Theses Doctoral

Structural and functional plasticity alterations at single spines in Fragile X Syndrome

Panzarino, Alexandra Marie

In the mammalian brain, information is believed to be encoded at the cellular level through alterations in synaptic weights. Furthermore, changes in synaptic strength are correlated with structural changes at dendritic spines, such as growth and shrinkage, which may serve to shape inputs into functional domains and increase the computational power of neurons. Neuroanatomical alterations in dendritic spines have been described in humans with intellectual disability, further supporting the relationship between neuronal structure and function.

Fragile X Syndrome (FXS) is the most common single-gene neurodevelopmental disorder, and a hallmark feature of this disorder is the increased density of long spines in several brain regions including the hippocampus. Identification of FXS spines as filopodia-like has led to the theory that these spines are immature, and that altered spine development underlies the cognitive dysfunction in this disorder. However, the functional capacity of the long spines observed in FXS is not well understood.

For my thesis work, I used two photon imaging, glutamate uncaging and electrophysiology to perform a high-resolution characterization of dendritic spine structure, function, and plasticity in the hippocampus of the FXS mouse model in order to determine what gives rise to these alterations and how this contributes to the observed neuronal dysfunction in this disorder. From my dissertation research, I find that while Fmr1 KO neurons have region-specific alterations in both dendrite and spine morphology, the functional responses of single synapses in FXS mutant neurons are grossly normal. FXS spines respond proportionally to increased levels of glutamate release, and the linear relationship between structure and function is preserved at these synapses. In addition, structural plasticity, both growth and shrinkage, at single inputs is similar in magnitude to control neurons following synaptic potentiation and depression, respectively.

However, upon more detailed examination of structural plasticity, either at single or multiple inputs, I find several deficits. First, following structural plasticity, I observe aberrant heterosynaptic plasticity in Fmr1 KO neurons, where unstimulated mutant spines located in close proximity to activated spines become significantly larger compared to neighboring spines in control neurons, which showed no significant change in size. Next, competition for mGluR-LTD does not occur in Fmr1 KO neurons, leading to an increase in spines that undergo spine shrinkage.

I conclude from this work that while spine morphology is altered in FXS, spines develop with functional synapses that have the capacity to express bidirectional forms of structural plasticity. However, these spines undergo abnormal structural plasticity across stimulated inputs, leading to the expression of aberrant heterosynaptic structural plasticity. As activity is integrated across a dendritic branch, such excess plasticity observed in Fmr1 KO neurons could contribute to the altered spine morphology as well as cognitive dysfunction observed in FXS.


  • thumnail for Panzarino_columbia_0054D_17893.pdf Panzarino_columbia_0054D_17893.pdf application/pdf 4.68 MB Download File

More About This Work

Academic Units
Neurobiology and Behavior
Thesis Advisors
Israely, Inbal
Ph.D., Columbia University
Published Here
June 28, 2023