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1.
Elife ; 102021 10 26.
Article in English | MEDLINE | ID: mdl-34698637

ABSTRACT

The piriform cortex (PCx) is essential for learning of odor information. The current view postulates that odor learning in the PCx is mainly due to plasticity in intracortical (IC) synapses, while odor information from the olfactory bulb carried via the lateral olfactory tract (LOT) is 'hardwired.' Here, we revisit this notion by studying location- and pathway-dependent plasticity rules. We find that in contrast to the prevailing view, synaptic and optogenetically activated LOT synapses undergo strong and robust long-term potentiation (LTP) mediated by only a few local NMDA-spikes delivered at theta frequency, while global spike timing-dependent plasticity (STDP) protocols failed to induce LTP in these distal synapses. In contrast, IC synapses in apical and basal dendrites undergo plasticity with both NMDA-spikes and STDP protocols but to a smaller extent compared with LOT synapses. These results are consistent with a self-potentiating mechanism of odor information via NMDA-spikes that can form branch-specific memory traces of odors that can further associate with contextual IC information via STDP mechanisms to provide cognitive and emotional value to odors.


Subject(s)
Dendrites/physiology , Mice, Inbred C57BL/physiology , N-Methylaspartate/physiology , Neuronal Plasticity , Olfactory Bulb/physiology , Piriform Cortex/physiology , Rats, Wistar/physiology , Animals , Female , Male , Mice , Rats
2.
Physiol Rep ; 9(6): e14774, 2021 03.
Article in English | MEDLINE | ID: mdl-33769694

ABSTRACT

N-methyl-d-aspartate (NMDA) application has conventionally been used to activate spinal networks to induce locomotion in spinalized animals. We recently described an alternative approach in which application of continuous blue light activates channelrhodopsin-2 in vesicular glutamate transporter 2a (vglut2a)-expressing spinal neurons to produce organized, rhythmic locomotor activity in spinally-transected larval zebrafish. This technique arguably enhances research validity, because endogenous glutamate is released into existing synapses instead of activating only a subset of glutamatergic (NMDA) receptors with an exogenous compound. Here, we explored the viability of this approach in the context of using it for longer-term experiments. Fictive swimming was induced through repetitive application of 10-s blue light stimuli to spinalized preparations for up to 60 min at intervals of 1, 3, or 15 min. Locomotor activity was maintained throughout the experimental timecourse, demonstrating the robustness of the system. Although locomotor bursts remained organized into episodes of activity, the number of bursts elicited during each successive stimulus decreased. This was in contrast to NMDA bath application, in which bursts became less episodically organized while the overall number of bursts remained unchanged. The efficacy of the repetitive optogenetic stimulation paradigm was demonstrated through application of exogenous dopamine, which reversibly decreased the number of bursts produced per stimulus compared with untreated preparations. Finally, increasing the stimulus interval to 15 min lessened, but did not eliminate locomotor fatigue from repetitive activation. Altogether, we established repetitive optogenetic stimulation of vglut2a-expressing neurons as a viable alternative to NMDA application for activation of the zebrafish spinal locomotor network.


Subject(s)
Glutamic Acid/physiology , Locomotion/physiology , Motor Neurons/physiology , N-Methylaspartate/physiology , Neurons/physiology , Optogenetics , Spinal Cord/physiology , Animals , Excitatory Amino Acid Agonists/administration & dosage , Fatigue , Locomotion/drug effects , Models, Animal , Motor Neurons/drug effects , N-Methylaspartate/administration & dosage , Neurons/drug effects , Spinal Cord/drug effects , Swimming , Zebrafish
3.
J Mol Med (Berl) ; 99(3): 327-334, 2021 03.
Article in English | MEDLINE | ID: mdl-33447926

ABSTRACT

Memantine is used in Alzheimer's disease treatment as a non-competitive modern-affinity strong voltage-dependent N-methyl-D-aspartate receptor antagonist. The fundamental role of these receptors is to bind glutamate: the main excitatory neurotransmitter in the brain, believed to play a crucial role in neuronal plasticity and learning mechanisms. Glutamate transmission plays an important role in all internal CNS structures and maintains the physiological state of the brain. Excessive glutamate transmission can lead to enlarged calcium ion current which may cause neurotoxicity; however, insufficient transmission can drastically alter the information flow in neurons and the brain, potentially causing schizophrenia-like symptoms by replacing lost information with completely new stimuli. Hence, it is possible that the modulation of NMDA activity may give rise to pathophysiological states. Available literature and clinical trials indicate that memantine is well tolerated by patients, with very few and light side effects. There is a belief that memantine may also benefit other conditions such as schizophrenia and depression.


