Our laboratory is studying molecular, cellular, and systems neuroscience of learning & memory (L&M) and dementia. We apply a combination of molecular biology, biochemistry, electrophysiology, and behavioral assays to genetically engineered mice in order to:

(1) clarify mechanisms by which information is encoded, stored and recalled in normal brain,
(2) understand how these processes are impaired in disease conditions, and
(3) validate the potential therapeutic strategies to improve and/or prevent the progression of dementia or cognitive disorders associated with Alzheimer’s disease (AD) or normal aging.

Our experiments focus on the hippocampus, a brain region that is required for the acquisition of new memories. This structure is also involved in a prolonged period of memory reorganization mechanisms after initial coding, including the consolidation, memory reconsolidation, and processes transferring and stabilizing memory traces into the cortex as remote memories (systems consolidation). By utilizing modern mouse genetics (knock-out, knock-in and transgenic) in combination with the multidisciplinary analysis as indicated above, we are studying molecular substrates (e.g., CaMKII, MAPK, CREB, etc.) and cellular events (e.g., LTP, neuron excitability chnages, neurogenesis, etc.) that underlie such divergent aspects of hippocampus-dependent L&M processes.

Another important aspect of our research is that we apply these findings to the development of therapeutic treatments for human memory deficits or dementia. Remarkably, we demonstrated for the first time that genetic deletion of the major β-secretase BACE1 reduces pathogenic amyloid-β (Aβ) production and rescues memory deficits in AD transgenic mice, as assessed by a battery of hippocampus-dependent behavioral paradigms (Ohno et al., 2004; 2006; submitted). Consistent with this, our study revealed that BACE1 gene deletion also rescues hippocampal cholinergic dysfunction evidenced by disregulated CA1 neuron excitability, pathological alterations such as amyloidosis and gliosis, and neuron loss in AD mouse models. Our results not only favor the idea that Aβ is central to the pathogenesis of AD but also provide an experimental foundation for the therapeutic inhibition of β-secretase for the treatment of AD. We are now focusing on molecular and cellular mechanisms by which BACE1 manipulations improve AD-associated impairments in various aspects of L&M in mouse models, unequivocally validating BACE1-inhibiting approaches as a disease-modifying therapeutic treatment for AD dementia.

Selected Publications

P.W. Frankland, C. O'Brien, M. Ohno, A. Kirkwood and A.J. Silva. a-CaMKII-dependent plasticity in the cortex is required for permanent memory. Nature, 411, 309–313 (2001)
•    This article was featured by “news and views” in Nature 411, 248–249 (2001).

M. Ohno, P.W. Frankland, A.P. Chen, R.M. Costa and A.J. Silva. Inducible, pharmacogenetic approaches to the study of learning and memory. Nat. Neurosci., 4, 1238–1243 (2001)
•    This article was featured by “Research Update” in TINS 25, 277–279 (2002).

R.M. Costa, N.B. Fedorov, J.H. Kogan, G.G. Murphy, J. Stern, M. Ohno, R. Kucherlapati, T. Jacks and A.J. Silva. Mechanism for the learning deficits in a mouse model of neurofibromatosis type 1. Nature, 415, 526–530 (2002)

M. Ohno, P.W. Frankland and A.J. Silva. A pharmacogenetic inducible approach to the study of NMDA/aCaMKII signaling in synaptic plasticity. Curr. Biol., 12, 654–656 (2002)

M. Ohno, E.A. Sametsky, L.H. Younkin, H. Oakley, S.G. Younkin, M. Citron, R. Vassar and J.F. Disterhoft. BACE1 deficiency rescues memory deficits and cholinergic dysfunction in a mouse model of Alzheimer’s disease. Neuron, 41, 27–33 (2004)
•    This article was featured by “news and views in brief” in Nature 427, 210 (2004).

G.G. Murphy, N.B. Fedorov, K.P. Giese, M. Ohno, E. Friedman, R. Chen and A.J. Silva. Increased neuronal excitability, synaptic plasticity, and learning in aged Kvβ1.1 knockout mice. Curr. Biol., 14, 1907–1915 (2004)

J.F. Disterhoft, W.W. Wu and M. Ohno. Biophysical alterations of hippocampal pyramidal neurons in learning, ageing and Alzheimer's disease. Ageing Res. Rev., 3, 383–406 (2004)

M. Ohno, W. Tseng, A.J. Silva and J.F. Disterhoft. Trace eyeblink conditioning requires the hippocampus but not autophosphorylation of aCaMKII in mice. Learn. Mem., 12, 211–215 (2005)

A.P. Chen, M. Ohno, K.P. Giese, R. Kühn, R.L. Chen and A.J. Silva. Forebrain-specific knockout of B-raf kinase leads to deficits in hippocampal long-term potentiation, learning, and memory. J. Neurosci. Res., 83, 28–38 (2006)

M. Ohno, L. Chang, W. Tseng, H. Oakley, M. Citron, W.L. Klein, R. Vassar and J.F. Disterhoft. Temporal memory deficits in Alzheimer's mouse models: rescue by genetic deletion of BACE1. Eur. J. Neurosci., 23, 251–260 (2006)

M. Ohno, E.A. Sametsky, A.J. Silva and J.F. Disterhoft. Differential effects of aCaMKII mutation on hippocampal learning and changes in intrinsic neuronal excitability. Eur. J. Neurosci., 23, 2235–2240 (2006)

H. Oakley, S.L. Cole, S. Logan, E. Maus, P. Shao, J. Craft, A. Guillozet-Bongaarts, M. Ohno, J. Disterhoft, L. Van Eldik, R. Berry and R. Vassar. Intraneuronal β-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer's disease mutations: potential factors in amyloid plaque formation. J. Neurosci., 26, 10129–10140 (2006)

M. Ohno. Genetic and pharmacological basis for therapeutic inhibition of β- and g-secretases in mouse models of Alzheimer’s memory deficits. Rev. Neurosci. (in press)

M. Ohno and J.F. Disterhoft. Alzheimer’s disease therapies: updates on genetic and pharmacological manipulations of β-secretase. In M.-K. Sun (Ed.), Research Progress in Alzheimer’s Disease and Dementia, Nova Science Publishers, New York (in press)

M. Ohno, S.L. Cole, M. Yasvoina, J. Zhao, M. Citron, R. Berry, J.F. Disterhoft and R. Vassar. BACE1 gene deletion prevents neuron loss and memory deficits in 5XFAD APP/PS1 transgenic mice. Neurobiol. Dis. (submitted)