Net synaptic drive of fast-spiking interneurons is inverted towards inhibition in human FCD I epilepsy.

Focal cortical dysplasia type I (FCD I) is the most common cause of pharmaco-resistant epilepsy with the poorest prognosis. To understand the epileptogenic mechanisms of FCD I, we obtained tissue resected from patients with FCD I epilepsy, and from tumor patients as control. Using whole-cell patch clamp in acute human brain slices, we investigated the cellular properties of fast-spiking interneurons (FSINs) and pyramidal neurons (PNs) within the ictal onset zone.

Burst firing is required for induction of Hebbian LTP at lateral perforant path to hippocampal granule cell synapses.

High frequency burst firing is critical in summation of back-propagating action potentials (APs) in dendrites, which may greatly depolarize dendritic membrane potential. The physiological significance of burst firings of hippocampal dentate GCs in synaptic plasticity remains unknown. We found that GCs with low input resistance could be categorized into regular-spiking (RS) and burst-spiking (BS) cells based on their initial firing frequency (F) upon somatic rheobase current injection, and investigated how two types of GCs differ in long-term potentiation (LTP) induced by high-frequency lateral perforant pathway (LPP) inputs.

L-type Ca channels mediate regulation of glutamate release by subthreshold potential changes.

Subthreshold depolarization enhances neurotransmitter release evoked by action potentials and plays a key role in modulating synaptic transmission by combining analog and digital signals. This process is known to be Ca dependent. However, the underlying mechanism of how small changes in basal Ca caused by subthreshold depolarization can regulate transmitter release triggered by a large increase in local Ca is not well understood.

Rewiring of Prelimbic Inputs to the Nucleus Accumbens Core Underlies Cocaine-Induced Behavioral Sensitization.

Background: Unbalanced activity of medium spiny neurons (MSNs) of the direct and indirect pathways mediates reward-related behaviors induced by addictive drugs. Prelimbic (PL) input to MSNs in the nucleus accumbens core (NAcC) plays a key role in cocaine-induced early locomotor sensitization (LS). However, the adaptive plastic changes at PL-to-NAcC synapses underlying early LS remain unclear.

Dopamine Receptor Supports the Potentiation of Intrinsic Excitability and Synaptic LTD in Temporoammonic-CA1 Synapse.

Dopaminergic projection to the hippocampus from the ventral tegmental area or locus ceruleus has been considered to play an essential role in the acquisition of novel information. Hence, the dopaminergic modulation of synaptic plasticity in the hippocampus has been widely studied. We examined how the D1 and D2 receptors influenced the mGluR5-mediated synaptic plasticity of the temporoammonic-CA1 synapses and showed that the dopaminergic modulation of the temporoammonic-CA1 synapses was expressed in various ways.

Involvement of Ca in Signaling Mechanisms Mediating Muscarinic Inhibition of M Currents in Sympathetic Neurons.

Acetylcholine can excite neurons by suppressing M-type (KCNQ) potassium channels. This effect is mediated by M muscarinic receptors coupled to the G protein. Although PIP depletion and PKC activation have been strongly suggested to contribute to muscarinic inhibition of M currents (I), direct evidence is lacking.

Gradual decorrelation of CA3 ensembles associated with contextual discrimination learning is impaired by Kv1.2 insufficiency.

The associative network of hippocampal CA3 is thought to contribute to rapid formation of contextual memory from one-trial learning, but the network mechanisms underlying decorrelation of neuronal ensembles in CA3 is largely unknown. Kv1.2 expressions in rodent CA3 pyramidal cells (CA3-PCs) are polarized to distal apical dendrites, and its downregulation specifically enhances dendritic responses to perforant pathway (PP) synaptic inputs.

Voltage-gated calcium channels contribute to spontaneous glutamate release directly via nanodomain coupling or indirectly via calmodulin.

Neurotransmitter release occurs either synchronously with action potentials (evoked release) or spontaneously (spontaneous release). Whether the molecular mechanisms underlying evoked and spontaneous release are identical, especially whether voltage-gated calcium channels (VGCCs) can trigger spontaneous events, is still a matter of debate in glutamatergic synapses. To elucidate this issue, we characterized the VGCC dependence of miniature excitatory postsynaptic currents (mEPSCs) in various synapses with different coupling distances between VGCCs and synaptic vesicles, known as a critical factor in evoked release.