Subject(s)
Antidepressive Agents/therapeutic use , Antipsychotic Agents/therapeutic use , Depression/drug therapy , Excitatory Amino Acid Antagonists/therapeutic use , Memantine/therapeutic use , Schizophrenia/drug therapy , Alzheimer Disease/drug therapy , Antidepressive Agents/pharmacology , Antipsychotic Agents/pharmacology , Clinical Trials as Topic , Drug Repositioning , Excitatory Amino Acid Antagonists/pharmacology , Glutamic Acid/physiology , Humans , Memantine/pharmacology , N-Methylaspartate/physiology , Neuronal Plasticity/drug effects , Receptors, N-Methyl-D-Aspartate/physiology , Serotonin 5-HT3 Receptor Antagonists/pharmacology , Serotonin 5-HT3 Receptor Antagonists/therapeutic use
4.
J Oral Pathol Med ; 49(6): 547-554, 2020 Jul.
Article in English | MEDLINE | ID: mdl-32531859

ABSTRACT

BACKGROUND: Adenosine triphosphate (ATP) and glutamate are associated with some headache conditions, and purinergic (P2X) and glutamatergic N-methyl-D-aspartate (NMDA) receptor-related processes in the medulla can modulate the effects of trigeminal nociceptive afferent inputs into the brainstem on craniofacial sensorimotor circuits. This study aimed to test whether neck muscle activity can be induced in rats by noxious stimulation of the frontal dura or superior sagittal sinus that involves P2X or NMDA receptor-dependent mechanisms. METHODS: While electromyographic activities of neck and craniofacial muscles were being recorded in anesthetized rats (n = 46), the inflammatory irritant mustard oil (0.2 µL, 20% MO) or vehicle (mineral oil) was topically applied to the dura or sinus, preceded by 10 µL of the ATP antagonist 2',3'-O-(2,4,6- trinitrophenyl) adenosine 5'-triphosphate (TNP-ATP, 0.1 mmol/L; n = 8) or 2-amino-5-phosphonopentanoic acid (APV, 0.05 mmol/L; n = 7) or phosphate-buffered saline (PBS as vehicle control; n = 10). RESULTS: Application of MO but not vehicle to the frontal dura significantly increased (P < .05) neck electromyographic activity whereas MO application to the superior sagittal sinus did not significantly increase neck electromyographic activity unless MO had previously been applied to the dura. Pre-treatment (i.t.) with TNP-ATP or APV but not vehicle control significantly reduced neck electromyographic activity evoked by MO application to the dura. CONCLUSIONS: These data suggest that noxious stimulation of the frontal dura (but not superior sagittal sinus) may enhance neck muscle activity that is P2X and NMDA receptor-dependent. These effects may contribute to neck muscle stiffness that occurs in some headache conditions.


Subject(s)
Headache , N-Methylaspartate , Neck Muscles , Adenosine Triphosphate , Animals , Dura Mater , Headache/complications , N-Methylaspartate/physiology , Neck Muscles/physiopathology , Rats , Rats, Sprague-Dawley , Receptors, N-Methyl-D-Aspartate
5.
J Comput Neurosci ; 48(2): 193-211, 2020 05.
Article in English | MEDLINE | ID: mdl-32363561

ABSTRACT

When similar visual stimuli are presented binocularly to both eyes, one perceives a fused single image. However, when the two stimuli are distinct, one does not perceive a single image; instead, one perceives binocular rivalry. That is, one perceives one of the stimulated patterns for a few seconds, then the other for few seconds, and so on - with random transitions between the two percepts. Most theoretical studies focus on rivalry, with few considering the coexistence of fusion and rivalry. Here we develop three distinct computational neuronal network models which capture binocular rivalry with realistic stochastic properties, fusion, and the hysteretic transition between. Each is a conductance-based point neuron model, which is multi-layer with two ocular dominance columns (L & R) and with an idealized "ring" architecture where the orientation preference of each neuron labels its location on a ring. In each model, the primary mechanism initiating binocular rivalry is cross-column inhibition, with firing rate adaptation governing the temporal properties of the transitions between percepts. Under stimulation by similar visual patterns, each of three models uses its own mechanism to overcome cross-column inhibition, and thus to prevent rivalry and allow the fusion of similar images: The first model uses cross-column feedforward inhibition from the opposite eye to "shut off" the cross-column feedback inhibition; the second model "turns on" a second layer of monocular neurons as a parallel pathway to the binocular neurons, rivaling out of phase with the first layer, and together these two pathways represent fusion; and the third model uses cross-column excitation to overcome the cross-column inhibition and enable fusion. Thus, each of the idealized ring models depends upon a different mechanism for fusion that might emerge as an underlying mechanism present in real visual cortex.


