In the Journals

Study challenges overpruning hypothesis in schizophrenia

Recent findings indicated only smaller spines, not larger spines, were lost in deep layer 3 of the primary auditory cortex among individuals with schizophrenia.

“Decreased density of dendritic spines in adult schizophrenia subjects has been hypothesized to result from increased pruning of excess synapses in adolescence,” Matthew L. MacDonald, PhD, of University of Pittsburgh School of Medicine, and colleagues wrote. “In vivo imaging studies have confirmed that synaptic pruning is largely driven by the loss of large or mature synapses. Thus, increased pruning throughout adolescence would likely result in a deficit of large spines in adulthood.”

To assess validity of this hypothesis, researchers used immunohistochemistry-confocal microscopy to examine density and volume of dendritic spines in deep layer 3 of the auditory cortex among 20 individuals with schizophrenia and 20 matched comparison subjects. Targeted mass spectrometry quantified postsynaptic density and voltage-gated calcium channel protein expression.

Researchers found that only smaller spines were lost in deep layer 3 of the primary auditory cortex in participants with schizophrenia, larger spines were retained.

Tryptic peptide ALFDFLK levels were inversely associated with density of smaller spines, but not larger spines, among participants with schizophrenia.

CACNB4 overexpression was associated with lower density of smaller spines in primary neuronal cultures, according to researchers.

“Our finding that A1 layer 3 spine loss in schizophrenia is limited to smaller spines strongly suggests that adult spine deficits result from a failure to generate and/or stabilize new or transient spines. This finding requires a rethinking of the overpruning hypothesis and should spur a more in-depth investigation of the mechanisms that govern spinogenesis, spine stabilization, and their role in schizophrenia,” the researchers wrote. “As a first step, we have identified one such mechanism, CACNB4 expression levels, which could contribute in part to the loss of small spines in schizophrenia. Future studies to confirm the effect of CACNB4 and other CACNB subunits in vivo are warranted and might include direct observation of spine dynamics.” – by Amanda Oldt

Disclosure: MacDonald reports no relevant financial disclosures. Please see the study for a full list of relevant financial disclosures.