ReviewDendritic spine dysgenesis in autism related disorders
Introduction
As Santiago Ramón y Cajal began his work describing the fine structure of nervous cells in the late nineteenth century, he noticed that many of the cells “appear bristling with thorns [puntas] or short spines [espinas]” [1], and he envisioned that these protrusions provided a source of functional connectivity between neurons [2], [3]. Though Sherrington provided the concept of the synapse soon thereafter [4], it was not until the development of electron microscopy in the 1950s and confocal fluorescence microscopy in the 1980s that spines were confirmed as an important structural component of the synapse. The functional connectivity envisioned by Cajal has been validated and it is now well-established that spines, located on the dendrites of most neurons, are the postsynaptic sites of the majority of excitatory synapses in the brain where they receive input from glutamatergic axons [5]. The ability of the dendrite to add new spines, change spine morphology, and remove spines in response to synaptic activity has led to the wide-held belief that dendritic spines are the center for synaptic plasticity, and therefore, a cellular correlate to learning and memory [6]. In support of this view, many neuropsychiatric disorders, including autism with the high comorbidity of intellectual disability (ID) [7], [8], [9], present with atypical numbers and structure of dendritic spines, a cellular pathology termed “spine dysgenesis” [10]. We will first briefly describe the development, structure, and function of typical dendritic spines, and progress to detail evidence for spine dysgenesis in autism related disorders (ARDs), tracing the commonalities in dysgenesis from disorders involving entire chromosomes to those caused by single gene mutations.
Section snippets
Dendritic spines: history, functions, structural types, and development
In the developing brain, dendrites first develop devoid of spines and synapses. Dynamic, finger-like protrusions called filopodia begin to project from dendrites during the synaptogenesis period and have the ability to form nascent synapses with nearby axons [11]. Filopodia are highly mobile, extending and retracting to form synapses on the dendritic shaft or on spine-like protrusions that may develop into fully functioning spines [12], [13]. One leading hypothesis is that filopodia recruit
Spine dysgenesis in autism related disorders
Spine dysgenesis has been described in autopsy brains of several ARDs, their genetic causes ranging from hundreds of affected genes to one, with their pervasiveness relating to both severity and number of clinical symptoms. By examining common clinical phenotypes correlated to spine and synaptic abnormalities between the disorders, we can work to recognize causalities in dysgenesis and identify potential targets for therapeutic intervention.
mTOR: a convergence point of spine dysgenesis and synaptopathologies in ASD
Dysgenesis of dendritic spines occurs in the majority of individuals afflicted with ARDs, as well as in most experimental mouse models of these syndromes. It would, therefore, follow that there must be a converging deregulated molecular pathway downstream of the affected genes and upstream of dendritic spine formation and maturation. Identifying this pathway will not only define a causal common denominator in autism-spectrum disorders, but also open new therapeutic opportunities for these
Conclusion
Cajal once postulated, “the future will prove the great physiological role played by the dendritic spines” [229]. And indeed, it is now widely accepted that dendritic spines are the site of neuronal plasticity of excitatory synapses and the focal point for synaptopathophysiologies of ARDs. Individuals and mouse models of ARDs all display spine dysgenesis, with mTOR-regulated protein translation being a critical point of convergence. Deviations from optimal levels of protein synthesis correlate
Conflict of interest
The authors do not have competing financial interests.
Acknowledgments
This work was supported by NIH grants NS-065027 and HD-074418, the International Rett Syndrome Foundation, and the Rett Syndrome Research Trust (to LP-M). We thank Drs. Xin Xu, Eric Miller, and Wei Li for thoughtful discussions.
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