Subject(s)
Models, Neurological , Vision Disparity/physiology , Vision, Binocular/physiology , Algorithms , Computer Simulation , Dominance, Ocular , Electrophysiological Phenomena/physiology , Feedback, Sensory/physiology , Humans , N-Methylaspartate/physiology , Neural Networks, Computer , Neurons/physiology , Neurotransmitter Agents/physiology , Stochastic Processes , Visual Perception/physiology
6.
J Integr Neurosci ; 18(2): 163-172, 2019 06 30.
Article in English | MEDLINE | ID: mdl-31321957

ABSTRACT

In this paper, the modulation of ascending commissural interneurons by N-methyl-D-aspartate was investigated in neonatal rats by using retrograde labeling and whole-cell patch clamp. Data shows these interneurons can be divided into three types (single spike, phasic, and tonic) based on their firing patterns. A hyperpolarization-activated nonselective cation current and persistent inward current are expressed in these interneurons. The parameters studied (n = 48) include: resting membrane potential (-59.2 ± 0.8 mV), input resistance (964.4 ± 49.3 MΩ), voltage threshold (-39.5 ± 0.6 mV), rheobase (13.5 ± 0.7 pA), action potential height (55.6 ± 2.2 mV), action potential half-width (2.8 ± 0.1 ms), afterhyperpolarization magnitude (16.1 ± 1.2 mV) and half-decay (217.9 ± 10.7 ms). 10 µM N-methyl-D-aspartate increases excitability of ascending commissural interneurons by depolarizing the membrane potential, hyperpolarizing voltage threshold, reducing rheobase, and shifting the frequency-current relationship to the left. N-methyl-Daspartate enhances persistent inward currents but reduces hyperpolarization-activated nonselective cation currents. This research uncovers unique ionic and intrinsic properties of ascending commissural interneurons which can be modulated by major excitatory neurotransmitters such as N-methyl-D-aspartate to potentially facilitate left-right alternation during locomotion.


Subject(s)
Commissural Interneurons/physiology , Membrane Potentials , N-Methylaspartate/physiology , Spinal Cord/physiology , Action Potentials/drug effects , Animals , Animals, Newborn , Commissural Interneurons/cytology , Commissural Interneurons/drug effects , Excitatory Amino Acid Agonists/administration & dosage , Membrane Potentials/drug effects , N-Methylaspartate/administration & dosage , Rats, Wistar , Spinal Cord/cytology , Spinal Cord/drug effects
7.
Article in Russian | MEDLINE | ID: mdl-30499496

ABSTRACT

AIM: To study the involvement of NMDA-dependent mechanisms in the development of posttraumatic stress disorder (PTSD) by investigation of the effects induced by NMDA application in olfactory cortex slices of active and passive rats exposed to inescapable water-immersion stress. MATERIAL AND METHODS: Wistar rats were selected in behavioral experiments according to their active or passive behavior. Rats were subjected to unavoidable water-immersion stress, and then after 10 days the surviving brain slices (olfactory cortex) were prepared. NMDA-dependent responses were recorded and analyzed after 50 µM NMDA applications on the slices. RESULTS AND CONCLUSION: Different changes in NMDA-stimulated amplitudes were detected in brain slices of rats depending on their passive or active behavior during the formation of PTSD. NMDA responses in the brains of rats with active behavioral strategy were more resistant to stress. Their activity was inhibited, but not blocked. In rats with passive behavior strategies, NMDA-dependent mechanisms were more vulnerable that was manifested as prominent depression of their activity.


Subject(s)
N-Methylaspartate , Stress Disorders, Post-Traumatic , Animals , Disease Models, Animal , N-Methylaspartate/physiology , Rats , Rats, Wistar , Stress Disorders, Post-Traumatic/physiopathology
8.
Neurobiol Aging ; 66: 75-84, 2018 06.
Article in English | MEDLINE | ID: mdl-29547750

ABSTRACT

Robust physiological circadian rhythms form an integral part of well-being. The aging process has been found to negatively impact systems that drive circadian physiology, typically manifesting as symptoms associated with abnormal/disrupted sleeping patterns. Here, we investigated the age-related decline in light-driven circadian entrainment in male C57BL/6J mice. We compared light-driven resetting of circadian behavioral activity in young (1-2 months) and old (14-18 months) mice and explored alterations in the glutamatergic pathway at the level of the circadian pacemaker, the suprachiasmatic nucleus (SCN). Aged animals showed a significant reduction in sensitivity to behavioral phase resetting by light. We show that this change was through alterations in N-Methyl-D-aspartate (NMDA) signaling at the SCN, where NMDA, a glutamatergic agonist, was less potent in inducing clock resetting. Finally, we show that this shift in NMDA sensitivity was through the reduced SCN expression of this receptor's NR2B subunit. Only in young animals did an NR2B antagonist attenuate behavioral resetting. These results can help target treatments that aim to improve both physiological and behavioral circadian entrainment in aged populations.


