Concentrations of extracellular free zinc (pZn)e in the central nervous system during simple anesthetization, ischemia and reperfusion.

"Free Zn2+" (rapidly exchangeable Zn2+) is stored along with glutamate in the presynaptic terminals of specific specialized (gluzinergic) cerebrocortical neurons. This synaptically releasable Zn2+ has been recognized as a potent modulator of glutamatergic transmission and as a key toxin in excitotoxic neuronal injury. Surprisingly (despite abundant work on bound zinc), neither the baseline concentration of free Zn2+ in the brain nor the presumed co-release of free Zn2+ and glutamate has ever been directly observed in the intact brain in vivo.

Characterization of extracellular accumulation of Zn2+ during ischemia and reperfusion of hippocampus slices in rat.

The mammalian CNS contains an abundance of chelatable zinc that is sequestered in the vesicles of glutamatergic presynaptic terminals and co-released with glutamate. Considerable Zn(2+) is also released during cerebral ischemia and reperfusion (I/R) although the mechanism of this release has not been elucidated. We report here the real time observation of increase of the concentration of extracellular Zn(2+) ([Zn(2+)](o)), accompanied by a rapid increase of intracellular free Zn(2+)concentration, in the areas of dentate gyrus (DG), CA1 and CA3 in acute rat hippocampus slices during ischemia simulated by deprivation of oxygen and glucose (OGD) followed by reperfusion with normal artificial cerebrospinal fluid.

Do we need zinc to think?

Chelatable Zn(2+), which is found in the synaptic vesicles of certain glutamatergic neurons in several regions of the forebrain, is released during neuronal activity. Zn(2+) exhibits numerous effects on ligand-gated and voltage-dependent ion channels, and released Zn(2+) is therefore likely able to modulate synaptic transmission. The physiologically relevant actions of Zn(2+), however, have remained unclear.

Modulation of epileptiform burst frequency by the metabotropic glutamate receptor subtype mGluR3.

Spontaneous epileptiform burst activity occurs in acute hippocampal slice dentate granule cells perfused with 10mM potassium and 0.5mM calcium [J. Neurophys.

Rapid translocation of Zn(2+) from presynaptic terminals into postsynaptic hippocampal neurons after physiological stimulation.

Zn(2+) is found in glutamatergic nerve terminals throughout the mammalian forebrain and has diverse extracellular and intracellular actions. The anatomical location and possible synaptic signaling role for this cation have led to the hypothesis that Zn(2+) is released from presynaptic boutons, traverses the synaptic cleft, and enters postsynaptic neurons. However, these events have not been directly observed or characterized.

Induction of mossy fiber --> Ca3 long-term potentiation requires translocation of synaptically released Zn2+.

The mammalian CNS contains an abundance of chelatable Zn(2+) sequestered in the vesicles of glutamatergic terminals. These vesicles are particularly numerous in hippocampal mossy fiber synapses of the hilar and CA3 regions. Our recent observation of frequency-dependent Zn(2+) release from mossy fiber synaptic terminals and subsequent entry into postsynaptic neurons has prompted us to investigate the role of synaptically released Zn(2+) in the induction of long-term potentiation (LTP) in field CA3 of the hippocampus.

beta-NAAG rescues LTP from blockade by NAAG in rat dentate gyrus via the type 3 metabotropic glutamate receptor.

N-Acetylaspartylglutamate (NAAG) is an agonist at the type 3 metabotropic glutamate receptor (mGluR3), which is coupled to a Gi/o protein. When activated, the mGluR3 receptor inhibits adenylyl cyclase and reduces the cAMP-mediated second-messenger cascade. Long-term potentiation (LTP) in the medial perforant path (MPP) of the hippocampal dentate gyrus requires increases in cAMP.

Fragile X (fmr1) mRNA expression is differentially regulated in two adult models of activity-dependent gene expression.

We sought to determine whether the fragile X mental retardation gene fmr1 is regulated in long-term potentiation (LTP) and electroconvulsive shock (ECS). In situ hybridization of fmr1 mRNA in hippocampus of rats given LTP in vivo showed no change in fmr1 mRNA levels relative to control. However, ECS induced a selective increase in fmr1 mRNA expression in the dentate gyrus (DG) granule cell layer at 6 h post-ECS.

Acute cold stress leading to elevated corticosterone neither enhances synaptic efficacy nor impairs LTP in the dentate gyrus of freely moving rats.

Exposure to stress has previously been found to impair long-term potentiation (LTP) in the hippocampus. Exposure to stress has also been proposed to induce an LTP-like effect. We examined the effect of acute cold stress on synaptic transmission, neuronal excitability, and LTP induction in the medial perforant path-granule cell synapse of freely moving rats.

