Author ORCID Identifier

Date of Graduation


Document Type

Dissertation (PhD)

Program Affiliation


Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

John H. Byrne, Ph.D.

Committee Member

Michael Beierlein, Ph.D.

Committee Member

Rebecca Berdeaux, Ph.D.

Committee Member

Ruth Heidelberger, M.D., Ph.D.

Committee Member

M. Neal Waxham, Ph.D.


Chemotherapeutic agents impair memory in humans as well as in animal models. Such memory impairments can be persistent, lasting years after exposure to chemotherapy. Doxorubicin (DOX), a common chemotherapeutic agent, has been associated with memory impairments in humans and induces memory deficits in rodent models. DOX also impairs serotonin (5-HT)-induced long-term synaptic facilitation (LTF) in Aplysia sensorimotor co-cultures, a cellular analog of long-term memory formation. In addition, DOX leads to dynamic activation of extracellular signal-regulated kinase (ERK), consisting of an immediate and a delayed phase of activation, and to transient activation of p38 mitogen-activated protein kinase (p38 MAPK) in Aplysia sensory neurons. These two MAPKs have competing roles in the induction of LTF, with ERK promoting LTF and p38 MAPK opposing it. Further characterization of the effects of DOX on the basal state of neurons may aid the understanding of how DOX interferes with memory processes. Using isolated Aplysia sensory neurons in culture, we characterized the persistent effects of a single, brief exposure to DOX to understand how such exposure may be producing complex ERK activation and to determine whether DOX modulates the basal biophysical properties of these neurons and whether any changes can be reversed. We also sought to determine how DOX affects a cellular analog of memory formation complimentary to LTF, 5-HT-induced long-term enhanced excitability (LTEE). The two phases of ERK activation appeared to have distinct induction mechanisms, with the early phase likely depending upon a transient decrease in MAPK phosphatase-1 (MKP-1) protein, and thus reduced dephosphorylation rates, and the late phase of ERK activation depending upon delayed ERK kinase (MEK) activation. Early MEK activation also contributed to the late ERK activity, seemingly indirectly through its influence on late MKP-1 expression. DOX also produced a persistent increase in sensory neuron excitability that coincided with impaired 5-HT-induced LTEE, similar to the LTF deficit. The DOX-induced increase in basal excitability was reversed by blocking early MEK activity and was negatively correlated with the late phase of ERK activation. These findings show that acute exposure to DOX can produce complex, persistent effects that may interfere with processes important for memory induction.


doxorubicin, Aplysia, excitability, ERK, memory, MKP-1



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