2026 Theses Doctoral

SRGAP2 Limits Experience-Dependent Structural Plasticity in the Adult Sensory Cortex

Bernal-Garcia, Sergio Manuel

The mammalian cortex rewires itself continuously in response to experience, retaining throughout life the capacity to acquire new information, stabilize learned representations and memories that are behaviorally relevant, and discard irrelevant ones. This rewiring is achieved through two complementary forms of synaptic modifications: functional plasticity, the strengthening and weakening of existing synapses, and structural plasticity, the formation if new synapses and elimination of pre-existing ones, the small protrusions that carry most excitatory synapses in the cortex. In the neocortex, structural plasticity is most pronounced during juvenile critical periods, when excitatory synapses, dendritic spines, turn over rapidly, through extensive structural remodeling shaped by changes in sensory experience. This is in sharp contrast with adult cortical circuits, when dendritic spines are more stable and significantly less sensitive to changes in sensory experience.

The molecular mechanisms that limits the extent of structural plasticity in adult cortical circuits remains largely unknown. Measuring structural forms of synaptic plasticity has remained challenging for two main reasons: (1) it requires longitudinal, high resolution 2-photon imaging in awake mice and (2) tracking the dynamics of many individual spines using manual annotation and parameter-sensitive analysis scales poorly and remains potentially biased by individual observers.

To address this, we developed RESPAN, an open-source deep-learning pipeline that integrates content-aware image restoration, three-dimensional fluorescent image segmentation, automated longitudinal tracking of dendritic spines, in a single user-friendly interface. I demonstrated that RESPAN outperforms expert annotators and previously developed open-access or commercially available tools across imaging modalities, including low signal-to-noise images obtained by *in vivo* two-photon microscopy (Chapter 2). Applying RESPAN to longitudinal *in vivo* imaging of layer 2/3 pyramidal neurons in the adult mouse cortex, we identify SRGAP2 as a postsynaptic brake on experience-dependent structural plasticity, acting in both pyramidal neurons and microglia; because its human-specific paralogs SRGAP2B/C reduce SRGAP2 protein, my results suggest that the adult human cortex may be characterized by increased levels of structural synaptic plasticity and therefore shaped by sensory experience-driven rewiring throughout life (Chapter 3).