Subject(s)
Aging/physiology , Aging/psychology , Chronobiology Disorders/etiology , Chronobiology Disorders/genetics , Circadian Rhythm/genetics , Circadian Rhythm/physiology , Eye/physiopathology , Light , N-Methylaspartate/physiology , Signal Transduction/physiology , Suprachiasmatic Nucleus/physiopathology , Visual Pathways/physiopathology , Animals , Male , Mice, Inbred C57BL , N-Methylaspartate/metabolism , Suprachiasmatic Nucleus/metabolism
9.
Neuropsychopharmacology ; 43(10): 2101-2108, 2018 09.
Article in English | MEDLINE | ID: mdl-29483660

ABSTRACT

Several aspects of schizophrenia can be mimicked acutely in healthy human volunteers via administration of NMDA glutamate receptor (NMDAR) antagonists. As these agents decrease firing rates in prefrontal cortical (PFC) GABAergic fast-spiking interneurons (FSI) in animal studies, a leading hypothesis on schizophrenia pathophysiology is that NMDAR in FSI are impaired. However, whole-cell recordings of FSI in slices of adult mouse PFC revealed limited amounts of NMDAR-mediated current. Since those studies used local electrical stimulation to activate a heterogeneous set of synaptic inputs to the recorded cell, it is unclear whether specific afferent inputs may preferentially drive NMDAR responses in FSI. Here, we expressed opsins in discrete brain regions projecting to the PFC in adult male mice, enabling light-activation of defined, homogenous sets of long-range inputs to FSI and pyramidal neurons recorded in slices containing medial PFC (mPFC). Stimulation of axons originating from either the contralateral mPFC, ventral hippocampus, or mediodorsal thalamus evoked NMDAR-mediated currents in the vast majority of FSI and in all pyramidal neurons recorded. The observation that multiple long-range inputs to mPFC FSI elicit NMDAR currents suggests that the NMDAR-hypofunction model of schizophrenia may still imply a loss of interneuron inputs, but the sources of reduced excitation may originate from sites upstream of the PFC.


Subject(s)
Interneurons/physiology , N-Methylaspartate/physiology , Prefrontal Cortex/physiology , Action Potentials , Animals , Axons/drug effects , Axons/physiology , Electric Stimulation , Electrophysiological Phenomena/drug effects , Electrophysiological Phenomena/physiology , Light , Male , Mediodorsal Thalamic Nucleus/drug effects , Mediodorsal Thalamic Nucleus/physiology , Mice , Patch-Clamp Techniques , Pyramidal Cells/drug effects , Pyramidal Cells/physiology , Schizophrenia/chemically induced
10.
Appetite ; 122: 17-25, 2018 03 01.
Article in English | MEDLINE | ID: mdl-27988368

ABSTRACT

The elucidation of the behavioral, neurochemical, neuroanatomical and genetic substrates mediating the development of conditioned flavor preferences (CFP) is one of the multi-faceted scientific contributions that Dr. Anthony Sclafani has made to the study of food intake. This review summarizes the results of thirty-five publications over nearly twenty years of collaborations between the Sclafani and Bodnar laboratories. This includes the different approaches employed to study the orosensory (flavor-flavor) and post-ingestive (flavor-nutrient) processes underlying CFP including its acquisition (learning) and expression. It describes how CFP is elicited by different sugars (sucrose, glucose, fructose) and fats (corn oil) in rats, and how strain-specific CFP effects can be observed through the use of inbred mouse strains to evaluate genetic variance. The roles of pharmacological substrates (dopamine, glutamate, opioids, acetylcholine, GABA, cannabinoids) mediating sugar- and fat-CFP acquisition and expression are elucidated. Finally, neuroanatomical sites of action (nucleus accumbens, amygdala, medial prefrontal and orbital frontal cortices, lateral hypothalamus) are evaluated at which dopamine signaling mediates acquisition and expression of different forms of CFP.


