Synaptic Plasticity and Development
in the Central Nervous System
We are interested in the mechanisms that allow synaptic connections to be plastic and change with learning and experience. This fundamental process drives development of neural circuits in young animals but also is required for the storage and consolidation of memories in adults. Many forms of plasticity exist in the brain. We take a functional approach to define the molecules and mechanism that drive plasticity in the brain and that can go awry in neurodevelopmental disorders as well as aging and memory disorders.
Some current interests:
How do hippocampal mossy fibers synapses contribute to specific forms of learning and memory?
The mossy fiber (MF) synapse is an atypical connection formed in a part of the brain critical to the formation of memories – the hippocampus. Over the last several decades a more complete understanding of the functional organization of the hippocampus has emerged. For example, we understand now that hippocampal microcircuits play distinct roles in the encoding and retrieval of episodic memories and that each subregion of the hippocampus itself has distinct roles to play. One of the most important microcircuits in the hippocampus is that connecting the dentate gyrus to CA3 region. The dentate granule cells project to CA3 via the mossy fiber (MF) synapse. This axonal projection forms large, en passant “bouton-style” synapses on the proximal dendrites of the mossy cells in the hilus, and the pyramidal neurons and surrounding local circuit interneurons in CA3. Each MF bouton synapses on to a structurally complex, multi-headed spine, that protrudes from the dentate hilar cells and the CA3 pyramidal cells. This large spine is known as a “thorny excrescence”. Each presynaptic MF terminal contains multiple release sites that are opposed to multiple postsynaptic densities on each thorny excrescence. The synapse demonstrates a large presynaptic plasticity which, when the dentate granule cells are active, can powerfully depolarize its postsynaptic targets producing coincident activation of many CA3 neurons. The CA3 region is known to be critical for the ability of animals to complete patterns that are required for the retrieval of partial or incomplete memories. Thus, understanding the mechanism(s) underlying presynaptic plasticity of the MF synapse is extremely important in understanding how episodic memories are encoded and retrieved within the hippocampal network.
The goal of our research is to uncover the molecular mechanisms that contribute to the proper function of MF synapses. This will provide a mechanistic understanding of how the CA3 region of the hippocampus contributes to episodic memory storage, spatial learning and retrieval processes including pattern separation and pattern completion which are both differentially disrupted in aging and aging related dementia, autism, schizophrenia and in several anxiety disorders.
What is the role of hippocampal neurogenesis in memory formation?
The adult hippocampus is capable of large-scale brain structural plasticity. This structural plasticity is mediated by the continuous generation of newborn dentate granule cells (DGCs) that are incorporated into an already established functional adult hippocampal network. Manipulations of neurogenesis that either ablate newborn neurons or increase adult neurogenesis have demonstrated that newborn neurons play a unique role in hippocampal-dependent spatial learning and episodic memory, including pattern separation and trace conditioning.
Adult-born hippocampal neurons go through distinct phases of maturity that make them functionally separate from mature DGCs. Immature DGCs exhibit elevated excitability and plasticity compared to mature DGCs. Therefore, these immature DGCs represent a distinct, more excitable, population of neurons in the DG that make unique contributions to the function of the adult hippocampus. This functional specificity means that the proliferation and rate of maturation of adult-born hippocampal neurons will have an impact on adult hippocampal circuit function. Therefore, the goal of our research is to understand the underlying mechanisms that regulate newborn DGC maturation and how they incorporate into the hippocampal circuit.