Energy metabolism and excitotoxicity in hippocampal slices

Rat hippocampal slice preparation is a useful method in histological and electrophysiological investigation of acute neurotoxicity induced by excitotoxins and pathological conditions such as hypoglycemima (photos blow). With this system we reported that nitric oxide is involved in NMDA toxicity. GAPDH, depression of which results in limited glucose utilization, was thought to be one of biological targets of nitric oxide. Under GAPDH depression or glucose deprivation, alternative energy substrates other than glucose must serve neuronal integrity.  We study roles of endogenous monocarboxylate to sustain neuronal function.

  1. Nitric oxide inhibitors attenuate N-methyl-D-aspartate excitotoxicity in rat hippocampal slices. Neurosci Lett. 1992 Feb 3;135(2):227-30. PubMed PMID: 1625799.
  2. Endogenous monocarboxylates sustain hippocampal synaptic function and morphological integrity during energy deprivation. J Neurosci. 1997 Dec 15;17(24):9448-57. PubMed PMID: 9391000.
  3. β-Hydroxybutyrate fuels synaptic function during development. Histological and physiological evidence in rat hippocampal slices. J Clin Invest. 1998 Mar 1;101(5):1121-32. PubMed PMID: 9486983; PubMed Central PMCID: PMC508664.

Hippocampal synaptic plasticity and metaplasticity

Long-term potentiation (LTP) is a cellular model of memory and learning. Although it is generally believed that the induction is through NMDA receptor activation, we found prior administration of NMDA inhibits LTP induction. Furthermore, we noticed that various stressful events impair LTP induction via NMDA receptor activation. We are investigating the involvement of neurosteroids in this paradoxical LTP inhibition.

If LTP is a mechanism of memory, there must be a feed-back depotentiation mechanism to avoid saturation of memory within the hippocampus. We have been studying LTP depotentiation (LTPD) via performant input.

  1. Direct cortical inputs erase long-term potentiation at Schaffer collateral synapses. J Neurosci. 2008 Sep 17;28(38):9557-63. PubMed PMID: 18799687; PubMed Central PMCID: PMC2610347.
  2. NMDA receptors, mGluR5, and endocannabinoids are involved in a cascade leading to hippocampal long-term depression. Neuropsychopharmacology. 2012 Feb;37(3):609-17. PubMed PMID: 21993209; PubMed Central PMCID: PMC3260982.
  3. Neuregulin and Dopamine D4 Receptors Contribute Independently to Depotentiation of Schaffer Collateral LTP by Temperoammonic Path Stimulation. eNeuro. 2017 Aug 21;4(4). pii: ENEURO.0176-17.2017 PubMed PMID:28828402

Roles of neurosteroidogenesis in anesthetics and ethanol actions

Roles of neurosteroidogenesis in anesthetics and ethanol actions

Ethanol intoxication and modulation of neuronal integrity is our long concern. We are testing if neurosteroids play a pivotal role in ethanol intoxication. We are also investigating if neurosteroids are important for modulation of synaptic plasticity during anesthesia.

  1. Midazolam inhibits hippocampal long-term potentiation and learning through dual central and peripheral benzodiazepine receptor activation and neurosteroidogenesis. J Neurosci. 2010 Dec 15;30(50):16788-95. PubMed PMID: 21159950; PubMed Central PMCID: PMC3073626.
  2. Ethanol enhances neurosteroidogenesis in hippocampal pyramidal neurons by paradoxical NMDA receptor activation. J Neurosci. 2011 Jul 6;31(27):9905-9. PubMed PMID: 21734282; PubMed Central PMCID: PMC3180997.
  3. Metaplastic effects of subanesthetic ketamine on CA1 hippocampal function. Neuropharmacology. 2014 Nov;86:273-81. PubMed PMID: 25128848; PubMed Central PMCID: PMC4188808.
  4. Nitrous oxide (laughing gas) facilitates excitability in rat hippocampal slices through gamma-aminobutyric acid A receptor-mediated disinhibition. Anesthesiology. 2005 Jan;102(1):230-4. PubMed PMID: 15618809.

Excitotoxicity in the retina and experimental retinopathology

Under supervision of Dr. John, W. Olney who ignited the research of excitotoxicity, we developed a method to investigate the role of glutamate in retinal excitotoxicity in ex vivo conditions. We study the role of glia in excitotoxity. Glutamate is excitotoxic only when it is not metabolized by glia. The retinal preparation is also a useful method to study retinal pathology with some conditions such as phototoxicity and glaucoma. Dr. Makoto Ishikawa (below), Akita University in Japan, is collaborating with us to investigate the role of neurosteroids in glaucoma.

  1. Involvement of illumination in indocyanine green toxicity after its washout in the ex vivo rat retina. Retina. 2009 Mar;29(3):371-9. PubMed PMID: 19174714; PubMed Central PMCID: PMC2657810.
  2. Effects of acutely elevated hydrostatic pressure in a rat ex vivo retinal preparation. Invest Ophthalmol Vis Sci. 2010 Dec;51(12):6414-23. PubMed PMID: 20688725; PubMed Central PMCID: PMC3055762.
  3. Neurosteroids are endogenous neuroprotectants in an ex vivo glaucoma model. Invest Ophthalmol Vis Sci. 2014 Nov 18;55(12):8531-41. PubMed PMID: 25406290; PubMed Central PMCID: PMC4280088.