Hippocampal synaptophysin gene expression in schizophrenia

217

The uptake of [jH] dopamine by platelets-rich plasma (PRP) from 116 neuroleptic free individuals (13 schizophrenics, 13 schizophreniform. 17 patients admitted to hospital with various diagnoses and 73 controls) was measured. The uptake of [3H] dopamine was measured after incubating PRP with varying concentrations (25 to 200 nh4) of [‘HI dopamine for 30 mins at 37°C. Under these conditions uptake was saturable and fitted the Lineweaver-Burk plot from which Km and Vmax were calculated. The Km and Vmax for t3H] dopamine uptake by PRP from the schizophreniform subjects was significantly lower than that for the control group (Km 334tiO6 vs 1052+1142 nM, Vmax l.m.8 vs 3.653.6 pmol/lO” platelets/30min: p-&005). In addition, uptake of [‘HI dopamine by PRP from 9 schizophrenic, 13 schizophreniform and 17 other patients in their fourth week of treatment was measured. Km was increased for the schizophrenic (230%) and schiiophreniform (120%) groups but decreased for the other patients (-50%). Similarly, there was increases in Vmax for the schizophrenic (492%) and schizophreniform (236%) group but a significant decrease in Vmax for the other patients (-46%). Thus, [3H] dopamine uptake by PRP seems to be treatment responsive and to change differentially in schizophrenic and schizophreniform subjects.

CORRELATION OF SCHIZOPHRENIC POSITIVE SYMPTOMS TO PERIPHERAL SEROTONIN MARKERS Bruce Diamond*,

Sarita

Shartna,

Richard

THE SPECIFIC ACTIVITY OF SYNAPSIN BUT NOT SYNAPTOPHYSIN IS GREATLY REDUCED IN THE BRAINS OF SOME SCHIZOPHRENICS Ellen M. Dudek, Sherry Michael D. Browning

Leonard,

Robert F. Freedman,

Department of Pharmacology, University of Colorado Health Sciences Center, Denver, CO, USA We have demonstrated recently that the specific activity of synapsins I and IIb was greatly reduced in the hippocampus of 4 of 6 schizophrenic brains we examined (Sot Neurosci. Abs. 1992, 18:571). The synapsin proteins are synaptic vesicle-associated phosphoproteins that regulate transmitter release and may play a role in forms of synaptic plasticity thought to underlie normal cognitive function. Thus the low levels of synapsin in the brain of some schizophrenics could reflect a deficiency in synapsin regulation of transmitter release and synaptic plasticity or it could simply reflect loss of synapses concomitant with the neuronal pathology commonly seen in schizophrenia. To evaluate these possibilities we examined the levels of another synaptic marker protein, the integral vesicle associated protein synaptophysin. We found that the specific activity of synaptophysin in hippocampi from postmortem schizophrenic brains was virtually identical to that seen in control material. These data suggest that the low concentration of the synapsins seen in some schizophrenic brains is not due to some generalized loss of synapses. Rather our data suggest that some schizophrenics may be deficient in synapsin regulation of transmitter release. Such a deficiency could underlie, in part, the cognitive and sensory impairment seen in some schizophrenics.

Borison

Psychiatry Service 116A-D, VAMC Augusta GA 30904-6285, USA The advent of new atypical antipsychotic drugs with serotonergic properties that are effective for not only positive but negative symptoms of schizophrenia (e.g. clozapine, risperidone) has altered the dopamine theory of schizophrenia. Recent fmdings suggest a role for serotonin in the symptomatology associated with schizophrenia. It was the aim of this study to determine if a peripheral marker, namely 3H-imipramine platelet binding would correlate with either positive or negative symptomatology. After signing informed consents, schizophrenic patients were washed out for at least 4 days and challenged with oral fenfluramine (60 mg), a drug that releases serotonin. Platelets were collected before and 4 hours after fenfluramine challenge. This procedure was repeated again 17 days after haloperidol treatment. Platelet ‘H-imipramine binding was performed using the WHO protocol. SH-imipramine binding increased after fenfluramine (Bmax 671 to 1066). and this increase was prevented by haloperidol treatment. There was no effect on affinity of this binding (Kd values) by any treatment. The increase in ‘H-imipramine binding following the fenfluramine challenge correlated with an increase in positive symptomatology only. These results suggest that not only is serotonin involved but that peripheral indices of serotonin may be an early indicator of schizophrenic worsening.

