Correcting deregulated Fxyd1 expression rescues deficits in neuronal arborization and potassium homeostasis in MeCP2 deficient male mice.

Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the MECP2 gene. In the absence of MeCP2, expression of FXYD domain-containing transport regulator 1 (FXYD1) is deregulated in the frontal cortex (FC) of mice and humans. Because Fxyd1 is a membrane protein that controls cell excitability by modulating Na, K-ATPase activity (NKA), an excess of Fxyd1 may reduce NKA activity and contribute to the neuronal phenotype of Mecp2 deficient (KO) mice.

Different AMPA receptor subtypes mediate the distinct kinetic components of a biphasic EPSC in hippocampal interneurons.

CA1 hippocampal interneurons at the border between stratum radiatum (SR) and stratum lacunosum-moleculare (SLM) have AMPA receptor (AMPAR)-mediated excitatory postsynaptic currents (EPSCs) that consist of two distinct phases: a typical fast component (FC), and a highly unusual slow component (SC) that persists for hundreds of milliseconds. To determine whether these kinetically distinct components of the EPSC are mediated by distinct AMPAR subpopulations, we examined the relative contributions of GluA2-containing and-lacking AMPARs to the SC. GluA2-containing AMPARs mediated the majority of the FC whereas GluA2-lacking AMPARs preferentially generated the SC.

Distinct roles for Cav2.1-2.3 in activity-dependent synaptic dynamics.

Synaptic transmission throughout most of the CNS is steeply dependent on presynaptic calcium influx through the voltage-gated calcium channels Cav2.1-Cav2.3.

A transgenic mouse model for Alzheimer's disease has impaired synaptic gain but normal synaptic dynamics.

The chronic accumulation of amyloid beta (Aβ) peptides is thought to underlie much of the pathology of Alzheimer's disease (AD), and transgenic mice overexpressing Aβ show both behavioral defects and impairments in hippocampal synaptic transmission. In the present study, we examined excitatory transmission at the Schaffer collateral synapse in acute hippocampal slices from APP(Swe)/PS-1(A246E) transgenic mice to determine whether the synaptic impairment in these mice is due to a reduction in the activity-independent synaptic gain, or to a change in the activity-dependent synaptic dynamics. We observed a strong reduction in synaptic transmission in slices from APP(Swe)/PS-1(A246E) mice compared to those from their wildtype littermates.

Coupled activity-dependent trafficking of synaptic SK2 channels and AMPA receptors.

Small conductance Ca(2+)-activated K(+) type 2 (SK2) channels are expressed in the postsynaptic density of CA1 neurons where they are activated by synaptically evoked Ca(2+) influx to limit the size of EPSPs and spine Ca(2+) transients. At Schaffer collateral synapses, the induction of long-term potentiation (LTP) increases the alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor (AMPAR)-mediated contribution to synaptic transmission and decreases the synaptic SK2 channel contribution through protein kinase A-dependent channel endocytosis. Using a combination of electrophysiology and immunoelectron microscopy in mice, the relationship between the dynamics of spine SK2 channels and AMPARs was investigated.

Dentate gyrus granule cell firing patterns can induce mossy fiber long-term potentiation in vitro.

Hippocampal granule cells transmit information about behaviorally-relevant stimuli to CA3 pyramidal cells via mossy fiber synapses. These synapses express a form of long-term potentiation (mfLTP) that is non-Hebbian and does not require NMDA receptors. mfLTP is thought to be induced and expressed presynaptically, hence, the major determinant of whether mfLTP occurs is activity in the granule cells.

Subunit-dependent postsynaptic expression of kainate receptors on hippocampal interneurons in area CA1.

Kainate receptors (KARs) contribute to postsynaptic excitation in only a select subset of neurons. To define the parameters that specify the postsynaptic expression of KARs, we examined the contribution of KARs to EPSCs on hippocampal interneurons in area CA1. Interneurons in stratum radiatum/lacunosum-moleculare express KARs both with and without the GluR5 subunit, but KAR-mediated EPSCs are generated mainly, if not entirely, by GluR5-containing KARs.

Delivery of AMPA receptors to perisynaptic sites precedes the full expression of long-term potentiation.

Trafficking of AMPA subtype glutamate receptors (AMPARs) from intracellular compartments to synapses is thought to be a major mechanism underlying the expression of long-term potentiation (LTP), a cellular substrate for learning and memory. However, it remains unclear whether the AMPAR trafficking that takes place during LTP is due to a targeted insertion of AMPARs directly into the synapse or delivery to extrasynaptic sites followed by translocation into the synapse. Here, we provide direct physiological evidence that LTP induced by a theta-burst pairing and tetanic stimulation protocols causes the rapid delivery of AMPARs to a perisynaptic site.

Spine expansion and stabilization associated with long-term potentiation.

Stable expression of long-term synaptic plasticity is critical for the developmental refinement of neural circuits and for some forms of learning and memory. Although structural remodeling of dendritic spines is associated with the stable expression of long-term potentiation (LTP), the relationship between structural and physiological plasticity remains unclear. To define whether these two processes are related or distinct, we simultaneously monitored EPSPs and dendritic spines, using combined patch-clamp recording and two-photon time-lapse imaging in the same CA1 pyramidal neurons in acute hippocampal slices.

FXYD1 is an MeCP2 target gene overexpressed in the brains of Rett syndrome patients and Mecp2-null mice.

Rett syndrome (RTT) is an X-linked neurodevelopmental disorder linked to heterozygous de novo mutations in the MECP2 gene. MECP2 encodes methyl-CpG-binding protein 2 (MeCP2), which represses gene transcription by binding to 5-methylcytosine residues in symmetrically positioned CpG dinucleotides. Direct MeCP2 targets underlying RTT pathogenesis remain largely unknown.

Presynaptic inhibition by kainate receptors converges mechanistically with presynaptic inhibition by adenosine and GABAB receptors.

Kainate receptors are widely reported to regulate the release of neurotransmitter in the CNS, but the mechanisms involved remain controversial. Previous studies have found that the kainate receptor agonist ATPA, which selectively activates Glu(K5)-containing kainate receptors, depresses glutamate release at Schaffer-collateral synapses in the hippocampus. In the present study, we provide pharmacological evidence that this depressant effect is mediated by Glu(K5)-containing heteromers, but is distinct from a similar depressant effect engaged by the kainate receptor agonist domoate.

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.

AMPA receptors and kainate receptors encode different features of afferent activity.

Postsynaptic kainate receptors (KARs) have been found in the CNS along with AMPA receptors (AMPARs), but because KAR-mediated EPSCs are much smaller and slower than AMPAR-mediated EPSCs, it remains unclear whether these postsynaptic KARs are functionally significant. In this study we measured KAR- and AMPAR-mediated EPSPs in hippocampal interneurons, and then we used these EPSPs in a model to examine the effects of afferent firing on each receptor. In this model the KARs generated a large tonic depolarization when activated by a small population of afferent fibers firing asynchronously at physiologically relevant firing rates (1-5 Hz).