Alterations in Prefrontal Cortical Somatostatin Neurons in Schizophrenia: Evidence for Weaker Inhibition of Pyramidal Neuron Dendrites.

Abstract

Background: Certain cognitive processes require inhibition provided by the somatostatin (SST) class of gamma-aminobutyric acid (GABA) neurons in the dorsolateral prefrontal cortex (DLPFC). This inhibition onto pyramidal neuron dendrites depends on both SST and GABA signaling. Although SST mRNA levels are lower in the DLPFC in schizophrenia, it is not known if SST neurons exhibit alterations in the capacity to synthesize GABA, principally via the 67-kilodalton isoform of glutamic acid decarboxylase (GAD67).

Methods: GAD67 and SST mRNA levels were quantified in individual SST neurons using fluorescence in situ hybridization in DLPFC layers 2-superficial 3, where SST neurons are enriched, in schizophrenia (n=46) and unaffected comparison (n=46) individuals. Findings were compared to GAD67 and SST mRNA levels quantified by polymerase chain reaction and to final educational attainment, a proxy measure for cognitive functioning.

Results: GAD67 (F_1,84=13.1, p=0.0005, Cohen's d = -0.78) and SST (F_1,84=10.1, p=0.002, Cohen's d = -0.64) mRNA levels in SST neurons were lower in schizophrenia, with no group differences in the relative density of SST neurons (F_1,84=0.21, p=0.65). A presynaptic index of dendritic inhibition, derived by summing the alterations in GAD67 and SST mRNAs, was lower in 80.4% of individuals with schizophrenia and was associated with final educational attainment (adjusted odds ratio=1.44, p=0.022).

Conclusions: Deficits in both GAD67 and SST mRNAs within SST neurons indicate that these neurons have a markedly reduced ability to inhibit postsynaptic pyramidal neuron dendrites in schizophrenia. These alterations likely contribute to cognitive dysfunction in schizophrenia.