Biomedical subjects

Kelvin A Yamada

Publications and source records attributed to Kelvin A Yamada.

10 recordsLinked to original sources

PubMed2006

Leptin contributes to slower weight gain in juvenile rodents on a ketogenic diet.

The ketogenic diet (KD) is an efficacious therapy for medically refractory childhood epilepsy that also slows weight gain. We tested the hypothesis that the KD slows weight gain via neurohormones involved in energy homeostasis. We found that juvenile rodents fed a KD had slower weight gain than those fed a standard diet (SD). Rats fed a KD had higher serum leptin levels and lower insulin levels compared with those fed an SD. We investigated the increase in leptin further because this change was the only one consistent with slower weight gain. Although rats fed the SD experienced slower weight gain when calorie restricted, they had serum leptin levels similar to those fed the SD ad libitum. Furthermore, leptin deficient (ob/ob) and leptin receptor deficient (db/db) mice did not show slower weight gain on the KD. All animals on the KD had elevated serum beta-hydroxybutyrate (betaHB) levels. Thus, ketosis is insufficient and a functioning leptin signaling system appears necessary for the KD to slow weight gain. The increase in leptin may contribute to the anticonvulsant effects of the KD.

Animals↗

PubMed2006

Ghrelin controls hippocampal spine synapse density and memory performance.

The gut hormone and neuropeptide ghrelin affects energy balance and growth hormone release through hypothalamic action that involves synaptic plasticity in the melanocortin system. Ghrelin binding is also present in other brain areas, including the telencephalon, where its function remains elusive. Here we report that circulating ghrelin enters the hippocampus and binds to neurons of the hippocampal formation, where it promotes dendritic spine synapse formation and generation of long-term potentiation. These ghrelin-induced synaptic changes are paralleled by enhanced spatial learning and memory. Targeted disruption of the gene that encodes ghrelin resulted in decreased numbers of spine synapses in the CA1 region and impaired performance of mice in behavioral memory testing, both of which were rapidly reversed by ghrelin administration. Our observations reveal an endogenous function of ghrelin that links metabolic control with higher brain functions and suggest novel therapeutic strategies to enhance learning and memory processes.

Animals↗

PubMed2005

Synaptic activity regulates interstitial fluid amyloid-beta levels in vivo.

Aggregation of the amyloid-beta (Abeta) peptide in the extracellular space of the brain is central to Alzheimer's disease pathogenesis. Abeta aggregation is concentration dependent and brain region specific. Utilizing in vivo microdialysis concurrently with field potential recordings, we demonstrate that Abeta levels in the brain interstitial fluid are dynamically and directly influenced by synaptic activity on a timescale of minutes to hours. Using an acute brain slice model, we show that the rapid effects of synaptic activity on Abeta levels are primarily related to synaptic vesicle exocytosis. These results suggest that synaptic activity may modulate a neurodegenerative disease process, in this case by influencing Abeta metabolism and ultimately region-specific Abeta deposition. The findings also have important implications for treatment development.

Action Potentials↗

PubMed2005

Ketogenic diet reduces hypoglycemia-induced neuronal death in young rats.

Hypoglycemia is an important complication of insulin treatment in diabetic children and may contribute to lasting cognitive impairment. Previous studies demonstrated that 21-day-old rats (P21) subjected to brief, repetitive episodes of hypoglycemia sustain cortical neuronal death. The developing brain is capable of utilizing alternative energy substrates acetoacetate and beta-hydroxybutyrate. In these studies we tested the hypothesis that the developing brain adapted to ketone utilization and provided with ketones during hypoglycemia by eating a ketogenic diet would sustain less brain injury compared to littermates fed a standard diet. Supporting this hypothesis, P21 rats weaned to a ketogenic diet and subjected to insulin-induced hypoglycemia at P25 had significantly less neuronal death than rats on a standard diet. This animal model may provide insight into the determinants influencing the brain's susceptibility to hypoglycemic injury.

