Schizophrenia and dendritic spines

Pyramidal neurons are the primary type of cells in the cerebral cortex; they are made of a cell body called soma, a single axon, an apical dendrite, multiple basal dendrites, and dendritic spines (Megias et al., 2001). Dendritic spines are small neuronal protrusions rising from a neuron’s dendrites; they typically receive excitatory input from one single axon, forming a synapse (Nimchinsky et al., 2002). They are made of a thin neck and a bulbous head.

The head in particular receives information crossing the synaptic cleft in the form of chemical messengers thanks to its glutamate receptors localised on the postsynaptic density within the spine head (Alvarez & Sabatini, 2007).

They were first discovered in 1888 by neuroscientist and pathologist Santiago Ramón y Cajal, who hypothesized their role in increasing the surface area of each neuron, thus multiplying the number of possible connexions between neurons (DeFelipe, 2015; Yuste, 2015).

Research has shown the important role dendritic spines play in maintaining normal brain functions, and in particular learning and memory. For example, a study where mice were trained to perform a motor task showed a rapid but long-lasting reorganisation at the dendritic spine level, suggesting that the organisation and stabilisation of these new neuronal connections is the foundation of durable motor memory (Xu et al., 2009). Other studies suggest that the number, stability, and size of dendritic spines are central to the functional acquisition of new behaviours in the juvenile brain (Roberts et al., 2010).

The role of dendritic spines is indeed most visible during early brain development. Throughout the early years of an individual, dendritic spines have been observed growing out of dendritic branches and exploring the neighbouring neuropil for a presynaptic partner to connect with, thus forming the neural networks in the brain (García-López et al., 2010), the main structure by which information is encoded and transported within the brain. This intimate association with synaptic transmission supports the critical role of dendritic spines (Koch & Zador, 1993).

Given the essential role of dendritic spines in maintaining normal brain functions, dendritic spine pathology is thought to be important for many neuropsychiatric disorders. Schizophrenia in particular seems to be impacted by dendritic spine pathology, with at least two lines of evidence supporting this theory.

The first line of evidence consists of several post-mortem studies revealing an abnormal number of dendritic spines in individuals suffering from schizophrenia compared to control individuals. A study compared the density of dendritic spines in prefrontal cortical pyramidal neurons in 15 schizophrenic subjects and 15 non-schizophrenic psychiatric subjects; it found a significant effect of diagnosis on dendritic spine density, with a lower dendritic spine density on dorsolateral prefrontal cortex layer 3 pyramidal cells for schizophrenic subjects (Glantz & Lewis, 2000).

A second line of evidence supporting the theory of dendritic spine pathology as central to schizophrenia are in vivo studies. For example, researchers repeatedly acquired high-resolution magnetic resonance images (MRI scans) from 12 schizophrenic and 12 healthy adolescents over the course of 5 years, exactly at the same ages and intervals and using the same scanner; the study found a progressive loss of gray matter in schizophrenic subjects, which started in the parietal association areas and spread to the parietal, motor, temporal and prefrontal areas as the disease progressed (Thompson et al., 2001).

Research suggests that the primary contributor to these smaller cortical grey matter volumes is a loss in dendritic spine density (Glausier, 2013). Furthermore, multiple experimental studies show that dendritic spine deficits are associated with impairments in sociability, sensory-motor processing, working memory and attention, suggesting that low dendritic spines densities may contribute to the clinical features of schizophrenia (Liston et al, 2006; Hains et al., 2009).

While there is strong supporting evidence that aberrant dendritic spine density resulting in an altered the neural network is a fundamental factor in the onset and progress of the symptoms of schizophrenia, the overall etiology of schizophrenia is still poorly understood. In particular, it has been found that a number of the genetic factors associated with schizophrenia encode for proteins that can be found at the synaptic level (Owen et al., 2005), with 108 common genetic variants that have been linked to schizophrenia (Ripke et al., 2014).

