Separation of presynaptic Ca2 and Ca1 channel function in synaptic vesicle exo- and endocytosis by the membrane anchored Ca pump PMCA.

Synaptic vesicle (SV) release, recycling, and plastic changes of release probability co-occur side by side within nerve terminals and rely on local Ca signals with different temporal and spatial profiles. The mechanisms that guarantee separate regulation of these vital presynaptic functions during action potential (AP)-triggered presynaptic Ca entry remain unclear. Combining genetics with electrophysiology and imaging reveals the localization of two different voltage-gated calcium channels at the presynaptic terminals of glutamatergic neuromuscular synapses (the Ca2 homolog, Dmca1A or cacophony, and the Ca1 homolog, Dmca1D) but with spatial and functional separation.

More than a pore: How voltage-gated calcium channels act on different levels of neuronal communication regulation.

Voltage-gated calcium channels (VGCCs) represent key regulators of the calcium influx through the plasma membrane of excitable cells, like neurons. Activated by the depolarization of the membrane, the opening of VGCCs induces very transient and local changes in the intracellular calcium concentration, known as calcium nanodomains, that in turn trigger calcium-dependent signaling cascades and the release of chemical neurotransmitters. Based on their central importance as concierges of excitation-secretion coupling and therefore neuronal communication, VGCCs have been studied in multiple aspects of neuronal function and malfunction.

Auxiliary α2δ1 and α2δ3 Subunits of Calcium Channels Drive Excitatory and Inhibitory Neuronal Network Development.

VGCCs are multisubunit complexes that play a crucial role in neuronal signaling. Auxiliary α2δ subunits of VGCCs modulate trafficking and biophysical properties of the pore-forming α1 subunit and trigger excitatory synaptogenesis. Alterations in the expression level of α2δ subunits were implicated in several syndromes and diseases, including chronic neuropathic pain, autism, and epilepsy.

Transient Confinement of Ca2.1 Ca-Channel Splice Variants Shapes Synaptic Short-Term Plasticity.

The precision and reliability of synaptic information transfer depend on the molecular organization of voltage-gated calcium channels (VGCCs) within the presynaptic membrane. Alternative splicing of exon 47 affects the C-terminal structure of VGCCs and their affinity to intracellular partners and synaptic vesicles (SVs). We show that hippocampal synapses expressing VGCCs either with exon 47 (Ca2.

Dynamic compartmentalization of calcium channel signalling in neurons.

Calcium fluxes through the neuronal membrane are strictly limited in time due to biophysical properties of voltage-gated and ligand-activated ion channels and receptors. Being embedded into the crowded dynamic environment of biological membranes, Ca-permeable receptors and channels undergo perpetual spatial rearrangement, which enables their temporary association and formation of transient signalling complexes. Thus, efficient calcium-mediated signal transduction requires mechanisms to support very precise spatiotemporal alignment of the calcium source and Ca-binding lipids and proteins in a highly dynamic environment.

Calcium Channel Subunit α2δ4 Is Regulated by Early Growth Response 1 and Facilitates Epileptogenesis.

Transient brain insults, including status epilepticus (SE), can trigger a period of epileptogenesis during which functional and structural reorganization of neuronal networks occurs resulting in the onset of focal epileptic seizures. In recent years, mechanisms that regulate the dynamic transcription of individual genes during epileptogenesis and thereby contribute to the development of a hyperexcitable neuronal network have been elucidated. Our own results have shown early growth response 1 (Egr1) to transiently increase expression of the T-type voltage-dependent Ca channel (VDCC) subunit Ca3.

Posttranslational modification impact on the mechanism by which amyloid-β induces synaptic dysfunction.

Oligomeric amyloid-β (Aβ) 1-42 disrupts synaptic function at an early stage of Alzheimer's disease (AD). Multiple posttranslational modifications of Aβ have been identified, among which N-terminally truncated forms are the most abundant. It is not clear, however, whether modified species can induce synaptic dysfunction on their own and how altered biochemical properties can contribute to the synaptotoxic mechanisms.

Metabotropic glutamate receptor, mGlu5, regulates hippocampal synaptic plasticity and is required for tetanisation-triggered changes in theta and gamma oscillations.

