Histamine and Corticosterone Modulate Acid Sensing Ion Channels (ASICs) Dependent Long-term Potentiation at the Mouse Anterior Cingulate Cortex.

Increase in proton concentration [H+] or decrease in local and global extracellular pH occurs in both physiological and pathological conditions. Acid-sensing ion channels (ASICs), belonging to the ENaC/Deg superfamily, play an important role in signal transduction as proton sensor. ASICs and in particular ASIC1a (one of the six ASICs subunits) which is permeable to Ca2+, are involved in many physiological processes including synaptic plasticity and neurodegenerative diseases. Activity-dependent long-term potentiation (LTP) is a major type of long-lasting synaptic plasticity in the CNS, associated with learning, memory, development, fear and persistent pain. Neurons in the anterior cingulate cortex (ACC) play critical roles in pain perception and chronic pain and express ASIC1a channels. During synaptic transmission, acidification of the synaptic cleft presumably due to the co-release of neurotransmitter and H+ from synaptic vesicles activates postsynaptic ASIC1a channels in ACC of mice. This generates ASIC1a synaptic currents that add to the glutamatergic excitatory postsynaptic currents (EPSCs). Here we report that modulators like histamine and corticosterone, acting through ASIC1a regulate synaptic plasticity, reducing the threshold for LTP induction of glutamatergic EPSCs. Our findings suggest a new role for ASIC1a mediating the neuromodulator action of histamine and corticosterone regulating specific forms of synaptic plasticity in the mouse ACC.

Simultaneous administration of cocaine and caffeine dysregulates HCN and T-type channels.

RATIONALE: The abuse of psychostimulants has adverse consequences on the physiology of the central nervous system. In Argentina, and other South American countries, coca paste or "PACO" (cocaine and caffeine are its major components) is massively consumed with deleterious clinical consequences for the health and well-being of the general population. A scant number of studies have addressed the consequences of stimulant combination of cocaine and caffeine on the physiology of the somatosensory thalamocortical (ThCo) system. OBJECTIVES: Our aim was to study ion conductances that have important implications regulating sleep-wake states 24-h after an acute or chronic binge-like administration of a cocaine and caffeine mixture following previously analyzed pasta base samples ("PACO"-like binge") using mice. METHODS: We randomly injected (i.p.) male C57BL/6JFcen mice with a binge-like psychostimulants regimen during either 1 day (acute) or 1 day on/1 day off during 13 days for a total of 7 binges (chronic). Single-cell patch-clamp recordings of VB neurons were performed in thalamocortical slices 24 h after the last psychostimulant injection. We also recorded EEG/EMG from mice 24 h after being systemically treated with chronic administration of cocaine + caffeine versus saline, vehicle. RESULTS: Our results showed notorious changes in the intrinsic properties of the VB nucleus neurons that persist after 24-h of either acute or chronic binge administrations of combined cocaine and caffeine ("PACO"-like binge). Functional dysregulation of HCN (hyperpolarization-activated cyclic nucleotide-gated) and T-type VGC (voltage-gated calcium) channels was described 24-h after acute/chronic "PACO"-like administrations. Furthermore, intracellular basal [Ca2+] disturbances resulted a key factor that modulated the availability and the activation of T-type channels, altering T-type "window currents." As a result, all these changes ultimately shaped the low-threshold spikes (LTS)-associated Ca2+ transients, regulated the membrane excitability, and altered sleep-wake transitions. CONCLUSION: Our results suggest that deleterious consequences of stimulants cocaine and caffeine combination on the thalamocortical physiology as a whole might be related to potential neurotoxic effects of soaring intracellular [Ca2+].

Synaptic signals mediated by protons and acid-sensing ion channels.

Extracellular pH changes may constitute significant signals for neuronal communication. During synaptic transmission, changes in pH in the synaptic cleft take place. Its role in the regulation of presynaptic Ca2+ currents through multivesicular release in ribbon-type synapses is a proven phenomenon. In recent years, protons have been recognized as neurotransmitters that participate in neuronal communication in synapses of several regions of the CNS such as amygdala, nucleus accumbens, and brainstem. Protons are released by nerve stimulation and activate postsynaptic acid-sensing ion channels (ASICs). Several types of ASIC channels are expressed in the peripheral and central nervous system. The influx of Ca2+ through some subtypes of ASICs, as a result of synaptic transmission, agrees with the participation of ASICs in synaptic plasticity. Pharmacological and genetical inhibition of ASIC1a results in alterations in learning, memory, and phenomena like fear and cocaine-seeking behavior. The recognition of endogenous molecules, such as arachidonic acid, cytokines, histamine, spermine, lactate, and neuropeptides, capable of inhibiting or potentiating ASICs suggests the existence of mechanisms of synaptic modulation that have not yet been fully identified and that could be tuned by new emerging pharmacological compounds with potential therapeutic benefits.

Calcium channels and synaptic transmission in familial hemiplegic migraine type 1 animal models.

One of the outstanding developments in clinical neurology has been the identification of ion channel mutations as the origin of a wide variety of inherited disorders like migraine, epilepsy, and ataxia. The study of several channelopathies has provided crucial insights into the molecular mechanisms, pathogenesis, and therapeutic approaches to complex neurological diseases. This review addresses the mutations underlying familial hemiplegic migraine (FHM) with particular interest in Cav2.1 (i.e., P/Q-type) voltage-activated Ca2+ channel FHM type-1 mutations (FHM1). Transgenic mice harboring the human pathogenic FHM1 mutation R192Q or S218L (KI) have been used as models to study neurotransmission at several central and peripheral synapses. FHM1 KI mice are a powerful tool to explore presynaptic regulation associated with expression of Cav2.1 channels. FHM1 Cav2.1 channels activate at more hyperpolarizing potentials and show an increased open probability. These biophysical alterations may lead to a gain-of-function on synaptic transmission depending upon factors such as action potential waveform and/or Cav2.1 splice variants and auxiliary subunits. Analysis of FHM knock-in mouse models has demonstrated a deficient regulation of the cortical excitation/inhibition (E/I) balance. The resulting excessive increases in cortical excitation may be the mechanisms that underlie abnormal sensory processing together with an increase in the susceptibility to cortical spreading depression (CSD). Increasing evidence from FHM KI animal studies support the idea that CSD, the underlying mechanism of aura, can activate trigeminal nociception, and thus trigger the headache mechanisms.

Acute modulation of calcium currents and synaptic transmission by gabapentinoids.

Gabapentin and pregabalin are anticonvulsant drugs that are extensively used for the treatment of several neurological and psychiatric disorders. Gabapentinoids (GBPs) are known to have a high affinity binding to α2δ-1 and α2δ-2 auxiliary subunit of specific voltage-gated calcium channels. Despite the confusing effects reported on Ca (2+) currents, most of the studies showed that GBPs reduced release of various neurotransmitters from synapses in several neuronal tissues. We showed that acute in vitro application of pregabalin can reduce in a dose dependent manner synaptic transmission in both neuromuscular junctions and calyx of Held-MNTB excitatory synapses. Furthermore presynaptic Ca (2+) currents treated with pregabalin are reduced in amplitude, do not show inactivation at a clinically relevant low concentration of 100 µM and activate and deactivate faster. These results suggest novel modulatory role of acute pregabalin that might contribute to better understanding its anticonvulsant/analgesic clinical effects.