LTP in the lateral perforant path is beta-adrenergic receptor-dependent.

Norepinephrine induces an activity-independent long-lasting depression of synaptic transmission in the lateral perforant path input to dentate granule cells, whereas high frequency stimulation induces activity-dependent long-term potentiation (LTP). We investigated the role of endogenous activation of beta-adrenergic receptors in LTP of the lateral and medial perforant paths under conditions affording selective stimulation of these pathways in the rat hippo-campal slice. Propranolol (1 microM), a beta-receptor antagonist, blocked LTP induction of both lateral and medial perforant path-evoked field excitatory postsynaptic potentials.

Endogenous activation of mu and delta-1 opioid receptors is required for long-term potentiation induction in the lateral perforant path: dependence on GABAergic inhibition.

Opioid peptides costored with glutamate have emerged as powerful regulators of long-term potentiation (LTP) induction in several hippocampal pathways. The objectives of the present study were twofold: (1) to identify which opioid receptor types (mu, delta, or kappa) regulate LTP induction at lateral perforant path-granule cell synapses and (2) to test the hypothesis that endogenous opioids regulate LTP induction via modulation of GABAergic inhibition. LTP of lateral perforant path-evoked field EPSPs was induced selectively by high-frequency stimulation applied to the outer third of the molecular layer of the dentate gyrus of rat hippocampal slices.

Unilateral LTP triggers bilateral increases in hippocampal neurotrophin and trk receptor mRNA expression in behaving rats: evidence for interhemispheric communication.

Induction of long-term potentiation (LTP) in the dentate gyrus of awake rats triggered a rapid (2 hour) elevation in tyrosine kinase receptor (trkB and trkC) gene expression and a delayed (6-24 hour) increase in brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) gene expression. Depending on the mRNA species, LTP induction led to highly selective unilateral or bilateral increases in gene expression. Specifically, trkB and NT-3 mRNA elevations were restricted to granule cells in the ipsilateral dentate gyrus, whereas bilateral increases in trkC, BDNF, and nerve growth factor (NGF) mRNA levels occurred in granule cells and hippocampal pyramidal cells.

Muscarinic depression of synaptic transmission and blockade of norepinephrine-induced long-lasting potentiation in the dentate gyrus.

Bath application of the muscarinic receptor agonist, muscarine, produced a concentration-dependent depression of synaptic activity in the dentate gyrus of hippocampal slices. A concentration of 10 microM muscarine produced a reversible depression that could be competitively antagonized by the muscarinic receptor antagonist pirenzepine. However, other muscarinic receptor subtype (M1-M3) antagonists could also block the effects of muscarine.

Long-lasting potentiation and epileptiform activity produced by GABAB receptor activation in the dentate gyrus of rat hippocampal slice.

Bath application of the GABAB receptor agonist baclofen produced a concentration-dependent long-lasting potentiation (LLP) of the evoked population spike in the dentate gyrus of rat hippocampal slices. A high concentration of baclofen (5 microM) also produced a loss of inhibition that was manifested as the appearance of epileptiform, multiple evoked population spikes and a decrease in paired-pulse inhibition. Both baclofen-induced potentiation and epileptiform activity could be blocked or significantly reduced in slices from pertussis toxin-treated animals (1 microgram, intradentate) or in slices pretreated with the NMDA receptor antagonist D-(-)-2-amino-5-phosphonovaleric acid (10 microM).

Free radicals accelerate the decay of long-term potentiation in field CA1 of guinea-pig hippocampus.

Free radicals have been implicated in a number of pathological conditions. To evaluate the neurophysiological consequences of free radical exposure, slices of hippocampus isolated from guinea-pigs were exposed to hydrogen peroxide which reacts with tissue iron to generate hydroxyl free radicals. Long-term potentiation, a sustained increase in synaptic responses, was elicited in field CA1 by high frequency stimulation of an afferent pathway.

Beta-adrenergic agonist-induced long-lasting synaptic modifications in hippocampal dentate gyrus require activation of NMDA receptors, but not electrical activation of afferents.

Isoproterenol induced long-lasting potentiation (LLP) of the medial perforant path-evoked excitatory post-synaptic potential (EPSP) and long-lasting depression (LLD) of the lateral perforant path-evoked EPSP in the absence of perforant path activation. The NMDA receptor antagonist D-(-)-2-amino-5-phosphonovaleric acid [D(-)APV] blocked the induction of LLP and LLD. After wash, a subsequent exposure to isoproterenol induced only LLP of medial perforant path EPSPs; LLD of lateral perforant path-evoked EPSPs did not occur.