Animals↗

PubMed2005

In vivo imaging of dendritic spines during electrographic seizures.

Epilepsy is associated with significant neurological morbidity, including learning disabilities, motor deficits, and behavioral problems. Although the causes of neurological dysfunction in epilepsy are multifactorial, accumulating evidence indicates that seizures in themselves may directly cause brain injury. Although it is clear that seizures can result in neuronal death, it is likely that under some circumstances seizures can induce more subtle functional or structural alterations in neurons. We induced focal neocortical seizures with 4-aminopyridine in transgenic mice expressing green fluorescent protein in cortical neurons and sequentially imaged individual dendrites in living animals with two-photon laser-scanning microscopy to determine whether these seizures caused acute alterations in dendritic spine morphology. No dendritic alterations were observed in anesthetized animals during electrographic seizures over a 3-hour period. Similarly, in unanesthetized mice, low-stage, clinical electrographic seizures had minimal effect on dendritic spines. More severe, high-stage seizures in unanesthetized mice were associated with a moderate loss of spines and dendritic swelling, but this effect may have been contingent on a synergistic action of phototoxicity from the imaging method itself. Overall, our results suggest that most neocortical seizures have minimal acute effects on dendrites over several hours, but may predispose to dendritic injury under extreme conditions.

4-Aminopyridine↗

PubMed2004

Differential presynaptic modulation of excitatory and inhibitory autaptic currents in cultured hippocampal neurons.

Short-term synaptic plasticity has an important role in higher cortical function. Hyperpolarization may effect a form of short-term plasticity by promoting recovery from sodium channel inactivation or by activating axonal A-type potassium channels. To determine whether one or both processes occur, we examined the effect of hyperpolarizing prepulses on autaptic currents in cultured postnatal rat hippocampal neurons. As expected of enhanced recovery from sodium channel inactivation, hyperpolarizing prepulses reversibly increased fast excitatory autaptic currents (eacs) mediated by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs), slow eacs mediated by N-methyl-D-aspartate receptors (NMDARs), and inhibitory autaptic currents (iacs) mediated by gamma-aminobutyric acidA receptors (GABAARs). Hyperpolarizing prepulses augmented nearly all fast and slow eacs but only half of the iacs. This change occurred without a change in autaptic current kinetics. Of note, hyperpolarizing prepulses did not significantly reduce autaptic currents in any neuron studied. The rapidly dissociating competitive antagonists kynurenate and L-2-amino-5-phosphonovaleric acid (LAPV) inhibited fast and slow eacs, respectively, to the same extent with and without a hyperpolarizing prepulse. In addition, hyperpolarizing prepulses revealed a slow eac even after the slow eac evoked without a prepulse was completely blocked by the open channel blocker, (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (MK-801). Finally, hyperpolarizing prepulses did not alter currents evoked by exogenous applications of glutamate and GABA. These findings suggest that hyperpolarizing prepulses preferentially enhance eacs over iacs, and that they do so, in part, by overcoming conduction block or by activating silent synapses.

Animals↗

PubMed2004

Effects of seven clinically important antiepileptic drugs on inhibitory glycine receptor currents in hippocampal neurons.

Although potentiation of the inhibitory glycine receptor (GlyR) may contribute to the mechanism of action of antiepileptic drugs (AEDs), the effects of AEDs on GlyRs have not been investigated in detail in forebrain neurons. We examined the effects of seven clinically important AEDs on GlyR-mediated currents using whole-cell patch clamp recordings from cultured embryonic mouse hippocampal neurons. At high therapeutic concentrations, topiramate (in 24% of neurons) and pentobarbital reversibly decreased glycine currents to 89+/-6 % and 81+/-7 % of control, respectively. At or below therapeutic concentrations, carbamazepine, felbamate, gabapentin, phenytoin, and valproate had no effect on glycine currents, while at supratherapeutic concentrations these agents produced modest reversible inhibition. We conclude that GlyR potentiation does not contribute to the antiepileptic action of the seven AEDs examined.

