Dr. Okun Eitan
Neuroscience, Neuroimmunology, Learning and Memory, Neurodegeneration
The innate immune system has long been thought to solely detect invading pathogens and to initiate the adaptive cellular immune response. Toll-like receptors (TLRs) are innate immune receptors that detect the presence of microbes such as viruses, bacteria, fungi and parasites, but also to detect tissue damage via endogenous ligands. In addition, evidence suggests that TLRs can be activated even in the absence of inflammation or tissue damage.
Our research is focused on finding novel roles for innate immune receptors in the Central Nervous System, and delineating the signaling mechanisms that underlie their roles.
So far, our research has identified novel roles for several TLR family members, particularly TLR2, TLR3 and TLR4, in shaping plasticity of the central nervous system. To name a few of the novel roles we have described:
I. TLR3, widely known for its roles in recognizing double-stranded RNA from viruses, is also a negative regulator of embryonic neuronal stem cells proliferation. Early, but not late, embryonic developmental stages are dependent on TLR3 expression for appropriate proliferation of neuronal stem cells in the developing brain (Okun & Lathia et al., J Neuriscience, 2008).
II. TLR3 constrains adult neurogenesis, the process of generating new neurons, in a specialized sub-region of the adult brain called the Hippocampus. Moreover, TLR3 impairs the ability to perform a short-term memory variant of spatial learning and memory called working memory. Glutamate receptor subunit 1 (GLuR1), a protein critical for this task is enhanced in the absence of TLR3 (Okun et al. PNAS, 2010).
III. Evidence indicates that infections during maternity can have adverse effects to the offspring that can last until many years into adulthood. These adverse effects include neurodegenerative disorders such as schizophrenia. We have shown that TLR2 activation in the developing embryo results in altered neurogenesis rates in the developing brain as well as structural abnormalities of the brain (Okun et al. J Neurochem, 2010).
So far, we have studied the roles of Toll-like receptors (TLRs) mostly using various transgenic mouse strains that are deficient for different TLRs as well as different signaling mediators that are relevant to TLR signaling, such as TRIF, MyD88 and IRF3. We are now utilizing molecular tools such as lentiviruses that either overexpress or down regulate (using short-hairpin RNA) specific TLRs, in order to dissect the roles of TLRs in cognition in a spatial and temporal manner within the central nervous system, while avoiding possible developmental effects.
Using stereotaxic methods, these viruses are then injected into various brain regions such as the hippocampus or the amygdala, and the mice are then tested in various behavioral tasks. In parallel, we plan on using these viruses to study the molecular mechanism for the observed effects of TLRs on neuronal plasticity.
Studying the functionality and mechanism of action of different TLRs in the brain is the basis for our understanding of the role of TLRs in pathological conditions of the central nervous systems, but also our understanding of mild cognitive decline in aging population.
Okun E, Griffioen K, Barak B, Roberts JN, Castro K, Pitta M, Cheng A, Mughal RM, Wan R, Ashery U and Mattson MP. Toll-like Receptor 3 Impairs Memory Retention and Constrains Adult Hippocampal Neurogenesis. Proceedings of the National Academy of Sciences (PNAS). 2010 Aug 31;107 (35):15625-30
Okun E, Mattson MP. Toll-Like Receptor signaling in neural plasticity and disease. Trends in Neuroscience Published Online: 16 Mar 2011
Okun E, Kathleen J. Griffioen, Tae Gen Son, Jong-Hwan Lee, Nicholas J. Roberts, Mohamed R. Mughal, Emmette Hutchison, Aiwu Cheng, Thiruma V. Arumugam, Justin D. Lathia, Henriette van Praag and Mark P. Mattson. TLR2 activation inhibits embryonic Neuronal progenitor cell proliferation. J Neurochem. 2010 Jul;114(2):462-74
Okun E, Griffioen K, Lathia JD, Tang SC, Mattson MP and Arumugam TV. Toll-Like Receptors in Neurodegeneration. Brain Res Rev. 2009 Mar;59(2):278-92