Mini Review: Dendritic Spine Density in the Prefrontal Cortex in Relation to Schizophrenia

Background Information

There is a lot of research which indicates that specific layers of pyramidal neurons are different in the brains of people with schizophrenia. In this post we’re going to be looking specifically at dendritic spine density in these populations, what this tells us about the overall functioning of these neurons, and the knock-on effects this can have on the conscious functioning of individuals.

Dendritic Spine Density

Glantz and Lewis (2000) conducted research on the density of dendritic spines present in pyramidal neurons from the dorsolateral prefrontal cortex (DLPFC) of human brains. The dorsolateral prefrontal cortex (DLPFC) is responsible for regulating a number of higher cognitive functions such as memory, decision making, reasoning, and social cognition. The researchers focused on the third layer of pyramidal neurons in the DLPFC, as this layer is usually the most densely packed, and as such is very important in the processing capabilities, and expected output, of the pyramidal neurons in this area as a whole.

45 autopsied brains were used, 15 from individuals who suffered from schizophrenia, 15 from individuals who experienced other psychiatric illnesses, and 15 from mentally healthy controls. The researchers found that not only were the basilar dendrites of the schizophrenic brains significantly shorter than both of the other groups, when the length difference was accounted for they also had 23% fewer dendritic spines (p = .006) in the deep sections of layer 3 of the DLPFC. This difference isn’t as pronounced in the surface of layer 3, at only 15% fewer spines, and while a reduction in the number of spines is expected when moving from the surface to the deeper parts of a layer the extent of this reduction was larger than average.

The researchers were able to determine, by comparing the brains of the subjects with schizophrenia to those with other psychiatric illnesses, that this effect was not caused by antipsychotics, and is therefore likely to be an aspect of the illness itself.

Similar results were found by Garey et al. (1998) when they compared the temporal lobes from the brains of people who had suffered from schizophrenia against the brains of those who had not. The schizophrenic layer 3 pyramidal neurons were found to house an average of 125 spines per neuron, less than 50% of the 276 spine average from non-schizophrenic layer 3 pyramidal neurons. This reduction in pyramidal dendritic spines was consistent across both apical and basilar dendrites.

When Kolluri et al. (2005) examined the 5th and 6th cortical layers of the DLPFC they found no significant difference in the number of spines present on the basilar dendrites of pyramidal neurons between schizophrenic and non-schizophrenic brains. They did, however, find a significant difference in the number of spines present on the basilar dendrites of pyramidal neurons between the 3rd vs 6th (p = .01) and the 3rd vs 5th (p = .0003) cortical layers of the DLPFC in the brains of people with schizophrenia. This finding further confirms the abnormal reduction in dendritic spine numbers in the 3rd layer of pyramidal neurons.

But what could be causing this consistent reduction in dendritic spine density? A 2006 study by Hill, Hashimoto and Lewis (2006) may have an answer. Their research suggests that CDC42, a protein responsible for the creation of spines, and Duo, a protein which plays a role in lining up the spine with an axon terminal to form a functioning synapse, are present in significantly smaller quantities in the autopsied brains of people with schizophrenia. Specifically, these reduced quantities were found in the pyramidal neuron populations of the DLPFC.

What are the Implications?

The main form of input to pyramidal neurons is excitatory and dendritic spines receive a large amount of that excitatory information. In very basic terms, the fewer excitatory inputs a cell has the less likely it is to fire and so the less overall communication these cells can have. Some research suggests that the pattern of firing is important for information encoding in the brain (McNaughton, Ruan & Woodnorth, 2006), and an alteration to the firing rate of a cell due to reduced spines could ultimately result in faulty information encoding. This may be why people with schizophrenia tend to have difficulty with tasks which require the use of areas we know are affected, like the dorsolateral prefrontal cortex (Weinberger, Berman & Zec, 1986).

Interestingly, a similar kind of dendritic spine reduction was found in socially isolated rats. Pyramidal neurons in both the medial prefrontal cortex (mPFC) and hippocampus of rats who were isolated after weaning had 48-51% and 58-70% fewer dendritic spines respectively (Silva-Gomez, Juárez & Flores, 2003). Social isolation is used to simulate long-term exposure to stress, but the similarity to pyramidal cell morphology in schizophrenic subjects is unmistakable. It would be interesting to know if this reduction in dendritic spines was also related to a reduction of CDC42 and Duo proteins, as is the likely cause in schizophrenia. If so, it may implicate stress in the development of schizophrenia, and explain why environmental factors such as child abuse (Morgan & Fisher, 2007) put people at much higher risk for developing schizophrenia.

So, due to a reduction in pyramidal neuron dendritic spines some areas of the brains of people with schizophrenia may not be encoding information correctly, does this matter? Yes. The symptomology of schizophrenia is typical of a system which isn’t processing information properly, constantly interpreting one type of cue (like an internal thought) as an external cue (like someone speaking to you), or latching onto unimportant background information (like the colour of car which passes by your house) and using it to make a functional decision (like whether or not you should go outside today). So much of our experiences are not at a conscious level, and so even when people with schizophrenia understand on a conscious level that what they’re experiencing is not consistent with reality they have no control over the part of their brain that is generating that inconsistency.

What we’re seeing here is a breakdown at a fundamental level of functioning, and that breakdown has to be addressed in order to fix the problem instead of just minimizing the knock-on effects.

Thank you for reading.

References

Garey, L. J., Ong, W. Y., Patel, T. S., Kanani, M., Davis, A., Mortimer, A. M., … & Hirsch, S. R. (1998). Reduced dendritic spine density on cerebral cortical pyramidal neurons in schizophrenia. Journal of Neurology, Neurosurgery & Psychiatry, 65(4), 446-453.

Glantz, L. A., & Lewis, D. A. (2000). Decreased dendritic spine density on prefrontal cortical pyramidal neurons in schizophrenia. Archives of general psychiatry, 57(1), 65-73.

Gusnard, D. A., Akbudak, E., Shulman, G. L., & Raichle, M. E. (2001). Medial prefrontal cortex and self-referential mental activity: relation to a default mode of brain function. Proceedings of the National Academy of Sciences, 98(7), 4259-4264.

Kolluri, N., Sun, Z., Sampson, A. R., & Lewis, D. A. (2005). Lamina-specific reductions in dendritic spine density in the prefrontal cortex of subjects with schizophrenia. American Journal of Psychiatry, 162(6), 1200-1202.

McNaughton, N., Ruan, M., & Woodnorth, M. A. (2006). Restoring theta‐like rhythmicity in rats restores initial learning in the Morris water maze.Hippocampus, 16(12), 1102-1110.

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

Silva-Gomez, A. B., Juárez, I., & Flores, G. (2003). Decreased dendritic spine density on prefrontal cortical and hippocampal pyramidal neurons in postweaning social isolation rats. Brain research, 983(1), 128-136.

Weinberger, D. R., Berman, K. F., & Zec, R. F. (1986). Physiologic dysfunction of dorsolateral prefrontal cortex in schizophrenia: I. Regional cerebral blood flow evidence. Archives of General Psychiatry, 43(2), 114-124.