In cortical sensory maps, thalamocortical afferents (TCAs) transmit peripheral sensations in organized arrays into distinct cortical neuronal modules to provide a topographic representation of the external sensory world. These cortical maps that form in every individual can be altered by exposure to abnormal sensory experience during a "critical period" of postnatal development. Mis-wiring of neuronal circuits during early life is likely to be a major cause of neurological disorders, including autism, schizophrenia, and congenital epilepsy. Using mouse whisker-maps as a model system, we found that metabotropic glutamate receptor 5 (mGluR5) signaling is involved in sculpting the anatomical structures and in regulating synaptic function and plasticity of thalamocortical connections. Eliminating mGluR5 function in cortical principal neurons resulted in a prolonged critical period for lesion-induced rearrangements of TCAs. Endocannabinoids (eCBs), known retrograde messengers in regulating synaptic transmission, are synthesized upon mGluR5 activation in many neurons. We hypothesize that during cortical map development mGluR5 signaling in cortical neurons instructs the anatomical modification of TCAs and that eCBs mediate, at least in part, the neural-activity dependent remodeling of thalamocortical synapses. In the proposed work we will address three specific aims: How does mGluR5 affect the development and plasticity of barrel cortex? How does mGluR5 affect functional development of cortical circuits and network activity? Do endocannabinoids mediate mGluR5 influences on developing cortical circuits? A combination of genetic, anatomical, electrophysiological, and pharmacological approaches will be employed to accomplish these aims. This study will provide a firm understanding of mGluR5 and eCBs signaling in developing neural circuits. Both mGluR5 and eCBs are potential drug targets for therapeutic interventions in humans. A detailed knowledge of their roles during neural development is critical not only for understanding normal brain function, but also to provide significant insights for the rational assessment of therapies or drug exposure (e.g., cannabis) that might affect the developing fetus.
Mis-wiring of neuronal circuits during early life is likely to be a major cause of neurological disorders, including autism, schizophrenia, and congenital epilepsy. We are studying how neural circuits can be shaped by sensory experience with the long-term goal of developing therapies to prevent neurological disorders.
|Itami, Chiaki; Huang, Jui-Yen; Yamasaki, Miwako et al. (2016) Developmental Switch in Spike Timing-Dependent Plasticity and Cannabinoid-Dependent Reorganization of the Thalamocortical Projection in the Barrel Cortex. J Neurosci 36:7039-54|
|Lu, Hui-Chen; Mackie, Ken (2016) An Introduction to the Endogenous Cannabinoid System. Biol Psychiatry 79:516-25|
|Ballester-Rosado, Carlos J; Sun, Hao; Huang, Jui-Yen et al. (2016) mGluR5 Exerts Cell-Autonomous Influences on the Functional and Anatomical Development of Layer IV Cortical Neurons in the Mouse Primary Somatosensory Cortex. J Neurosci 36:8802-14|
|Ciupek, Sarah M; Cheng, Jingheng; Ali, Yousuf O et al. (2015) Progressive functional impairments of hippocampal neurons in a tauopathy mouse model. J Neurosci 35:8118-31|
|Pita-Almenar, Juan Diego; Yu, Dinghui; Lu, Hui-Chen et al. (2014) Mechanisms underlying desynchronization of cholinergic-evoked thalamic network activity. J Neurosci 34:14463-74|
|Majid, Tabassum; Ali, Yousuf O; Venkitaramani, Deepa V et al. (2014) In vivo axonal transport deficits in a mouse model of fronto-temporal dementia. Neuroimage Clin 4:711-7|
|Wang, Baiping; Wang, Zilai; Sun, Lu et al. (2014) The amyloid precursor protein controls adult hippocampal neurogenesis through GABAergic interneurons. J Neurosci 34:13314-25|
|Wu, Chia-Shan; Morgan, Daniel; Jew, Chris P et al. (2014) Long-term consequences of perinatal fatty acid amino hydrolase inhibition. Br J Pharmacol 171:1420-34|
|Sun, Yan-Gang; Pita-Almenar, Juan D; Wu, Chia-Shan et al. (2013) Biphasic cholinergic synaptic transmission controls action potential activity in thalamic reticular nucleus neurons. J Neurosci 33:2048-59|
|Jew, Chris P; Wu, Chia-Shan; Sun, Hao et al. (2013) mGluR5 ablation in cortical glutamatergic neurons increases novelty-induced locomotion. PLoS One 8:e70415|
Showing the most recent 10 out of 30 publications