Neurotensin (NT) is a tridecapeptide distributed in the CNS, including the entorhinal cortex (EC), a structure that is crucial for learning and memory and undergoes the earliest pathological alterations in Alzheimer's disease (AD). Whereas NT has been implicated in modulating cognition, the cellular and molecular mechanisms by which NT modifies cognitive processes and the potential therapeutic roles of NT in AD have not been determined. Here we examined the effects of NT on neuronal excitability and spatial learning in the EC, which expresses high density of NT receptors. Brief application of NT induced persistent increases in action potential firing frequency, which could last for at least 1 h. NT-induced facilitation of neuronal excitability was mediated by downregulation of TREK-2 K ϩ channels and required the functions of NTS1, phospholipase C, and protein kinase C. Microinjection of NT or NTS1 agonist, PD149163, into the EC increased spatial learning as assessed by the Barnes Maze Test. Activation of NTS1 receptors also induced persistent increases in action potential firing frequency and significantly improved the memory status in APP/PS1 mice, an animal model of AD. Our study identifies a cellular substrate underlying learning and memory and suggests that NTS1 agonists may exert beneficial actions in an animal model of AD.
Whereas vasopressin has been shown to enhance memory possibly by increasing long-term potentiation and direct excitation of the pyramidal neurons in the hippocampus, the effects of vasopressin on GABAergic transmission in the hippocampus remain to be determined. Here we examined the effects of vasopressin on GABAergic transmission onto CA1 pyramidal neurons and our results demonstrate that bath application of [Arg8]-vasopressin (AVP) dose-dependently increased the frequency of spontaneous IPSCs (sIPSCs) recorded from CA1 pyramidal neurons via activation of V1A receptors. Immunohistological staining and western blot further confirmed that both CA1 pyramidal neurons and interneurons expressed V1A receptors. Bath application of AVP altered neither the frequency nor the amplitude of miniature IPSCs in the presence of tetradotoxin and failed to change significantly the amplitude of evoked IPSCs recorded from CA1 pyramidal neurons. AVP increased the firing frequency of action potentials by depolarizing the GABAergic interneurons in the stratum radiatum of CA1 region. AVP-mediated depolarization of interneurons was mediated by inhibition of a background K+ conductance which was insensitive to extracellular tetraethylammonium, Cs+, 4-aminopyridine, tertiapine-Q and Ba2+. AVP-induced depolarization of interneurons was dependent on Gαq/11 but independent of phospholipase C, intracellular Ca2+ release and protein kinase C. The inhibitory effects of AVP-mediated modulation of GABA release onto CA1 pyramidal neurons were overwhelmed by its strong excitation of CA1 pyramidal neurons in physiological condition but revealed when its direct excitation of the pyramidal neurons was blocked suggesting that AVP-mediated modulation of GABAergic transmission fine-tunes the excitability of CA1 pyramidal neurons.
Whereas the entorhinal cortex (EC) receives profuse dopaminergic innervations from the midbrain, the effects of dopamine (DA) on γ-Aminobutyric acid (GABA)ergic interneurons in this brain region have not been determined. We probed the actions of DA on GABAA receptor-mediated synaptic transmission in the EC. Application of DA increased the frequency, not the amplitude, of spontaneous IPSCs (sIPSCs) and miniature IPSCs (mIPSCs) recorded from entorhinal principal neurons, but slightly reduced the amplitude of the evoked IPSCs. The effects of DA were unexpectedly found to be mediated by α1 adrenoreceptors, but not by DA receptors. DA endogenously released by the application of amphetamine also increased the frequency of sIPSCs. Ca(2+) influx via T-type Ca(2+) channels was required for DA-induced facilitation of sIPSCs and mIPSCs. DA depolarized and enhanced the firing frequency of action potentials of interneurons. DA-induced depolarization was independent of extracellular Na(+) and Ca(2+) and did not require the functions of hyperpolarization-activated (Ih) channels and T-type Ca(2+) channels. DA-generated currents showed a reversal potential close to the K(+) reversal potential and inward rectification, suggesting that DA inhibits the inward rectifier K(+) channels (Kirs). Our results demonstrate that DA facilitates GABA release by activating α1 adrenoreceptors to inhibit Kirs, which further depolarize interneurons resulting in secondary Ca(2+) influx via T-type Ca(+) channels.
Glutamate interacts with ionotropic and metabotropic glutamate receptors (mGluRs). Whereas the entorhinal cortex (EC) is a principal structure involved in learning and memory, the roles of mGluRs in synaptic transmission in the EC have not been completely determined. Here, we show that activation of group II mGluRs (mGluR II) induced robust depression of glutamatergic transmission in the EC. The mGluR II--induced depression was due to a selective reduction of presynaptic release probability without alterations of the quantal size and the number of release sites. The mechanisms underlying mGluR II--mediated suppression of glutamate release included the inhibition of presynaptic release machinery and the depression of presynaptic P/Q-type Ca 21 channels. Whereas mGluR II--induced depression required the function of Ga i/o proteins, protein kinase A (PKA) pathway was only involved in mGluR II--mediated inhibition of release machinery and thereby partially required for mGluR II--induced inhibition of glutamate release. Presynaptic stimulation at 5 Hz for 10 min also induced depression of glutamatergic transmission via activation of presynaptic mGluR II suggesting an endogenous role for mGluR II in modulating glutamatergic transmission.
The neural mechanisms of altered consciousness that accompanies most epileptic seizures are not known. We have reported alteration of consciousness resulting from electrical stimulation of the claustrum via a depth electrode in a woman with refractory focal epilepsy. Additionally, there are reports that suggest possible claustral involvement in focal epilepsy, including MRI findings of bilaterally increased T2 signal intensity in patients with status epilepticus (SE). Although its cytoarchitecture and connectivity have been studied extensively, the precise role of the claustrum in consciousness processing, and, thus, its contribution to the semiology of dyscognitive seizures are still elusive. To investigate the role of the claustrum in rats, we studied the effect of high-frequency stimulation (HFS) of the claustrum on performance in the operant chamber. We also studied the inter-claustral and the claustro-hippocampal connectivity through cerebro-cerebral evoked potentials (CCEPs), and investigated the involvement of the claustrum in kainate (KA)-induced seizures. We found that HFS of the claustrum decreased the performance in the operant task in a manner that was proportional to the current intensity used. In this article, we present previously unpublished data about the effect of stimulating extra-claustral regions in the operant chamber task as a control experiment. In these animals, stimulation of the corpus callosum, the largest interhemispheric commissure, as well as the orbitofrontal cortex in the vicinity of the claustrum did not produce that same effect as with claustral stimulation. Additionally, CCEPs established the presence of effective connectivity between both claustra, as well as between the claustrum and bilateral hippocampi indicating that these connections may be part of the circuitry involved in alteration of consciousness in limbic seizures. Lastly, some seizures induced by KA injections showed an early involvement of the claustrum with later propagation to the hippocampi. Further work is needed to clarify the exact role of the claustrum in mediating alteration of consciousness during epileptic seizures.
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