Calbindin regulates Kv4.1 trafficking and excitability in dentate granule cells via CaMKII-dependent phosphorylation.

Calbindin, a major Ca buffer in dentate granule cells (GCs), plays a critical role in shaping Ca signals, yet how it regulates neuronal function remains largely unknown. Here, we found that calbindin knockout (CBKO) mice exhibited dentate GC hyperexcitability and impaired pattern separation, which co-occurred with reduced K current due to downregulated surface expression of Kv4.1.

Postnatal maturation of glutamate clearance and release kinetics at the rat and mouse calyx of Held synapses.

Although calyx of Held synapses undergo dramatic changes around the hearing onset, previous in vivo studies suggest that the calyx synapses undergo further post-hearing maturation process. While developmental changes over the hearing onset have been extensively studied, this post-hearing maturation process remained relatively little investigated. Because of post-hearing maturation, previous results from studies around hearing onset and studies of post-hearing calyx synapses are somewhat inconsistent.

Impaired pattern separation in Tg2576 mice is associated with hyperexcitable dentate gyrus caused by Kv4.1 downregulation.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that causes memory loss. Most AD researches have focused on neurodegeneration mechanisms. Considering that neurodegenerative changes are not reversible, understanding early functional changes before neurodegeneration is critical to develop new strategies for early detection and treatment of AD.

Ca α2δ Autoimmune Encephalitis: A Novel Antibody and its Characteristics.

Objective: Discovery of a novel antibody would enable diagnosis and early treatment of autoimmune encephalitis. The aim was to discover a novel antibody targeting a synaptic receptor and characterize the pathogenic mechanism.

Method: We screened for unknown antibodies in serum and cerebrospinal fluid samples from autoimmune encephalitis patients.

Inter-spike mitochondrial Ca release enhances high frequency synaptic transmission.

Key Points: Presynaptic mitochondria not only absorb but also release Ca during high frequency stimulation (HFS) when presynaptic [Ca ] is kept low (<500 nm) by high cytosolic Ca buffer or strong plasma membrane calcium clearance mechanisms under physiological external [Ca ]. Mitochondrial Ca release (MCR) does not alter the global presynaptic Ca transients. MCR during HFS enhances short-term facilitation and steady state excitatory postsynaptic currents by increasing vesicular release probability.

Cellular and systemic mechanisms for glucose sensing and homeostasis.

Glucose is a major source of energy in animals. Maintaining blood glucose levels within a physiological range is important for facilitating glucose uptake by cells, as required for optimal functioning. Glucose homeostasis relies on multiple glucose-sensing cells in the body that constantly monitor blood glucose levels and respond accordingly to adjust its glycemia.

Kv4.1, a Key Ion Channel For Low Frequency Firing of Dentate Granule Cells, Is Crucial for Pattern Separation.

The dentate gyrus (DG) in the hippocampus may play key roles in remembering distinct episodes through pattern separation, which may be subserved by the sparse firing properties of granule cells (GCs) in the DG. Low intrinsic excitability is characteristic of mature GCs, but ion channel mechanisms are not fully understood. Here, we investigated ionic channel mechanisms for firing frequency regulation in hippocampal GCs using male and female mice, and identified Kv4.

Disparities in Short-Term Depression Among Prefrontal Cortex Synapses Sustain Persistent Activity in a Balanced Network.

Persistent activity of cue-representing neurons in the prefrontal cortex (PFC) is regarded as a neural basis for working memory. The contribution of short-term synaptic plasticity (STP) at different types of synapses comprising the cortical network to persistent activity, however, remains unclear. Characterizing STP at synapses of the rat PFC layer 5 network, we found that PFC synapses exhibit distinct STP patterns according to presynaptic and postsynaptic identities.

Prenatal selective serotonin reuptake inhibitor (SSRI) exposure induces working memory and social recognition deficits by disrupting inhibitory synaptic networks in male mice.

Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed antidepressant drugs in pregnant women. Infants born following prenatal exposure to SSRIs have a higher risk for behavioral abnormalities, however, the underlying mechanisms remains unknown. Therefore, we examined the effects of prenatal fluoxetine, the most commonly prescribed SSRI, in mice.

