Levels of mRNAs encoding synaptic vesicle and synaptic plasma membrane proteins in the temporal cortex of elderly schizophrenic patients

Abstract

Background: Electron microscopy and biochemical studies indicate that developmental abnormalities in synaptic organization may be present in brains of schizophrenic patients. This study determined whether these synaptic abnormalities are reflected in differential or uniform alterations in the expression of various synaptic protein genes in the left superior temporal gyrus of schizophrenic patients.

Methods: Levels of mRNAs encoding four synaptic vesicle proteins (synaptotagmin I [p65], rab3a, synaptobrevin 1, and synaptobrevin 2) and two synaptic plasma membrane proteins (syntaxin 1A and SNAP-25) were measured postmortem in the left superior temporal gyrus from elderly (58–95 years) schizophrenic patients (n = 14) and age-matched control subjects (n = 9).

Results: There were significant negative correlations between age and levels of synaptotagmin I (p65), rab3a, synaptobrevin 1, SNAP-25, and syntaxin 1A mRNAs in schizophrenic patients (−.692 <r < −.517, .003 <p < .030) but not in control subjects. Levels of all six synaptic mRNAs studied were increased in the younger (58–79 years) subgroup of schizophrenic patients compared to control subjects and older (80–95 years) subgroup of schizophrenic patients.

Conclusions: That similar abnormalities were found for mRNAs encoding different synaptic vesicle and synaptic plasma membrane proteins suggests that they reflect overall neurodevelopmental abnormalities in synaptic connectivity in the temporal cortex of schizophrenic patients rather than changes in the number of synaptic vesicles per synapse or abnormalities in a specific synaptic function.

Introduction

Synaptic abnormalities may be involved in various sensory processing deficits associated with schizophrenia (Feinberg 1982). Electron microscopy studies have revealed ultrastructural changes in the synaptic organization of some brain regions of schizophrenic patients Miyakawa et al 1972, Ong and Garey 1993, Soustek 1989. Consistent with these data are biochemical findings indicating that region, age, and gene-specific abnormalities in expression of some synaptic proteins may be present in brains of schizophrenic patients. These studies have shown a pattern of synaptic protein disregulation with the levels of different synaptic proteins increased, decreased, or unchanged in different brain regions Browning et al 1993, Eastwood et al 1995, Eastwood and Harrison 1995, Glantz and Lewis 1997, Karson et al 1999, Thompson et al 1998.

In one series of studies increased concentrations of synaptophysin, as well as two other synaptic proteins (SNAP-25 and syntaxin), were revealed in cingulate cortex from a group of chronically hospitalized elderly schizophrenic patients (Gabriel et al 1997). A subsequent mRNA study in the same cohort of elderly schizophrenic patients provided further evidence that the expression of synaptic protein genes may be increased in some cortical regions of schizophrenic patients, but only in a subgroup of patients younger than 75 years (Tcherepanov and Sokolov 1997). Levels of mRNAs encoding three synaptic vesicle-associated proteins (synaptophysin, synapsin 1A, and synapsin 1B) were increased in the temporal cortex (Brodmann’s areas 21 and 22) of 52–73-year-old schizophrenic patients, compared to age matched control subjects, and declined significantly with age in schizophrenic patients, but not in control subjects. Coordinated age-associated alterations in expression of mRNAs encoding three major synaptic proteins (synaptophysin and synapsin 1A and synapsin 1B) were hypothesized to indicate overall age-related alterations in synaptic function in the temporal cortex of elderly schizophrenic patients (Tcherepanov and Sokolov 1997). It remains unclear, however, whether these alterations reflect overall abnormalities in synaptic density/activity or whether they are restricted to some specific synaptic functions or structures. For example, synaptophysin and synapsin 1 are localized solely to synaptic vesicles; thus, changes in their expression may reflect abnormalities in the number of synaptic vesicles per synapse rather than in the number of synapses.

One way to address these questions is to examine expression of other synaptic protein genes in brains of schizophrenic patients. Different synaptic proteins have different functions and localization in nerve terminals (synaptic vesicles or synaptic plasma membrane) and are differentially expressed in different neurons Jahn and Sudhof 1994, Oyler et al 1989, Sudhof 1995, Ullrich and Sudhof 1995. Therefore, differential alterations of different synaptic protein genes may reveal abnormalities in a specific synaptic function/structure and in specific subclasses of synapses. Alternatively, similar abnormalities in expression of many synaptic protein genes may indicate a general failure of synaptic function or a generalized reduction in synaptic specializations.

This study used measurements of mRNAs encoding four synaptic vesicle proteins (synaptotagmin I [p65], rab3a, synaptobrevin 1, synaptobrevin 2) and two synaptic plasma membrane proteins (syntaxin 1A and SNAP-25) to address the question of whether levels of these synaptic protein mRNAs were differentially or uniformly altered in elderly schizophrenic patients who had previously been found to have abnormal levels of some other synaptic protein mRNAs and synaptic proteins Gabriel et al 1997, Tcherepanov and Sokolov 1997. The superior temporal gyrus was chosen for study because of multiple studies showing structural abnormalities in this region in schizophrenia and suggesting a role for this region in the mediation of thought disorders and auditory hallucinations Barta et al 1997, Hirayasu et al 1998, Levitan et al 1999, Menon et al 1995, Nestor et al 1993, Pearlson 1997, Pearlson et al 1996, Penfield and Perot 1963, Ross and Pearlson 1986, Shenton et al 1992.