The Lu Chen Lab Research

Our Mission

What distinguishes us humans from other animals is our ability to reflect on our perceptions, emotions, actions, communicate using explicit language, and plan complex behaviors. All of these activities are performed by the brain, which functions as a vast assembly of interlocking networks formed by neurons connected by synapses. Synapses are the communication nodes of neurons that not only transfer information between neurons, but also process this information. The long-term objective of my research is to understand the molecular and cellular mechanisms underlying structural and functional changes of the synapses and how these mechanisms may be compromised in neurological disorders.

Toward this goal, we have established a research program that enables us to study synaptic functions using multiple approaches including electrophysiology, molecular biology, biochemistry, confocal and 2-photon imaging, and animal behavior. In particular, we have discovered a novel synaptic signaling mechanism mediated by all-trans retinoic acid (RA). We demonstrated that RA plays an essential role in mediating activity-dependent homeostatic changes of both excitatory and inhibitory synaptic strength. This novel action of RA is non-genomic (independent of transcriptional regulation), but requires activation of dendritic protein synthesis and is mediated by the RNA-binding function of the RA receptor RARα.

Our current research has two major goals. First, taking advantage of the unique involvement of RA signaling in homeostatic synaptic plasticity, we are investigating the function of homeostatic plasticity in vivo using RA as a molecular handle. Second, we are exploring potential contributions of impairments in RA signaling and the synaptic excitation/inhibition balance to the pathophysiology of neuropsychiatric disorders.  The following research directions will be pursued to systematically approach these two goals.

1. Defining the molecular mechanisms of retinoic acid (RA)-mediated synaptic signaling

The existing literature on RA’s function in the nervous system largely focuses on its function as a transcriptional regulator in development. Only recently is the role of RA signaling in synaptic plasticity beginning to emerge, primarily by work from our lab. Building on what we have uncovered, we are currently exploring several fundamental aspects of RA signaling at the molecular level.

1) We have established that influx of calcium induced by synaptic activity, through a process involving calcineurin, suppresses RA synthesis and blocks RA signaling at the synapse.  We are currently working on mapping out the signaling pathway that mediates the activity-dependent regulation of RA synthesis.

2) We have shown that RA receptor RARα (a transcription factor operating during early development) functions as a mRNA-binding protein that inhibits translation of specific mRNAs in mature neurons. We are in the process of identifying the mRNA species whose translation is regulated by RARα.

2. Investigating RA signaling in intact neural network - interaction between Hebbian and homeostatic synaptic plasticity

Although the synaptic action of RA has been tightly linked to homeostatic synaptic plasticity, this finding does not mean that the impact of RA on synapses is limited to homeostatic plasticity. The history of a neuron’s activity determines its current biochemical state and its ability to undergo synaptic plasticity, a phenomenon referred to as meta-plasticity. Acting through a distinct molecular mechanism, RA is capable of rapidly changing excitatory and inhibitory synaptic strength. Thus, RA acts as a candidate ‘metaplasticity molecule’ that changes the state of a neuron (e.g., its excitatory/inhibitory balance) and influences Hebbian plasticity.

Indeed, earlier studies show that vitamin A deficiency (which depletes RA) leads to impaired hippocampal Hebbian plasticity and learning. In our hands, RA-induced increases in excitatory synaptic transmission significantly impaired subsequent induction of LTP, a phenomenon that can be reversed by acute genetic deletion of RARα or inhibiting protein synthesis during RA treatment. These findings suggest that the functional impact of RA may go beyond homeostatic plasticity. Thus, we are currently investigating the function of synaptic RA signaling in vivo in the context of animal learning, which should provide important insights into how homeostatic synaptic plasticity may operate in an intact circuit, and how it contributes to the function of the circuit.

Sensory deprivation beyond the critical period has been shown to induce homeostatic synaptic plasticity in sensory cortical circuits. To investigate whether RA signaling mediates these changes in the sensory cortices, we are exploring: 1) whether acute RA treatment alters synaptic transmission in the cortical circuit; 2) whether RA signaling is required for sensory experience-induced homeostatic synaptic plasticity and structural plasticity; 3) whether changing cortical RA signaling has a behavioral impact on sensory perception. We will focus on visual and somatosensory cortices because robust homeostatic synaptic changes have been reported in these regions.

Additionally, we are exploring how RA-mediated metaplasticity may impact Hebbian plasticity and learning with a primary focus on the hippocampus. We apply a behavioral experience that alters hippocampal synaptic E/I state in an RA-dependent manner, which allows us to access synaptic RA signaling through behavioral manipulation. The functional consequence of synaptic RA signaling (or lack thereof) is probed with hippocampus-dependent learning tasks whose outcome is influenced by the synaptic E/I state,  and thus may be affected by altered RA signaling. 

3. Involvement of synaptic RA signaling in mental retardation and autism-spectrum disorders

In the past decade, there has been an explosion of reports identifying genes implicated in various neuropsychiatric disorders. Among these genes, mutations in Fmr1, which encodes the protein FMRP, stand out because of their relatively high prevalence. In human patients, impaired expression of Fmr1 causes Fragile-X syndrome (FXS), the most common inherited form of mental retardation that is also associated in some cases with symptoms characteristic of autism spectrum disorders. We first proposed a potential involvement of FMRP in RA-mediated translational regulation when we observed that dendritic RNA granules that actively translate GluA1 protein upon RA stimulation are also enriched in FMRP. Indeed, we found that in Fmr1 knockout mice RA-dependent homeostatic synaptic plasticity is completely absent. Since inactivity-dependent RA synthesis still occurs normally in Fmr1 knockout neurons, cellular events downstream of RA were examined. Consistent with FMRP’s role in regulating protein synthesis, RA-induced translational upregulation of various target mRNAs was abolished in the absence of FMRP. These findings led us to speculate that FMRP- and RARα-mediated translational regulation may be mechanistically related, and exploring this relation is one of our current directions.

At circuit level, we are conducting experiments to test the hypothesis that FMRP participates in multifarious activity-dependent postsynaptic signaling pathways whose overall role is to fine-tune synaptic strength for optimal information processing. The abnormal RA signaling in FXS and the consequent lack of a synaptic E/I adjustment in response to changes in network activity prompted us to posit that FXS develops because inactivation of FMR1 causes impairments in the normal adjustment of the synaptic E/I state upon changes in neuronal activity, a hypothesis that we refer to as the ‘synaptic E/I state hypothesis of FXS’.

One exciting project branching out from this direction is that we have extended the study of synaptic RA signaling into human neurons induced from iPS or ES cell lines. These induced neurons (iN) are highly useful tools for studying human diseases. We show that RA also regulates synaptic transmission of human iN synapses. Moreover, chronic blockade of synaptic activity leads to homeostatic plasticity at both excitatory and inhibitory synapses, a process also requires RA synthesis. This is the first study demonstrating that certain forms of synaptic plasticity and their mechanisms are conserved in human neurons, establishing RA as a universal synaptic signaling molecule. We are now investigating changes in RA-mediated synaptic plasticity in iN cells modeling FXS. Results from this study will have far-reaching implications in understanding synaptic dysfunction associated with mental disorders.