A role for the SHANK1 scaffold protein in experience-induced synaptic plasticity and memory consolidation

Collins, Sean M.

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https://hdl.handle.net/2142/101455 Copy

Description

Title

A role for the SHANK1 scaffold protein in experience-induced synaptic plasticity and memory consolidation

Author(s)

Collins, Sean M.

Issue Date

2018-05-03

Director of Research (if dissertation) or Advisor (if thesis)

Galvez, Roberto

Doctoral Committee Chair(s)

Galvez, Roberto

Committee Member(s)

• Juraska, Janice M.
• Gulley, Joshua M.
• Wickesberg, Robert E.
• Llano, Daniel A.

Department of Study

Psychology

Discipline

Psychology

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

SHANK1, synaptic plasticity, associative learning, glia, developmental plasticity, shRNA knockdown

Abstract

The processes by which the brain acquires, stores, and retrieves external information has been an extensively researched field in psychology. Findings from these studies have overwhelmingly suggested that plasticity of neuroanatomical networks across development and during various experiences provide a critical mechanism mediating learning. Specifically, numerous studies have suggested dendritic spine plasticity across development and during learning as a likely process for memory consolidation. During early postnatal development, dendritic spine density increases in numerous sensory cortices, reaching a peak in adolescence, followed by a subsequent reduction in dendritic spine density to adult levels. In the hippocampus, dendritic spine density steadily increases during postnatal development, and plateaus in adulthood. Similar to the plasticity observed across development, increases in dendritic spine density occur in the neocortex and hippocampus following various learning paradigms, suggesting synaptic remodeling. While the anatomical properties for these forms of plasticity are well investigated, the underlying molecular processes remain largely unknown. Interestingly, recent studies have strongly suggested a role for SHANK1 in normal synaptic development and plasticity. SHANK1 is a scaffolding protein that is concentrated to the postsynaptic density (PSD) of excitatory synapses and is involved in the binding of glutamate receptors to their active zones. Previous developmental studies have demonstrated that SHANK1 is initially localized in the cytoplasm of neurons followed by an increased dendritic spine expression during periods of postnatal dendritic spine proliferation. Likewise, SHANK1 expression is increased across postnatal development in purified postsynaptic fractions, further suggesting a role in developmental properties of dendritic spines. Interestingly, global SHANK1 knockout (SHANK1 -/-) mice have also been shown to exhibit a reduction in dendritic spine density and increased immature dendritic spine phenotype. Consistent with that observed in development, SHANK1 has been hypothesized to play an important role in learning-induced dendritic spine plasticity and cognition. SHANK1-/- mice exhibit marked impairments in contextual fear-conditioning and radial-arm-maze retention. Similarly, mice that overexpress SHANK1 exhibit impairments in both cued and contextual fear conditioning, further suggesting that appropriate SHANK1 regulation is crucial for normal cognition.Collectively, these studies strongly suggest a role for SHANK1 in developmental and learning-induced dendritic spine plasticity; however, a detailed examination of this has never been conducted. Furthermore, many of these studies genetically dysregulated SHANK1 from birth, thus a role for SHANK1 in normal adult learning-induced plasticity has not yet been examined. The studies in the present thesis further explored SHANK1 as an underlying mediator of dendritic spine plasticity in three specific aims. In Aim 1, a detailed examination of layer and cell-specific dendritic spine plasticity in S1 during distinct learning phases for WTEB was conducted. Findings from this study revealed no significant changes in dendritic spine density on layer III or layer V pyramidal cells at the specific time points examined across WTEB. In exploring these findings, we further discussed the implications of these findings, possible explanations as well as potential future studies to explore this research question. Aim 2 explored a role for SHANK1 expression during neuronal development, a well characterized period of dendritic spine plasticity. These studies demonstrated SHANK1 localization to neurons as well as astrocytes and microglia. Furthermore, this study also characterized cell-specific changes in SHANK1 expression during periods of developmental synaptic plasticity. Aim 3 expanded upon these findings to explore a role SHANK1 expression, during learning-induced neocortical dendritic spine plasticity and learning of WTEB. These studies demonstrated a transient increase in SHANK1 levels during periods of neocortical synaptic plasticity across WTEB. Collectively, these studies further support a role of SHANK1 in the organization and remodeling of synaptic networks during development and learning. In so doing these studies also provided additional insight into potential specific mechanisms underlying developmental and experience-induced synaptic remodeling, deepening our understanding of memory consolidation within specific learning networks.

Graduation Semester

2018-08

Type of Resource

text

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http://hdl.handle.net/2142/101455

Copyright and License Information

Copyright 2018 Sean Collins

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