Molecular NeuroBiology Lab
We are focusing on revealing novel molecular mechanisms critical for regulating synaptic plasticity in the normal or diseased brain, through molecular, cellular, and electrophysiological approaches.
Postsynaptic activation of N-methyl-D-aspartate subtype of glutamate receptors (NMDARs) at many excitatory synapses is required for activity-dependent induction of long-term potentia- tion (LTP), a cellular substrate for learning and memory. However, presynaptic NMDARs are also found in a variety of brain tissues and can regulate glutamate release via elevating presynaptic Ca2+ signals. Exact molecular mechanisms responsible for presynaptic NMDAR-mediated LTP induction remains to be thoroughly examined.
Previous study demonstrated that presynaptic NMDARs are responsible for triggering BDNF secretion via elevating presynaptic Ca2+, leading to LTP at corticostriatal synapses. Further studies need to dissect the presynaptic NMDAR-dependent signaling pathways for directly regulating BDNF secretion (Ca2+ signaling, Ca2+ sensors for BDNF-containing secretory granules).
By combining molecular tools for selective manipulation of target genes, electrophysiological analysis of synaptic properties, and optogenetic induction of the specific synaptic activity, we will try to answer to the questions as following:
(1) Can TBS-LTP be induced at synapses between cortical pyramidal neurons and D1- or D2-MSN? Either presynaptic NMDARs or BDNF secretion is also required for this type of LTP?
(2) What are the molecular machineries activated by presynaptic NMDAR-dependent signaling and triggering BDNF secretion in response to LTP inducing stimuli (such as TBS)?
(3) Are these mechainsms specific for corticostriatal LTP or general mechanisms responsible for BDNF-dependent LTP?
A line of evidence has suggested abnormal glial functions in neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington's disease (HD). This idea implies that BDNF- mediated neuron-glia interaction may also be impaired in brains of neurodegenerative disease, in addition to disrupted BDNF expression, transport, and secretion.
By dissecting affected signaling components related with neurotrophin-mediated neuron-glia interaction, we expect the better therapeutic approaches can be designed to alleviate/treat neurodegenerative diseases.
Our plans are:
(1) By utilizing model mice for neurodegenerative diseases, we will examine how neurotrophine- mediated neuron-astrocyte communication is altered and what causes such alterations, to identify novel targets for treating neurodegenerative diseases in human.
(2) Through collaboration with investigators who have expertise in medicinal pharmacology, we will try to design and develop novel medicines to recover disruptive synaptic functions and cell survivals in the brain.
Neurotrophins, especially BDNF, are known to be mostly derived from neuronal cells, but astrocytes can uptake and store BDNF secreted from neurons. It is possible that BDNF proteins secreted from neuronal synaptic terminal could be stored at nearby astrocytes and re- secreted by the certain type of physiological activities (called BDNF-recycling).
Given that astrocyte can modulate neuronal activity and synaptic functions by releasing active substances such as glutamate/GABA, it is also possible that neurotrophin-mediated neuro-glia crosstalk play a role in regulating neural circuit functions.
Especially we are interested in:
(1) Examination of the physiological role of neurotrophins (BDNF) in neuron-glia interaction and its involvement in synaptic plasticity and cognitive functions.
(2) Regulation of long- term synaptic plasticity at central synapses by BDNF recycling or BDNF-induced excitation of astrocytes.
(3) How cognitive functions are regulated by BDNF-mediated neuron-astrocyte interaction.
Molecular mechanisms for BDNF-mediated
neuron-glia interaction
Any role of BDNF in neuron-glia interaction??