Animals↗

PubMed2003

Repetitive hypoglycemia in young rats impairs hippocampal long-term potentiation.

Mechanisms underlying cognitive dysfunction in young diabetic children are poorly understood, and may include synaptic dysfunction from insulin-induced hypoglycemia. We developed a model of repetitive insulin-induced hypoglycemia in young rats and examined hippocampal long-term potentiation, an electrophysiologic assay of synaptic plasticity, 3-5 d after the last hypoglycemic event. Three hypoglycemic events between postnatal d 21-25 produced modest cortical (17 +/- 2.9 dead neurons per section in parasagittal cortex), but not hippocampal, neuron death quantified by Fluoro-Jade B staining. There was no change in neurogenesis in the hippocampal dentate granule cell region by quantification of bromodeoxyuridine incorporation. Although normal baseline hippocampal synaptic responses were elicited from hippocampal slices from hypoglycemic animals, long-term synaptic potentiation could not be induced in hippocampal slices from rats subjected to hypoglycemia. These results suggest that repetitive hypoglycemia in the developing brain can cause selective impairment of synaptic plasticity in the absence of cell death, and without complete disruption of basal synaptic transmission. We speculate that impaired synaptic plasticity in the hippocampus caused by repetitive hypoglycemia could underlie memory and cognitive deficits observed in young diabetic children, and that cortical neuron death caused by repetitive hypoglycemia in the developing brain may contribute to other neurologic, cognitive, and psychological problems sometimes encountered in diabetic children.

Animals↗

PubMed2003

Impaired glial glutamate transport in a mouse tuberous sclerosis epilepsy model.

Excessive astrocytosis in cortical tubers in tuberous sclerosis complex (TSC) suggests that astrocytes may be important for epileptogenesis in TSC. We previously demonstrated that astrocyte-specific Tsc1 gene inactivation in mice (Tsc1 cKO mice) results in progressive epilepsy. Here, we report that glutamate transporter expression and function is impaired in Tsc1 cKO astrocytes. Tsc1 cKO mice exhibit decreased GLT-1 and GLAST protein expression. Electrophysiological assays demonstrate a functional decrease in glutamate transport currents of Tsc1 cKO astrocytes in hippocampal slices and astrocyte cultures. These findings suggest that Tsc1 inactivation in astrocytes causes dysfunctional glutamate homeostasis, leading to seizure development in TSC.

Animals↗

PubMed2003

An animal model of generalized nonconvulsive status epilepticus: immediate characteristics and long-term effects.

Absence seizures are traditionally believed to have no significant long-term neurological consequences, but few basic scientific studies have examined the effects of absence seizures on neuronal function, especially regarding absence status epilepticus. We developed a model of generalized nonconvulsive status epilepticus (GNCSE) in rats to study behavioral, functional, and histological effects of GNCSE. Using repetitive timed injections of low-dose pentylenetetrazol (PTZ), a state of prolonged behavioral arrest and immobility associated with frequent generalized spike-wave discharges on EEG could be induced for hours, consistent with GNCSE. GNCSE occurred reproducibly in adult rats, but surprisingly not in juvenile rats or adult mice. There was no evidence of pathological damage following GNCSE using Fluoro-Jade B and Cresyl Violet histological methods. Although a transient, subtle deficit in place learning occurred in PTZ-treated rats, there were no long-term behavioral effects of GNCSE on spatial learning or sensorimotor function. However, 1 week after a single episode of GNCSE, there was an increase in absence seizures in response to a repeat dose of PTZ compared to controls. These results indicate that an animal model of GNCSE can be generated and that even in the absence of overt neuronal damage, GNCSE may produce functional changes in neurons that alter electrical excitability of neural circuits.

Age Factors↗