Subject(s)
Brain/physiology , Food Preferences/physiology , Pharmacogenomic Variants , Taste , Acetylcholine/pharmacology , Animals , Cannabinoids/pharmacology , Dietary Fats/administration & dosage , Dietary Sugars/administration & dosage , Dopamine/physiology , Mice , N-Methylaspartate/physiology , Quinine/pharmacology , Rats , Receptor, Cannabinoid, CB1/physiology , Receptors, GABA-B/physiology , Receptors, Muscarinic/physiology
11.
Neuron ; 96(5): 1099-1111.e3, 2017 Dec 06.
Article in English | MEDLINE | ID: mdl-29107522

ABSTRACT

Retinal direction-selective ganglion cells (DSGCs) have the remarkable ability to encode motion over a wide range of contrasts, relying on well-coordinated excitation and inhibition (E/I). E/I is orchestrated by a diverse set of glutamatergic bipolar cells that drive DSGCs directly, as well as indirectly through feedforward GABAergic/cholinergic signals mediated by starburst amacrine cells. Determining how direction-selective responses are generated across varied stimulus conditions requires understanding how glutamate, acetylcholine, and GABA signals are precisely coordinated. Here, we use a combination of paired patch-clamp recordings, serial EM, and large-scale multi-electrode array recordings to show that a single high-sensitivity source of glutamate is processed differentially by starbursts via AMPA receptors and DSGCs via NMDA receptors. We further demonstrate how this novel synaptic arrangement enables DSGCs to encode direction robustly near threshold contrasts. Together, these results reveal a space-efficient synaptic circuit model for direction computations, in which "silent" NMDA receptors play critical roles.


Subject(s)
Motion Perception/physiology , N-Methylaspartate/physiology , Retina/physiology , Synapses/physiology , Acetylcholine/physiology , Animals , Glutamic Acid/physiology , Mice , Patch-Clamp Techniques , Receptors, AMPA/physiology , Retina/ultrastructure , Retinal Bipolar Cells/physiology , Retinal Bipolar Cells/ultrastructure , Retinal Ganglion Cells/physiology , Retinal Ganglion Cells/ultrastructure , Signal Transduction/physiology , Synapses/ultrastructure , gamma-Aminobutyric Acid/physiology
12.
Article in English | MEDLINE | ID: mdl-28093558

ABSTRACT

Synapses are complex because they perform multiple functions, including at least six mechanistically different forms of plasticity. Here, I comment on recent developments regarding these processes. (i) Short-term potentiation (STP), a Hebbian process that requires small amounts of synaptic input, appears to make strong contributions to some forms of working memory. (ii) The rules for long-term potentiation (LTP) induction in CA3 have been clarified: induction does not depend obligatorily on backpropagating sodium spikes but, rather, on dendritic branch-specific N-methyl-d-aspartate (NMDA) spikes. (iii) Late LTP, a process that requires a dopamine signal (and is therefore neoHebbian), is mediated by trans-synaptic growth of the synapse, a growth that occurs about an hour after LTP induction. (iv) LTD processes are complex and include both homosynaptic and heterosynaptic forms. (v) Synaptic scaling produced by changes in activity levels are not primarily cell-autonomous, but rather depend on network activity. (vi) The evidence for distance-dependent scaling along the primary dendrite is firm, and a plausible structural-based mechanism is suggested.Ideas about the mechanisms of synaptic function need to take into consideration newly emerging data about synaptic structure. Recent super-resolution studies indicate that glutamatergic synapses are modular (module size 70-80 nm), as predicted by theoretical work. Modules are trans-synaptic structures and have high concentrations of postsynaptic density-95 (PSD-95) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor. These modules function as quasi-independent loci of AMPA-mediated transmission and may be independently modifiable, suggesting a new understanding of quantal transmission.This article is part of the themed issue 'Integrating Hebbian and homeostatic plasticity.'


Subject(s)
Neuronal Plasticity , Synapses/physiology , Animals , Long-Term Potentiation , Long-Term Synaptic Depression , N-Methylaspartate/physiology , Receptors, AMPA/physiology
13.
Anat Sci Int ; 91(1): 8-21, 2016 Jan.
Article in English | MEDLINE | ID: mdl-26439731

ABSTRACT

Glutamate mediates most fast excitatory transmission in the central nervous system by activating primarily two types of ionotropic glutamate receptors: α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors. Differential subunit combinations generate great functional diversity in both categories of receptors, making them highly suitable for meeting complex functional requirements. Converging evidence has indicated that distinct AMPA and NMDA receptor subtypes are selectively targeted to functionally different synapses according to different factors, including presynaptic inputs, postsynaptic cell types, and synaptic configurations. This article provides an overview of recent progress in understanding the basic principles governing the synaptic allocation of AMPA and NMDA receptors, and discusses the underlying mechanisms and functional implications.


