Kristen M. Harris

Kristen M. Harris, Ph.D. at work in her lab of Synapses Structure and Function, July 2003 Address:

The University of Texas at Austin
1 University Station, C7000
Austin, TX 78712-0805
Office: NHB 3.406A

Place Of Birth:

Fargo, North Dakota USA

Personal:

Married, Max Snodderly; Son, Collin

Education:

Postdoctoral Training:

Academic Appointments:

Awards and Honors:

Memberships and Committee Assignments:

  • University of Texas at Austin
  • Medical College of Georgia:
  • Boston University:
  • Harvard Medical School:
  • Children's Hospital:

    • Editorial Boards:

    Journal Reviewer:

    Research Interests and Accomplishments:

        Our goal is to elucidate structural components involved in the cell biology of learning and memory. We study long-term potentiation (LTP) and its complement long-term depression (LTD) in the developing and mature hippocampus because these phenomena have many of the physiological characteristics that are expected for learning and memory in the brain. Our working hypothesis is synaptic plasticity that serves to modify synapses in the creation of new memories competes with homeostatic mechanisms that serve to prevent saturation of synaptic strength and neuropathology. Our focus has been on dendritic spines because they are the major postsynaptic targets of excitatory axons throughout the brain and because their structure and composition serve both synaptic plasticity and stabilizing homeostatic mechanisms.

        Dendritic spines and their synaptic components are too small to measure accurately with light microscopy so we have developed and standardized computer-assisted approaches to analyze them in three-dimensions through serial section transmission electron microscopy (ssTEM). We have established the rat hippocampal slice as a model system for structural synaptic plasticity by developing a microwave-enhanced procedure that produces rapid fixation to the center of the slice within a minute after the last physiological recording. We have collaborated with Dr. Sergei Kirov to use two-photon and confocal microscopy to visualize global effects of different levels of synaptic activity on spine density along dendrites prior to ultrastructural analyses. We have received a Javits Merit award to extend our studies regarding the functional ultrastructure of LTP into the hippocampus of the awake rat in collaboration with Dr. Wickcliffe Abraham at the University of Otago, Dunedin, New Zealand. We collaborate with Dr. Michael Ehlers at Duke University to understand the dynamics and identity of organelles, such as recycling endosomes and Golgi apparatus in dendrites and at synapses.

        Our research has revealed contrasting effects of synapse activation on spine structure and formation in the immature and mature rat hippocampus. Prior to postnatal day (PN) 11, hippocampal CA1 synapses are located on the dendritic shafts or along dendritic filopodia, often piled up around the base of a filopodium. By PN15, shorter dendritic spines have emerged with enlarged heads each of which hosts one synapse, filopodia are rare, and shaft synapses have diminished almost to their low (<5%) adult level. In parallel, we have shown that LTP develops during PN11 to 15 after dendritic spines have begun to emerge. Recent studies from our lab show that if LTP is induced at PN15, the predominant location of polyribosomes shifts from dendritic shafts into dendritic spines and those spines containing polyribosomes have enlarged synapses by 2 hours after induction. Our recent findings show a robust increase in the number of dendritic spines with synapses, nonsynaptic filopodia, and polyribosomes throughout the dendrites by 5 and 30 minutes after induction of LTP. Spine number returns to control levels by 2 hours suggesting a rapid competition and elimination for synaptic sites during 1-2 hours after induction of LTP. These findings provide strong evidence for local changes in protein synthesis at a subpopulation of synapses on developing hippocampal neurons during LTP. Like PN15, mature hippocampal dendrites also show a synapse specific increase in size at 2 hours after the induction of LTP associated with a local elevation in polyribosomes. With Dr. Abraham we will determine how soon, and for how long after induction of LTP the synapses remain altered in vivo in the mature hippocampus to provide a stable mechanism of enduring LTP.

        We have measured dendritic spines and their presynaptic partners in several mature brain regions. We established that interneurons do not synapse with hippocampal dendritic spines, thereby removing differences in presynaptic input types as a potential source of the large (>10 fold) variation in spine dimensions along even a short 5-micron long segment of dendrite. Our findings show that larger spines have proportionately larger and more complex subcellular organelles, and postsynaptic receptive surfaces, and more presynaptic vesicles. We have shown that spine necks are constricted just enough to allow the heads to be relatively isolated biochemical compartments near the synapses, without choking off transmission of electrotonic signals to the postsynaptic dendrite. Furthermore, our recent studies show that different subsets of spines contain smooth endoplasmic reticulum, or endosomal compartments suggesting the independence of these organelles in modulating synaptic efficacy. These findings demonstrate the power of ssTEM to capture and illustrate dynamic processes on the ultrastructural scale by comparing across ages, conditions, times, dendrites, and brain regions.

        Studies using confocal and two-photon microscopy in collaboration with Dr. Kirov show that blocking synaptic transmission on mature hippocampal neurons results in a prodigious up regulation in the number of dendritic spines. These findings suggest that a homeostatic mechanism was triggered to maintain a constant level of synaptic input on mature neurons. In contrast, if synaptic transmission was blocked at ages younger than postnatal day 21, there was no net effect on spine number. It appears that the manifestation of this homeostatic mechanism requires a substantial period of postnatal development. Three-dimensional studies at the ultrastructural level demonstrated a recapitulation of development in the formation of new synapses during conditions of blocked synaptic transmission in the adult.

        Others have shown that astrocytic processes are heavily endowed with glutamate transporters and neurons grown in culture without astrocytes are 12 fold less active than neurons grown with glia. Therefore, measuring the degree to which astroglia surround and intervene between synapses is integral to understanding their role in synaptic transmission and plasticity. We found that about 50% of hippocampal synapses have astrocytic processes surrounding a portion of their perimeters and those synapses that have perisynaptic astroglia are substantially larger than those without. LTP induces filopodia which eventually become dendritic spines, but the new smaller spines have no perisynaptic astroglia.

        Areas in which I plan to expand our research include models of learning and memory and mental retardation in vivo, the role of sleep and circadian rhythms in modulating synapse number and structure, and mapping the location of key molecules in three dimensions. In addition, I am working to understand the role of protein synthesis in structural synaptic plasticity. In earlier work, I showed that LTP has a circadian cycle, being more likely to occur at a higher magnitude during the rat’s sleep cycle for hippocampal area CA1 and during the rat’s active wake cycle in hippocampal area dentata. One goal will be to determine whether circadian and sleep rhythms in the mature nervous system influence spine formation and/or preservation after LTP, LTD, or learning and memory. I also plan new efforts towards producing accurate three-dimensional maps of relevant molecules at the synapse, along dendrites, presynaptically, and in relationship to astroglial processes. In addition, I plan to expand our database of dendrites and synapses (see synapses.clm.utexas.edu) and to implement automatic alignment and segmentation algorithms in collaboration with Dr. Dmitri Chklovski (Janelia Farm) and Chadrajit Bajaj (UT-Austin).

    Current Grant Support:

    Past Grant Support:

    Teaching:

    Regional, National and International Contributions

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