Grand challenge topic: stem cells and regenerative medicine. Stem cell strategy for nervous system disorders

In the adult mammalian brain, neurons are continuously generated from neural stem cells. These newly generated neurons are then integrated into the neural circuit. This observation has led to two promising approaches to treat various brain disorders: transplanting exogenous neural progenitors (precursors of neurons) and increasing endogenous production of neurons. Examples include replacing lost/damaged neurons by exogenous neural progenitors in Parkinson’s disease, and promoting endogenous production of neurons to enhance the action of antidepressants in various psychiatric disorders such as clinical depression. However, the mechanism by which neural stem cells amplify, proliferate, and differentiate into neurons and integrate into the existing neural circuit remains unclear, and represents a major obstacle to developing therapeutic interventions. This inter-disciplinary project has two goals: (i) to understand the process by which neurons are generated from neural stem cells and then integrate into the neural network; and (ii) to identify small molecules derived from traditional Chinese medicine (TCM) to treat brain disorders. We have made significant progress in the first year and some of the highlights are featured below. First, we have identified a novel mechanism that regulates neurogenesis and cortical expansion, a finding which has significant implications in understanding the evolution of the brain and the pathophysiology of autism. There is an enormous production of neurons and growth in brain size during embryonic development, deregulation of neuronal production at the embryonic stage results in neurodevelopmental disorders such as autism. Development of the mammalian cerebral cortex has been thought to be regulated by the generation and differentiation of a specific type of neural progenitor cells known as intermediate progenitor cells. However, direct evidence to prove his has been elusive. Our recent studies show that precise regulation of amplification and differentiation of these neural progenitor cells controls the growth of the cerebral cortex and the brain. Additionally, we have successfully identified the key molecular signals that direct this process. Proper integration of newborn neurons into the neural circuit is critical for normal brain functioning. To achieve this, the neurons need to migrate to the correct position. We have successfully identified new molecular controls that initiate the migration of these neurons. This important discovery will promote understanding of the pathophysiology of neurodevelopmental disorders such as autism and schizophrenia. The third finding concerns a protein complex that controls the division and differentiation of neural stem cells. We have delineated the structures of several proteins in the complex at atomic resolution and obtained biochemical evidence of how the interaction of these proteins controls neuronal production. This will enable us to develop therapeutic interventions for diseases that require enhancement of endogenous neuronal production or neuron replacement therapy. We have also successfully identified small molecules from TCM that can help neurons to connect with, and integrate into, the existing neural network. Furthermore, adult neurogenesis is functionally important for mood control and cognition, and we have demonstrated the beneficial effects of the small molecules in learning and memory as well as in mood control. Additional studies will determine their candidacy as cognitive enhancers or antidepressants

From understanding synaptic plasticity to drug discovery for neurogenerative diseases

Neurodegenerative diseases are among the most devastating diseases in modern society. Nonetheless, treatments that are effective in retarding the disease progression are essentially lacking, underscoring the need to elucidate the underlying mechanisms for these disorders. Increasing evidence suggests that synaptic loss resulting from abnormal formation or maintenance of synapses plays a key role in the onset and progression of neurodegenerative diseases. Explicating the molecular mechanisms underlying the establishment and plasticity of neuronal connections may therefore aid the development of novel therapeutic agents. Synaptic plasticity in the adult brain circuit can be regulated in multiple ways, including morphological changes in dendritic spines and alterations in neurotransmitter receptor functions. In this talk, I will highlight the role of a receptor tyrosine kinase, EphA4, and its downstream signaling pathway in regulating synaptic plasticity. EphA4 activation not only regulates dendritic spine morphology through modulating actin cytoskeletal dynamics, it can also regulate the stability and expression of neurotransmitter receptors. In addition, we have leveraged our research strengths in molecular neuroscience and traditional Chinese medicine to establish a focused drug discovery program in search of therapeutic agents for development. Novel neuroactive lead compounds have been identified and are currently at various stages of pre-clinical development with the ultimate goal of developing these candidates into effective treatments against neurodegenerative diseases

Synergistic effects of muscarinic agonists and secretin or vasoactive intestinal peptide on the regulation of tyrosine hydroxylase activity in sympathetic neurons

Cholinergic agonists and certain peptides of the glucagon-secretin family acutely increase tyrosine hydroxylase activity in the superior cervical ganglion in vitro. The present study was designed to investigate possible interactions between these two classes of agonists in regulating catecholamine biosynthesis. Synergistic effects were found between carbachol and either secretin or vasoactive intestinal peptide in the regulation of DOPA (dihydroxyphenylalanine) synthesis. In addition, synergism was found at the level of the accumulation of cyclic adenosine monophosphate, the likely second messenger in the peptidergic regulation of tyrosine hydroxylase activity. The synergism seen with carbachol was blocked by a muscarinic, but not by a nicotinic, antagonist. Synergism was also found between bethanechol, a muscarinic agonist, and secretin, but not between secretin and dimethylphenylpiperazinium, a nicotinic agonist. Since previous immunohistochemical results suggest that vasoactive intestinal peptide and acetylcholine are colocalized in some preganglionic sympathetic neurons, the present data raise the possibility that the two might act synergistically in vivo in regulating catecholamine biosynthesis. Synergistic postsynaptic actions may be a common feature at synapses where peptides of the secretin- glucagon and acetylcholine are colocalized