Subject(s)
Glutamates/physiology , N-Methylaspartate/metabolism , Receptors, AMPA/metabolism , Synapses/metabolism , Synapses/physiology , Animals , Hippocampus , Humans , Immunohistochemistry , N-Methylaspartate/physiology , Purkinje Cells , Receptors, AMPA/physiology , Synaptic Transmission
14.
J Addict Med ; 9(6): 499-501, 2015.
Article in English | MEDLINE | ID: mdl-26441400

ABSTRACT

Dextromethorphan, an antitussive (cough suppressant) drug of the morphinan class with sedative and dissociative properties found in cough syrup and other over-the-counter products, is also a substance of abuse, seen primarily in young adults all over the world. A case of dextromethorphan use disorder is presented in a 45-year-old women. Her repeated attempts at abstinence were unsuccessful secondary to continued intense cravings. Treatment with topiramate resulted in complete resolution of her cravings. Topiramate was chosen empirically because of a common action with dextromethorphan in the NMDA system. Genetic testing was obtained and the patient was found to be a carrier of the GRIK1 rs2832407(C:C) allele. The (C:C) allele has been associated with an increased risk of alcohol use disorder and a treatment response of patients with heavy drinking to topiramate. This case provides an opportunity to discuss personalized medicine (treatment options aided by the use of genetic testing) and the possible shared genetic susceptibility for dependence in 2 substances of abuse.


Subject(s)
Behavior, Addictive/genetics , Dextromethorphan/adverse effects , Fructose/analogs & derivatives , N-Methylaspartate/physiology , Receptors, Kainic Acid/genetics , Substance-Related Disorders/drug therapy , Alleles , Female , Fructose/therapeutic use , Humans , Middle Aged , Topiramate
15.
J Neuroendocrinol ; 27(3): 187-97, 2015 Mar.
Article in English | MEDLINE | ID: mdl-25582792

ABSTRACT

Kisspeptin, encoded by the Kiss1 gene, has attracted attention as a key candidate neuropeptide in controlling puberty and reproduction via regulation of gonadotrophin-releasing hormone (GnRH) secretion in mammals. Pioneer studies with Kiss1 or its cognate receptor Gpr54 knockout (KO) mice showed the indispensable role of kisspeptin-GPR54 signalling in the control of animal reproduction, although detailed analyses of gonadotrophin secretion, especially pulsatile and surge-mode of luteinising hormone (LH) secretion, were limited. Thus, in the present study, we have generated Kiss1 KO rats aiming to evaluate a key role of kisspeptin in governing reproduction via pulse and surge modes of GnRH/LH secretion. Kiss1 KO male and female rats showed a complete suppression of pulsatile LH secretion, which is responsible for folliculogenesis and spermatogenesis, and an absence of puberty and atrophic gonads. Kiss1 KO female rats showed no spontaneous LH/follicle-stimulating hormone surge and an oestrogen-induced LH surge, suggesting that the GnRH surge generation system, which is responsible for ovulation, does not function without kisspeptin. Furthermore, challenge of major stimulatory neurotransmitters, such as monosodium glutamate, NMDA and norepinephrine, failed to stimulate LH secretion in Kiss1 KO rats, albeit they stimulated LH release in wild-type controls. Taken together, the results of the present study confirm that kisspeptin plays an indispensable role in generating two modes (pulse and surge) of GnRH/gonadotrophin secretion to regulate puberty onset and normal reproductive performance. In addition, the present study suggests that kisspeptin neurones play a critical role as a hub integrating major stimulatory neural inputs to GnRH neurones, using newly established Kiss1 KO rats, which serve as a useful model for detailed analysis of hormonal profiles.


Subject(s)
Glutamic Acid/physiology , Kisspeptins/physiology , Luteinizing Hormone/metabolism , Sexual Maturation/physiology , Animals , Female , Follicle Stimulating Hormone/metabolism , Kisspeptins/genetics , Male , Mice, Knockout , N-Methylaspartate/physiology , Norepinephrine/physiology , Rats , Sexual Maturation/genetics
16.
J Neurosci ; 34(41): 13614-28, 2014 Oct 08.
Article in English | MEDLINE | ID: mdl-25297090

ABSTRACT

Degeneration of basal forebrain (BF) cholinergic neurons is one of the early pathological events in Alzheimer's disease (AD) and is thought to be responsible for the cholinergic and cognitive deficits in AD. The functions of this group of neurons are highly influenced by glutamatergic inputs from neocortex. We found that activation of metabotropic glutamate receptor 7 (mGluR7) decreased NMDAR-mediated currents and NR1 surface expression in rodent BF neurons via a mechanism involving cofilin-regulated actin dynamics. In BF cholinergic neurons, ß-amyloid (Aß) selectively impaired mGluR7 regulation of NMDARs by increasing p21-activated kinase activity and decreasing cofilin-mediated actin depolymerization through a p75(NTR)-dependent mechanism. Cell viability assays showed that activation of mGluR7 protected BF neurons from NMDA-induced excitotoxicity, which was selectively impaired by Aß in BF cholinergic neurons. It provides a potential basis for the Aß-induced disruption of calcium homeostasis that might contribute to the selective degeneration of BF cholinergic neurons in the early stage of AD.