In addition to these nebulous genetic factors, a number of environmental factors seem to be involved (Morgan & Fisher, 2007). In order to develop treatments that can reverse or stop schizophrenic symptoms, it will be essential to understand and address all of these factors.

References:

Alvarez, V. A., & Sabatini, B. L. (2007). Anatomical and physiological plasticity of dendritic spines. Annu. Rev. Neurosci.30, 79-97.

DeFelipe, J. (2015). The dendritic spine story: an intriguing process of discovery. Frontiers in neuroanatomy9, 14.

García-López, P., García-Marín, V., & Freire, M. (2010). Dendritic spines and development: towards a unifying model of spinogenesis—a present day review of Cajal’s histological slides and drawings. Neural plasticity2010.

Glantz, L. A., & Lewis, D. A. (2000). Decreased dendritic spine density on prefrontal cortical pyramidal neurons in schizophrenia. Archives of general psychiatry57(1), 65-73.

Glausier, J. R., & Lewis, D. A. (2013). Dendritic spine pathology in schizophrenia. Neuroscience251, 90-107.

Hains, A. B., Vu, M. A. T., Maciejewski, P. K., van Dyck, C. H., Gottron, M., & Arnsten, A. F. (2009). Inhibition of protein kinase C signaling protects prefrontal cortex dendritic spines and cognition from the effects of chronic stress. Proceedings of the National Academy of Sciences.

Koch, C., & Zador, A. (1993). The function of dendritic spines: devices subserving biochemical rather than electrical computation. Journal of Neuroscience13, 413-413.

Liston, C., Miller, M. M., Goldwater, D. S., Radley, J. J., Rocher, A. B., Hof, P. R., … & McEwen, B. S. (2006). Stress-induced alterations in prefrontal cortical dendritic morphology predict selective impairments in perceptual attentional set-shifting. Journal of Neuroscience26(30), 7870-7874.

Megias, M., Emri, Z. S., Freund, T. F., & Gulyas, A. I. (2001). Total number and distribution of inhibitory and excitatory synapses on hippocampal CA1 pyramidal cells. Neuroscience102(3), 527-540.

Morgan, C., & Fisher, H. (2007). Environment and schizophrenia: environmental factors in schizophrenia: childhood trauma—a critical review. Schizophrenia bulletin, 33(1), 3-10.

Owen, M. J., O’donovan, M. C., & Harrison, P. J. (2005). Schizophrenia: a genetic disorder of the synapse?.

Ripke, S., Neale, B. M., Corvin, A., Walters, J. T., Farh, K. H., Holmans, P. A., … & Pers, T. H. (2014). Biological insights from 108 schizophrenia-associated genetic loci. Nature511(7510), 421.

Roberts, T. F., Tschida, K. A., Klein, M. E., & Mooney, R. (2010). Rapid spine stabilization and synaptic enhancement at the onset of behavioural learning. Nature463(7283), 948.

Thompson, P. M., Vidal, C., Giedd, J. N., Gochman, P., Blumenthal, J., Nicolson, R., … & Rapoport, J. L. (2001). Mapping adolescent brain change reveals dynamic wave of accelerated gray matter loss in very early-onset schizophrenia.Proceedings of the National Academy of Sciences98(20), 11650-11655.

Nimchinsky, E. A., Sabatini, B. L., & Svoboda, K. (2002). Structure and function of dendritic spines. Annual review of physiology64(1), 313-353.

Xu, T., Yu, X., Perlik, A. J., Tobin, W. F., Zweig, J. A., Tennant, K., & Zuo, Y. (2009). Rapid formation and selective stabilization of synapses for enduring motor memories. Nature462(7275), 915.

Yuste, R. (2015). The discovery of dendritic spines by Cajal. Frontiers in neuroanatomy9, 18.


Join 100,000 mindful makers!

Ness Labs is a weekly newsletter with science-based insights on creativity, mindful productivity, better thinking and lifelong learning.

One email a week, no spam, ever. See our Privacy policy.