Research
The cell biology of long-lasting synaptic plasticity and memory
Synaptic plasticity, the ability of neurons to change the strength of their connections with experience, provides a cellular mechanism for learning and memory. The persistence of synaptic plasticity and memory requires new gene expression. Research in the Martin lab is aimed at understanding how various forms of neuronal activity alter gene expression to form long-lasting memories. By elucidating the cell and molecular biological basis of synaptic plasticity, we hope to provide insights into the etiologies of many neuropsychiatric and cognitive diseases.
The remarkable polarity and compartmentalization of neurons raise two cell biological questions that the Martin lab studies:
- How are signals relayed from distal synapses to the nucleus to regulate gene expression
- How do the products of gene expression regulate structure and function at some but not all synapses made by a given neuron?
In addressing the first question, we identified a role for synaptonuclear signaling molecules, including kinases and transcription factors that undergo stimulus-induced active transport from stimulated synapses to the nucleus to regulate transcription. In addressing the second question, we identified a role for local, activity-dependent translation of synaptically localized mRNAs during synapse-specific forms of long-term plasticity.
Current projects in the lab are directed at understanding how different types of synaptic stimulation induce distinct gene programs to in turn generate distinct forms of plasticity (e.g. long-term potentiation or long-term depression). We combine electrophysiological, cell and molecular biological and genomic approaches in primary rodent neuronal cultures and in acute slice preparations to investigate whether and how distinct patterns of stimulation regulate several steps involved in gene regulation, including synapse-to-nuclear trafficking, transcription factor binding and transcriptional activation, alternative splicing, mRNA stability and localization, and translational regulation. Specific ongoing projects are listed below.
What is the role of CRTC1 in transcription-dependent activity-dependent synaptic plasticity?
We have previously shown that CREB Regulated Transcriptional Co-regulator-1 (CRTC1) localizes in dendrites and spines in silenced neurons, and undergoes stimulus-induced synapse to nucleus transport to regulate the expression of a suite of immediate early genes. We found that glutamatergic stimulation triggers complex changes in the pattern of CRTC1 phosphorylation, with dephosphorylation of specific residues being required for nuclear import. We also found that the rephosphorylation and hence the persistence of CRTC1 in the nucleus is regulated by intracellular concentrations of cAMP. Together, our studies indicate that changes in CRTC1 phosphorylation may couple distinct patterns of synaptic stimulation with distinct transcriptional programs, and suggest that neuromodulatory inputs that increase intracellular cAMP may enhance long-term plasticity and memory in a CRTC1-dependent manner. Our current studies on CRTC1 are aimed at 1) identifying the proteins CRTC1 interacts with in the cytoplasm of silenced neurons and in the nucleus of stimulated neurons; 2) identifying the regions of DNA CRTC1 binds to in response to distinct types of synaptic stimulation; and 3) determining the function of CRTC1-dependent transcriptional regulation during long-lasting forms of synaptic plasticity.
What is the role of neuromodulation in regulating gene expression in the hippocampus?
The release of catecholamines in response to novelty/unexpected reward and during times of stress or strong emotion has long been known to enhance long-term memory. We are interested in understanding the role of catecholamines (including both norepinephrine and dopamine) in the regulation of gene expression during long-lasting hippocampal plasticity. Using optogenetics to activate axonal inputs from the locus coeruleus, we are studying the molecular mechanisms underlying catecholaminergic-facilitated changes in gene expression in hippocampal pyramidal neurons, with the goal of providing insights into the physiological function of neuromodulation in the brain and of identifying candidate therapeutic targets for disorders ranging from drug addiction to post-traumatic stress.
Do changes in gene expression in astrocytes contribute to long-lasting forms of neuronal plasticity?
Astrocytes, an abundant type of glial cell in the brain have been shown to be critical for synapse formation and function. To understand whether and how gene expression in astrocytes contributes to long-lasting forms of neuronal activity, we have used genetic approaches to monitor the gene expression in astrocytes following induction of hippocampal long-term potentiation (LTP) using electrical stimulation of CA3 to CA1 synapses. These experiments have led to the identification of genes that are regulated in astrocytes during long-lasting neuronal activity. Current studies are aimed at elucidating how changes in astrocytic gene expression contribute to long-term synaptic plasticity.
How does aging alter gene expression to impact memory?
As memory loss is a common symptom of aging, we have focused attention on understanding how aging alters gene expression to impact long-term memory. We are investigating this question specifically in the context of sex differences and have found that aging leads to an increase in sex differences in both gene expression and chromatin accessibility in the hippocampus. We found that aging results in more open chromatin accessibility and increased expression of LINE1 retrotransposon elements. We also found sex differences in chromatin accessibility, with aged female chromatin showing less accessibility at many promoter regions compared to aged male chromatin. These studies not only detail how aging impacts the hippocampus to reveal possible therapeutic avenues to address aging-related memory loss, but also underline the importance of including females in aging brain research.