Hippocampal synaptic plasticity and learning are regulated by metabotropic glutamate receptors (mGlu) and particularly by mGlu5. In the hippocampus, synaptic plasticity is tightly linked to neuronal network oscillations in theta (5-10 Hz) and gamma (∼30-100 Hz) frequency ranges, and specific changes in theta and gamma spectral power can predict for the success of patterned afferent stimulation in inducing robust long-term potentiation (LTP). In this study, we hypothesized that activation of mGlu5 mediates tetanisation-driven changes in network oscillations and thereby determines the longevity of LTP.

Surface dynamics of voltage-gated ion channels.

Neurons encode information in fast changes of the membrane potential, and thus electrical membrane properties are critically important for the integration and processing of synaptic inputs by a neuron. These electrical properties are largely determined by ion channels embedded in the membrane. The distribution of most ion channels in the membrane is not spatially uniform: they undergo activity-driven changes in the range of minutes to days.

Brain extracellular matrix retains connectivity in neuronal networks.

The formation and maintenance of connectivity are critically important for the processing and storage of information in neuronal networks. The brain extracellular matrix (ECM) appears during postnatal development and surrounds most neurons in the adult mammalian brain. Importantly, the removal of the ECM was shown to improve plasticity and post-traumatic recovery in the CNS, but little is known about the mechanisms.

Synaptically released matrix metalloproteinase activity in control of structural plasticity and the cell surface distribution of GluA1-AMPA receptors.

Synapses are particularly prone to dynamic alterations and thus play a major role in neuronal plasticity. Dynamic excitatory synapses are located at the membranous neuronal protrusions called dendritic spines. The ability to change synaptic connections involves both alterations at the morphological level and changes in postsynaptic receptor composition.

Relationship of hippocampal theta and gamma oscillations to potentiation of synaptic transmission.

In the hippocampus in vivo, both synaptic plasticity and network activity are closely interdependent. We have found that immediately after an attempt to induce long-term potentiation (LTP), changes in theta (5-10 Hz) and gamma (30-100 Hz) activity correlate tightly with the occurrence of LTP, suggesting that tetanisation-driven activation of sensory inputs synchronises the activity of granule cells and interneurons, and thus, facilitates the encoding of acquired stimuli. This results in increase of theta and gamma power, and elevates the probability that afferent stimuli both coincide with the peak of theta cycle and reach their post-synaptic target within the gamma time-window (of 10-30 ms).

Hippocampal network activity is transiently altered by induction of long-term potentiation in the dentate gyrus of freely behaving rats.

A role for oscillatory activity in hippocampal neuronal networks has been proposed in sensory encoding, cognitive functions and synaptic plasticity. In the hippocampus, theta (5-10 Hz) and gamma (30-100 Hz) oscillations may provide a mechanism for temporal encoding of information, and the basis for formation and retrieval of memory traces. Long-term potentiation (LTP) of synaptic transmission, a candidate cellular model of synaptic information storage, is typically induced by high-frequency tetanisation (HFT) of afferent pathways.

MGluR5 mediates the interaction between late-LTP, network activity, and learning.

Hippocampal synaptic plasticity and learning are strongly regulated by metabotropic glutamate receptors (mGluRs) and particularly by mGluR5. Here, we investigated the mechanisms underlying mGluR5-modulation of these phenomena. Prolonged pharmacological blockade of mGluR5 with MPEP produced a profound impairment of spatial memory.

Midfrequency cortico-thalamic oscillations and the sleep cycle: genetic, time of day and age effects.

WAG/Rij rats have various types of mid frequency cortico-thalamic oscillations, such as anterior and posterior sleep spindles and two types of spike-wave discharges (SWD). The generalized SWD (type I) preferentially occur at transitions from wake to sleep, type II can be found at the occipital cortex during quite wakefulness. In the present experiment sleep spindles, SWD and sleep cycle characteristics of 6-month-old WAG/Rij rats were studied and compared with those of younger WAG/Rij rats with much less SWD and age-matched control (ACI) rats.

Morphometric Golgi study of cortical locations in WAG/Rij rats: the cortical focus theory.

Recently it was demonstrated that for the absence epilepsy characteristic spike-wave discharges initially emerge from the somatosensory cortex and quickly involve the rest of the cortex and cortico-thalamic network. This has led to the development of the focal theory of absence epilepsy. In this experiment, this theory was further investigated by studying the neuronal organization of the cortical focal zone, a non-focal zone in genetic epileptic WAG/Rij rats and functional related areas in non-epileptic age matched control rats.