Hot Publication - MacDonald et al.
Selective Loss of Smaller Spines in Schizophrenia
MacDonald ML, Alhassan J, Newman JT, Richard M, Gu H, Kelly RM, Sampson AR, Fish KN, Penzes P, Wills ZP, Lewis DA and Sweet RA
American Journal of Psychiatry, Published online 2017
Deceased density of dendritic spines in adult schizophrenia subjects has been hypothesized to result from increased pruning of excess synapses in adolescence. In vivo imaging studies have confirmed that synaptic pruning is largely driven by the loss of large/mature synapses. Thus, increased pruning throughout adolescence would likely result in a deficit of large spines in adulthood. In his recent article in the American Journal of Psychiatry, Dr. Matthew MacDonald examined the density and volume of dendritic spines in deep layer 3 auditory cortex of 20 individuals with schizophrenia and matched control subjects as well as aberrant voltage-gated calcium channel subunit protein expression linked to spine loss.
Dr. MacDonald assessed primary auditory cortex deep layer 3 spine density and volume in 20 pairs of individuals with schizophrenia and matched comparison research participants in an initial and replication cohort (12 and 8 pairs) by immunohistochemistry-confocal microscopy. He used Targeted Mass Spectrometry to quantify postsynaptic density and voltage-gated calcium channel protein expression. The effect of increased voltage-gated calcium channel subunit protein expression on spine density and volume was assessed in primary rat neuronal culture.
Findings from the study demonstrate that only the smallest spines are lost in deep layer 3 primary auditory cortex of schizophrenia, while larger spines are retained. Levels of the tryptic peptide ALFDFLK, found in the schizophrenia risk gene CACNB4, inversely correlated with the density of smaller, but not larger, spines in individuals with schizophrenia. Consistent with this observation, Dr. MacDonald found that CACNB4 overexpression resulted in a lower density of smaller spines in primary neuronal cultures.
Dr. MacDonald's findings demonstrate a link between small spine loss and a schizophrenia risk gene, and the need to rethink the over pruning hypothesis. More in-depth investigations are needed to examine the mechanisms that govern new/small spine generation and stabilization under normal conditions as well as how this process is impaired in schizophrenia.
Matthew L. MacDonald, PhD, Jamil Alhassan, BS, Jason T. Newman, PhD, Michelle Richard, MS, Kenneth N. Fish, PhD, David A. Lewis, MD and Robert A. Sweet, MD (Department of Psychiatry, University of Pittsburgh School of Medicine)
Hong Gu, MS, Ryan M. Kelly, BS, Allan R. Sampson, PhD, (Department of Statistics, University of Pittsburgh School of Medicine)
Peter Penzes, PhD (Departments of Physiology, and Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine)
Zachary P. Wills, PhD (Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine)
This article appears in the American Journal of Psychiatry. To view the abstract, click here.