Molecular evidence for decreased synaptic efficacy in the postmortem olfactory bulb of individuals with schizophrenia

Abstract

Multiple lines of evidence suggest altered synaptic plasticity/connectivity as a pathophysiologic mechanism for various symptom domains of schizophrenia. Olfactory dysfunction, an endophenotype of schizophrenia, reflects altered activity of the olfactory circuitry, which conveys signals from olfactory receptor neurons to the olfactory cortex via synaptic connections in the glomeruli of the olfactory bulb. The olfactory system begins with intranasal olfactory receptor neuron axons synapsing with mitral and tufted cells in the glomeruli of the olfactory bulb, which then convey signals directly to the olfactory cortex. We hypothesized that olfactory dysfunction in schizophrenia is associated with dysregulation of synaptic efficacy in the glomeruli of the olfactory bulb. To test this, we employed semi-quantitative immunohistochemistry to examine the olfactory bulbs of 13 postmortem samples from schizophrenia and their matched control pairs for glomerular expression of 5 pre- and postsynaptic proteins that are involved in the integrity and function of synapses. In the glomeruli of schizophrenia cases compared to their matched controls, we found significant decreases in three presynaptic proteins which play crucial roles in vesicular glutamate transport- synapsin IIa (−18.05%, p= 0.019), synaptophysin (−24.08% p=0.0016) and SNAP-25 (−23.9%, p=0.046). Two postsynaptic proteins important for spine formation and glutamatergic signaling were also decreased- spinophilin (−17.40%, p=0.042) and PSD-95 (−34.06%, p=0.015). These findings provide molecular evidence for decreased efficacy of synapses within the olfactory bulb, which may represent a synaptic mechanism underlying olfactory dysfunction in schizophrenia.

Dysregulations of Synaptic Vesicle Trafficking in Schizophrenia

“…Similar significant reductions in SNAP25 expression in schizophrenia measured with quantitative IHC have also been reported in other brain regions including ventromedial caudate (VMC) and Nucleus accumbens (NAc), [53] and glomeruli of olfactory bulb [37••]. However one study looking at the hippocampus using Western blotting found no significant changes in SNAP-25 between schizophrenia and controls.…”

“…Reductions in synaptophysin expression in schizophrenia have also been reported in different brain regions by various groups including, in the left thalamus using radioimmunoassay by [34] and in the medial temporal lobe using immunoradiography [35]. Furthermore synaptophysin immunoreactivity was significantly reduced in both the inner and outer molecular layers of the dentate gyrus [36] and also in the glomeruli of the olfactory bulb [37••]…”

“…Another study that used immunohistochemistry to study protein expression with the glomeruli of olfactory bulbs also reported significantly decreased synapsin-2a in schizophrenia compare to matched controls. [37••]…”

Disrupted Olfactory Integration in Schizophrenia: Functional Connectivity Study

“…Olfactory bulb volume has been found to be smaller in schizophrenia ( Turetsky et al, 2003 ). A postmortem study showed decreased synaptic efficacy in the olfactory bulb of schizophrenia patients ( Egbujo et al, 2015 ). Smaller olfactory bulb volume has also been seen in first-degree relatives of schizophrenic patients ( Kamath et al, 2011 ).…”

Treating the Synapse in Major Psychiatric Disorders: The Role of Postsynaptic Density Network in Dopamine-Glutamate Interplay and Psychopharmacologic Drugs Molecular Actions

“…Nonetheless, an increasing body of evidence is locating PSD alterations in specific brain sites. In post-mortem brain samples from schizophrenia patients, significant changes in key PSD molecules (i.e., PSD-95, Homer 1a, Homer 1b, Preso) have been demonstrated in multiple brain regions, including the hippocampal CA1 region, the prefrontal cortex, and the olfactory bulb [ 96 ]. Exact delivery of PSD-targeting therapeutic agents in brain subdivisions or cell types implicated in disease pathophysiology may be crucial to maximize pharmacological efficacy and/or minimize untoward effects.…”