Subject(s)
Alzheimer Disease/pathology , Amyloid beta-Peptides/toxicity , N-Methylaspartate/physiology , Neurons/drug effects , Parasympathetic Nervous System/pathology , Prosencephalon/physiology , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Signal Transduction/drug effects , Animals , Choline O-Acetyltransferase/metabolism , Nerve Degeneration/chemically induced , Nerve Degeneration/pathology , Prosencephalon/cytology , Prosencephalon/drug effects , Rats , Rats, Sprague-Dawley
17.
J Neurosci ; 34(38): 12778-87, 2014 Sep 17.
Article in English | MEDLINE | ID: mdl-25232114

ABSTRACT

Reactive oxygen species (ROS) are signaling factors involved in many intracellular transduction pathways. In the nervous system, ROS are thought to modulate various mechanisms of synaptic plasticity. One important source of ROS production in the brain is the NADPH oxidase complex. Stimulation of NMDA receptors activates NADPH oxidase, which provides selective oxidative responses accompanying the induction of synaptic changes. The activity of NADPH oxidase is known to be crucial for the induction of LTP in the hippocampus. However, the involvement of this complex in cortical synaptic plasticity is still unclear. Here we provide evidence that genetic ablation of NOX2 (the prototypical member of NADPH oxidase family of proteins) suppresses LTP and LTD in the primary visual cortex of the mouse. We also found that the involvement of NOX2 on LTP is partially age-dependent, as the activity of this complex is not critical for mechanisms of synaptic potentiation occurring in immature animals. Furthermore, we show that inhibition of NOX2 reduces the NMDA receptor function, suggesting a possible mechanism that could be the basis of the effects on synaptic plasticity.


Subject(s)
Aging/physiology , Long-Term Potentiation/physiology , Long-Term Synaptic Depression/physiology , Membrane Glycoproteins/physiology , NADPH Oxidases/physiology , Visual Cortex/metabolism , Acetophenones/pharmacology , Animals , Antioxidants/pharmacology , Dizocilpine Maleate/pharmacology , Enzyme Activation , Excitatory Amino Acid Antagonists/pharmacology , Male , Membrane Glycoproteins/antagonists & inhibitors , Membrane Glycoproteins/genetics , Membrane Potentials/drug effects , Membrane Potentials/physiology , Mice , Mice, Knockout , N-Methylaspartate/antagonists & inhibitors , N-Methylaspartate/physiology , NADPH Oxidase 2 , NADPH Oxidases/antagonists & inhibitors , NADPH Oxidases/genetics , Reactive Oxygen Species/metabolism , Visual Cortex/physiology
18.
J Pharmacol Exp Ther ; 349(2): 239-47, 2014 May.
Article in English | MEDLINE | ID: mdl-24610957

ABSTRACT

Clinically used calcineurin inhibitors, including tacrolimus (FK506) and cyclosporine A, can induce calcineurin inhibitor-induced pain syndrome (CIPS), which is characterized as severe pain and pain hypersensitivity. Increased synaptic N-methyl-D-aspartate receptor (NMDAR) activity in the spinal dorsal horn plays a critical role in the development of CIPS. Casein kinase II (CK2), a serine/threonine protein kinase, can regulate synaptic NMDAR activity in the brain. In this study, we determined whether spinal CK2 is involved in increased NMDAR activity and pain hypersensitivity caused by systemic administration of FK506 in rats. FK506 treatment caused a large increase in the amplitude of NMDAR-mediated excitatory postsynaptic currents (EPSCs) evoked by primary afferent stimulation and in the frequency of miniature EPSCs of spinal dorsal horn neurons. CK2 inhibition with either 5,6-dichloro-1-ß-d-ribofuranosylbenzimidazole (DRB) or 4,5,6,7-tetrabromobenzotriazole (TBB) completely normalized the amplitude of evoked NMDAR-EPSCs of dorsal horn neurons in FK506-treated rats. In addition, DRB or TBB significantly attenuated the amplitude of NMDAR currents elicited by puff application of N-methyl-D-aspartate to dorsal horn neurons in FK506-treated rats. Furthermore, treatment with DRB or TBB significantly reduced the frequency of miniature EPSCs of spinal dorsal horn neurons increased by FK506 treatment. In addition, intrathecal injection of DRB or TBB dose-dependently reversed tactile allodynia and mechanical hyperalgesia in FK506-treated rats. Collectively, our findings indicate that CK2 inhibition abrogates pain hypersensitivity and increased pre- and postsynaptic NMDAR activity in the spinal cord caused by calcineurin inhibitors. CK2 inhibitors may represent a new therapeutic option for the treatment of CIPS.


