inhibitory responses when compared to age-matched controls at the end of the second postnatal week. This transient change in evoked inhibition was strikingly layer specific, observed only when stimulating in the strata radiatum and pyramidale but not in the stratum oriens. In addition, the frequency (but not amplitude) of spontaneous action-potential independent miniature inhibitory postsynaptic currents (mIPSCs) was significantly increased in the Ts65Dn mice during the second postnatal week. Additional measurements of paired pulse ratios showed no significant difference between the genotypes. We conclude that the excess inhibition at the end of the second postnatal week in Ts65Dn mice is not due to increases in release probability or post-synaptic quantal size. Overall these experiments indicate that there is a specific disruption of the normal developmental progression of inhibitory synaptic transmission in Ts65Dn mice at a critical time point in the development of neuronal circuitry. This raises the possibility that a transient early disruption of inhibitory function may have lasting impact on other network properties and could contribute to later neural circuit dysfunction in DS.
PMCID: PMC4114405  PMID: 22284618
postnatal development; CA1; inhibitory synaptic transmission; Down syndrome; Hippocampus; GABA; development
2.  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.
PMCID: PMC3268828  PMID: 22197030
Glutamate receptor; AMPA receptor; knockout; synaptic plasticity; silent synapse; long-term potentiation; long-term depression; hippocampus
3.  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.
PMCID: PMC4326226  PMID: 20232175
Parkin; PARK2; Hippocampus; LTP; Plasticity; EPSP; Mouse; Compensatory; Aging; CA1
4.  A Dramatic Increase of C1q Protein in the CNS during Normal Aging 
The Journal of Neuroscience  2013;33(33):13460-13474.
The decline of cognitive function has emerged as one of the greatest health threats of old age. Age-related cognitive decline is caused by an impacted neuronal circuitry, yet the molecular mechanisms responsible are unknown. C1q, the initiating protein of the classical complement cascade and powerful effector of the peripheral immune response, mediates synapse elimination in the developing CNS. Here we show that C1q protein levels dramatically increase in the normal aging mouse and human brain, by as much as 300-fold. This increase was predominantly localized in close proximity to synapses and occurred earliest and most dramatically in certain regions of the brain, including some but not all regions known to be selectively vulnerable in neurodegenerative diseases, i.e., the hippocampus, substantia nigra, and piriform cortex. C1q-deficient mice exhibited enhanced synaptic plasticity in the adult and reorganization of the circuitry in the aging hippocampal dentate gyrus. Moreover, aged C1q-deficient mice exhibited significantly less cognitive and memory decline in certain hippocampus-dependent behavior tests compared with their wild-type littermates. Unlike in the developing CNS, the complement cascade effector C3 was only present at very low levels in the adult and aging brain. In addition, the aging-dependent effect of C1q on the hippocampal circuitry was independent of C3 and unaccompanied by detectable synapse loss, providing evidence for a novel, complement- and synapse elimination-independent role for C1q in CNS aging.
PMCID: PMC3742932  PMID: 23946404
5.  Imbalanced pattern completion vs. separation in cognitive disease: network simulations of synaptic pathologies predict a personalized therapeutics strategy 
BMC Neuroscience  2010;11:96.
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).
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.
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.
PMCID: PMC2931521  PMID: 20704756
6.  Dynamin-dependent NMDAR endocytosis during LTD and its dependence on synaptic state 
BMC Neuroscience  2005;6:48.
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.
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.
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.
PMCID: PMC1187896  PMID: 16042781

Results 1-6 (6)