Muscarinic receptor activation facilitates the induction of long-term potentiation (LTP) in the rat dentate gyrus.

Bath application of two different concentrations of muscarine produced two different effects on evoked responses in the dentate gyrus of rat hippocampal slices. A concentration of 1 microM muscarine did not affect the evoked population spike or excitatory postsynaptic potential (EPSP), but facilitated the induction of LTP. In contrast, a concentration of 10 microM muscarine depressed both the population spike and EPSP, but had no effect on LTP induction.

NMDA receptor antagonists reduce medial, but not lateral, perforant path-evoked EPSPs in dentate gyrus of rat hippocampal slice.

NMDA receptor antagonists produced differential effects on medial and lateral perforant path-evoked excitatory postsynaptic potentials (EPSPs) recorded in the dentate gyrus molecular layer of hippocampal slices. D-(-)-2-amino-5-phosphonovaleric acid (D(-)-APV) and 3[(+/-)-2-carboxypiperazin-4-yl]-propyl-1-phosphonic acid (CPP) significantly reduced the peak amplitude and total area, but not the initial negative slope, of the medial perforant path-evoked EPSP. Neither antagonist affected any component of the lateral perforant path-evoked EPSP.

Norepinephrine induces pathway-specific long-lasting potentiation and depression in the hippocampal dentate gyrus.

The study presented here indicates that norepinephrine (NE) selectively induces long-lasting modifications of synaptically mediated responses in the dentate gyrus of the rat hippocampal slice. A low concentration of NE (1.0 microM; in the presence of 50 microM phentolamine, an alpha-adrenergic antagonist) or a 1.

Long-term potentiation: studies in the hippocampal slice.

Long-term potentiation (LTP) is an example of activity-dependent plasticity that was discovered in the hippocampal formation. There is growing evidence that LTP not only is a useful model for mnemonic processes, but also may represent the cellular substrate for at least some kinds of learning and memory. The hippocampal slice preparation has proven exceptionally useful in pharmacological studies of possible mechanisms of LTP.

NMDA receptor antagonists block norepinephrine-induced long-lasting potentiation and long-term potentiation in rat dentate gyrus.

In the in vitro rat dentate gyrus, norepinephrine-induced long-lasting potentiation (NELLP) and long-term potentiation (LTP) of responses to perforant path stimulation were blocked by the N-methyl-D-aspartate (NMDA) receptor antagonists, D(-)-2-amino-5-phosphonovaleric acid (D(-)APV) and 3-[(+/-)-2-carboxypiperazin-4-yl]propyl-1-phosphonic acid (CPP). CPP and D(-)APV, but not L(+)APV, also depressed the orthodromic population spike but not the antidromic spike, which suggests that these receptors may function in low-frequency evoked activity of granule cells. We conclude that NELLP, like LTP in the dentate gyrus, requires NMDA receptor activation.

Slow synaptic inhibition in relation to frequency habituation in dentate granule cells of rat hippocampal slices.

In paired pulse stimulation experiments the mechanism underlying frequency habituation of postsynaptic potentials in dentate granule cells of rat hippocampal slices was studied by measuring extra- and intracellular potentials as well as changes in extracellular calcium [( ([Ca2+]0) and potassium concentrations ([K+]0). Orthodromic stimulation of the perforant path induced in most granule cells a late, slow hyperpolarization (SH), lasting for up to 1.2 s.

Lowering extracellular calcium reverses paired pulse habituation into facilitation in dentate granule cells and removes a late IPSP.

Simultaneous measurements of cellular responses and extracellular field potentials as well as extracellular Ca2+ concentration [( Ca2+]0) were performed in the dentate gyrus granule cell layer during paired pulse stimulation of the lateral perforant path at resting [Ca2+]o and during washout of calcium. At resting [Ca2+]o the second response to a paired stimulus was smaller than the first response. This frequency habituation reversed into frequency potentiation (second response larger than the first one) during lowering of [Ca2+]o at about the same time when a late presumed inhibitory postsynaptic potential (IPSP) was abolished.

Physiological correlates of responses to gamma-aminobutyric acid (GABA) recorded from rat visual cortical neurons in vitro.

Responses to focal application of gamma-aminobutyric acid (GABA) were compared to synaptic potentials elicited by afferent stimulation of rat visual cortical neurons, using a slice preparation and conventional intracellular recording techniques. GABA produced three types of responses: a brief hyperpolarization (mean reversal potential, -72 mV), brief depolarization (mean reversal potential, -50 mV), or a prolonged hyperpolarization (mean reversal potential, -80 mV). Synaptic potentials included simple or complex EPSPs and EPSPs followed by mono- or biphasic IPSPs.