Subject(s)
Calcineurin Inhibitors , Casein Kinase II/antagonists & inhibitors , Hyperalgesia/drug therapy , N-Methylaspartate/physiology , Spinal Cord/metabolism , Tacrolimus/adverse effects , Animals , Dichlororibofuranosylbenzimidazole/pharmacology , Dichlororibofuranosylbenzimidazole/therapeutic use , Excitatory Postsynaptic Potentials , Hyperalgesia/metabolism , Hyperalgesia/physiopathology , Male , Miniature Postsynaptic Potentials , Physical Stimulation , Posterior Horn Cells/metabolism , Posterior Horn Cells/physiopathology , Rats, Sprague-Dawley , Spinal Cord/physiopathology , Touch , Triazoles/pharmacology , Triazoles/therapeutic use
19.
Neurosci Lett ; 566: 172-6, 2014 Apr 30.
Article in English | MEDLINE | ID: mdl-24530380

ABSTRACT

This study investigated the effects of ketamine on fluoxetine-induced antidepressant behavior using the forced swimming test (FST) in mice. In order to understand the possible role of N-methyl-d-aspartate (NMDA) neurotransmission in the antidepressant effect of fluoxetine, different groups of mice (n=10) were administered with acute ketamine (3mg/kg, i.p.), acute NMDA (75mg/kg and 150mg/kg, i.p.) and a 21-day chronic ketamine (15mg/kg, i.p./day) were administered prior to the administration of fluoxetine (20mg/kg, i.p.) in the mice. Antidepressant related behavior (immobility score) was measured using the forced swimming test. The results showed that the acute ketamine and fluoxetine alone treatments elicited a significant (p<0.05) reduction in immobility score compared with saline control. Furthermore, pre-treatment with acute ketamine significantly enhanced by the fluoxetine-induced decrease in immobility score. In contrast, pre-treatment with NMDA (150mg/kg) significantly (p<0.05) reversed fluoxetine-induced decrease in immobility score. On the other hand, chronic administration of ketamine significantly elicited an increase in immobility score as well as reversed the reduction induced by fluoxetine. Similarly, NMDA administration at both 75mg/kg and 150mg/kg increased immobility score in chronically administered ketamine groups. Furthermore, chronic administration of ketamine, followed by NMDA (75mg/kg) and fluoxetine significantly elevated the immobility score when compared with the group that received NMDA and fluoxetine but not chronically treated with ketamine. It can be suggested) that facilitation of NMDA transmission blocked fluoxetine-induced reduction in immobility score, while down-regulation of NMDA transmission is associated with increase in fluoxetine-induced antidepressant-related behavior in mice. Down-regulation of the NMDA transmission is proposed as an essential component of mechanism of suppression of depression related behaviors by fluoxetine. Modulation of NMDA transmission is suggested to be relevant in the mechanism of action of fluoxetine.


Subject(s)
Antidepressive Agents, Second-Generation/pharmacology , Depression/psychology , Fluoxetine/pharmacology , Ketamine/pharmacology , N-Methylaspartate/pharmacology , Receptors, N-Methyl-D-Aspartate/agonists , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Animals , Antidepressive Agents, Second-Generation/therapeutic use , Behavior, Animal/drug effects , Depression/drug therapy , Fluoxetine/therapeutic use , Mice , N-Methylaspartate/physiology , Swimming , Synaptic Transmission
20.
Neuron ; 80(6): 1438-50, 2013 Dec 18.
Article in English | MEDLINE | ID: mdl-24360546

ABSTRACT

The hippocampal CA3 region is essential for pattern completion and generation of sharp-wave ripples. During these operations, coordinated activation of ensembles of CA3 pyramidal neurons produces spatiotemporally structured input patterns arriving onto dendrites of recurrently connected CA3 neurons. To understand how such input patterns are translated into specific output patterns, we characterized dendritic integration in CA3 pyramidal cells using two-photon imaging and glutamate uncaging. We found that thin dendrites of CA3 pyramidal neurons integrate synchronous synaptic input in a highly supralinear fashion. The amplification was primarily mediated by NMDA receptor activation and was present over a relatively broad range of spatiotemporal input patterns. The decay of voltage responses, temporal summation, and action potential output was regulated in a compartmentalized fashion mainly by a G-protein-activated inwardly rectifying K(+) current. Our results suggest that plastic dendritic integrative mechanisms may support ensemble behavior in pyramidal neurons of the hippocampal circuitry.


Subject(s)
CA3 Region, Hippocampal/physiology , Dendrites/physiology , N-Methylaspartate/physiology , Pyramidal Cells/physiology , Action Potentials/physiology , Animals , G Protein-Coupled Inwardly-Rectifying Potassium Channels/physiology , Glutamic Acid/pharmacology , Male , Potassium Channels , Rats , Sodium/physiology
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