Intracellular Zn Signaling Facilitates Mossy Fiber Input-Induced Heterosynaptic Potentiation of Direct Cortical Inputs in Hippocampal CA3 Pyramidal Cells.

Repetitive action potentials (APs) in hippocampal CA3 pyramidal cells (CA3-PCs) backpropagate to distal apical dendrites, and induce calcium and protein tyrosine kinase (PTK)-dependent downregulation of Kv1.2, resulting in long-term potentiation of direct cortical inputs and intrinsic excitability (LTP-IE). When APs were elicited by direct somatic stimulation of CA3-PCs from rodents of either sex, only a narrow window of distal dendritic [Ca] allowed LTP-IE because of Ca-dependent coactivation of PTK and protein tyrosine phosphatase (PTP), which renders non-mossy fiber (MF) inputs incompetent in LTP-IE induction.

Association of mGluR-Dependent LTD of Excitatory Synapses with Endocannabinoid-Dependent LTD of Inhibitory Synapses Leads to EPSP to Spike Potentiation in CA1 Pyramidal Neurons.

The input-output relationships in neural circuits are determined not only by synaptic efficacy but also by neuronal excitability. Activity-dependent alterations of synaptic efficacy have been extensively investigated, but relatively less is known about how the neuronal output is modulated when synaptic efficacy changes are associated with neuronal excitability changes. In this study, we demonstrate that paired pulses of low-frequency stimulation (PP-LFS) induced metabotropic glutamate receptor (mGluR)-dependent LTD at Schaffer collateral (SC)-CA1 synapses in Sprague Dawley rats (both sexes), and this LTD was associated with EPSP to spike (E-S) potentiation, leading to the increase in action potential (AP) outputs.

Reliable autapse formation using the single-cell patterning method.

Auto neuronal synapses, or autapses, are aberrant structures where the synaptic contact of a neuron forms onto its own branch. The functions of autapses, however, remain unknown. Here, we introduce a simple patterning method for capturing a single-cell, in which we maintained the isolated cell until it reached maturity, and developed arrays of autapses for electrophysiological analysis using multi-electrode arrays (MEA).

Enhancement of dendritic persistent Na currents by mGluR5 leads to an advancement of spike timing with an increase in temporal precision.

Timing and temporal precision of action potential generation are thought to be important for encoding of information in the brain. The ability of single neurons to transform their input into output action potential is primarily determined by intrinsic excitability. Particularly, plastic changes in intrinsic excitability represent the cellular substrate for spatial memory formation in CA1 pyramidal neurons (CA1-PNs).

mGluR5-dependent modulation of dendritic excitability in CA1 pyramidal neurons mediated by enhancement of persistent Na currents.

Key Points: High-frequency stimulation (HFS) of the Schaffer collateral pathway activates metabotropic glutamate receptor 5 (mGluR5) signalling in the proximal apical dendrites of CA1 pyramidal neurons. The synaptic activation of mGluR5-mediated calcium signalling causes a significant increase in persistent sodium current (I ) in the dendrites. Increased I by HFS underlies potentiation of synaptic inputs at both the proximal and distal dendrite, leading to an enhanced probability of action potential firing associated with decreased action potential thresholds.

Dendritic spikes in hippocampal granule cells are necessary for long-term potentiation at the perforant path synapse.

Long-term potentiation (LTP) of synaptic responses is essential for hippocampal memory function. Perforant-path (PP) synapses on hippocampal granule cells (GCs) contribute to the formation of associative memories, which are considered the cellular correlates of memory engrams. However, the mechanisms of LTP at these synapses are not well understood.

Impairment of Release Site Clearance within the Active Zone by Reduced SCAMP5 Expression Causes Short-Term Depression of Synaptic Release.

Despite being a highly enriched synaptic vesicle (SV) protein and a candidate gene for autism, the physiological function of SCAMP5 remains mostly enigmatic. Here, using optical imaging and electrophysiological experiments, we demonstrate that SCAMP5 plays a critical role in release site clearance at the active zone. Truncation analysis revealed that the 2/3 loop domain of SCAMP5 directly interacts with adaptor protein 2, and this interaction is critical for its role in release site clearance.