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 have demonstrated that RA plays an essential role in mediating activity-dependent homeostatic changes in 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 RA signaling (or lack thereof) to the pathophysiology of diseases, including neuropsychiatric disorders and neuropathic pain.  The following research directions are being 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 has the role of RA signaling in synaptic plasticity begun 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 (Figure 1).

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 (Wang et al., 2011; Arendt et al., 2015).  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. Among the many mRNA targets of RARα, we identified two key mRNA species encoding GluA1 and BDNF, respectively, whose de novo translation upon RA synthesis drives pre- and post-synaptic changes during homeostatic plasticity at excitatory synapses (Aoto et al., 2008; Poon and Chen, 2008; Maghsoodi et al., 2008; Thapliyal et al., 2023).

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

Balanced synaptic excitation and inhibition (E/I ) in both strength and timing, is a central characteristic of a functional network, and a means operated by homeostatic plasticity to achieve the goal of optimal information coding (Park et al., 2018; Zhong et al., 2018) (Figure 2). Thus, although the synaptic action of RA has been tightly linked to homeostatic synaptic plasticity, its impact on synaptic function goes beyond homeostatic regulation. A neuron’s activity history determines its current biochemical state and thus its ability to undergo synaptic plasticity, a phenomenon referred to as meta-plasticity. Acting through a distinct molecular mechanism, RA acts as a candidate ‘meta-plasticity molecule’ that changes the state of a neuron (e.g., its E/I balance) and influences Hebbian plasticity through rapid modification of excitatory and inhibitory synaptic strength.

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 (Arendt et al., 2015). Conversely, deletion of RARα in animals with enriched environment experience drives runaway Hebbian plasticity and enhanced memory strength at the expense of cognitive flexibility (Hsu et al., 2019). 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 that circuit.

3. Involvement of synaptic RA signaling in cognitive impairment 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 intellectual disability that is also associated in some cases with symptoms characteristic of autism spectrum disorders. Using both mouse and human models of FXS, we have established the essential role of FMRP in synaptic RA signaling, homeostatic synaptic plasticity, and cognition (Soden and Chen, 2010; Sarti et al., 2013; Zhang et al., 2018; Li et al., 2019; Park et al., 2021). 

At the 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 have shown 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.

4. Peripheral nerve injury-induced neuropathic pain and homeostatic synaptic plasticity in spinal cord circuit

Proper synaptic connections in the sensory systems form during early development through critical period sensory experiences. Critical period plasticity in the CNS greatly diminishes in adulthood. However, homeostatic plasticity persists into adulthood. Many injuries or pathological conditions lead to sensory deafferentation, ranging from partial to complete loss of afferent inputs, and result in loss of vision, hearing, and touch. In the absence of instructions from proper sensory input, these forms of homeostatic plasticity often do not fully restore lost function but cause reorganization of the circuit that leads to tinnitus, visual hallucination, and neuropathic pain.

In the spinal cord dorsal horn circuit, we recently discovered that partial denervation of sensory input results in RA-dependent homeostatic plasticity, which drives the chronification process of neuropathic pain (Cao et al., 2022) (Figure 3). This new finding suggests that targeting homeostatic plasticity may be an effective method of therapeutic intervention for deafferentation-induced neuropathic pain.