HIPPOCAMPAL SYNAPTOPHYSIN EXPRESSION IN SCHIZOPHRENIA S.L. Eastwood, P.J. Harrison*

P. Falkai,

B. Bogerts,

R.W.

GENE

Kerwin,

univ. Dept. Psychiatry, Warneford Hospital, Oxford 0x3 UK

7JX,

It has been hypothesised that the schizophrenic disease process may involve aberrant development or pruning of synapses within the medial temporal lobe and connected structures. Synaptophysin is a presynaptic vesicle protein whose distribution and abundance has been shown to provide a useful indicator of synaptic density. We have used in situ hybridization with a 35Slabelled synthetic oligonucleotide probe to compare the location and amount of messenger RNA (mRNA) encoding synaptophysin in the right and left hippocampus in schizophrenics (n=6) with normal controls (n=5). Experimental methods and image analysis were as described [l]. No differences or consistent asymmetries were found in synaptophysin mRNA levels in the cases of schizophrenia in any hippocampal subfields or in the parahippocampal gyms. It is

218

concluded that synaptic density, as reflected by expression of synaptophysin, is unlikely markedly to be altered in these areas in schizophrenia. The hypothesis of quantitative differences in synapse numbers in schizophrenia is therefore not supported by these data. However, it remains possible that other synaptic parameters might be affected without changes in synaptophysin mRNA. [l] Harrison 271-312

PJ, Pearson

Acknowledgment: Stanley Foundation

RCA (1990)

Prog

Neurobiol

We are indebted to the Theodore for support.

34:

and Vada

ASYMMETRY OF GENE EXPRESSION IN HUMAN PARAHIP POCAMPAL GYRUS Sharon L. Eastwood

and Paul J. Harrison*

Univ. Dept. Psychiatry, UK

Warneford Hospital, Oxford, OX3 7JX,

Asymmetries exist in certain morphological and neurochemical parameters between right and left human cerebral hemispheres. There are also indications that schizophrenia may preferentially affect the left temporal lobe. With the extension of gene expression studies to schizophrenia, it is thus important to determine if there are asymmetries of gene expression in human brain. The amount of polyadenylated messenger RNA (polyA+mRNA) was examined bilaterally in medial temporal lobe, striate cortex and cerebellum, using in situ hybridization detection of poly(A) tails of mRNA as described [l]. Nine neurologically normal brains were used (age 47-84~); no information about handedness was available. PolyA+mRNA content was found to be higher (p=O.O2, paired t-test; 35% in OD units) in the right parahippocampal gyms (PHG) than the left. There were no significant differences be-

tween left and right in any other region. Levels of mRNA are in general proportional

to protein synthetic rates. Thus, the data suggest that neurons in the right PHG are more metabolically active than those on the left. Elevated poly(A)+mRNA may reflect greater expression of all mRNAs or selective enhancement of particular transcripts. The cause of the left-right difference remains unknown but may relate to differential afferent or efferent connectivity. These data provide another indication of functional asymmetry in an area implicated in the pathogenesis of schizophrenia. [l] Harrison

PJ et al (1991) Psycho1 Med 21: 855-866

Acknowledgment: port.

To the Stanley Foundation

EVIDENCE AGAINST DEPOLARIZATON BLOCK HYPOTHESIS OF THE MECHANISM OF ACTION OF ANTIPSYCHOTIC DRUGS: EFFECTS OF TETRODOTOXIN INFUSION INTO THE MEDIAN FOREBRAIN BUNDLE AFTER ACUTE AND CHRONIC NEUROLEPTIC TREATMENT Michael F. Egan, Stanislaw J. Chrapusta, Farouk Karoum, Richard J. Wyatt NIMH Neuroscience Research Center at St. Elizabeth’s, M.L. King Jr. Ave, SE, Washington, DC 20032, USA

2700

The delayed therapeutic effects of antipsychotic agents has been attributed to depoltizaton inactivation (DI) of dopaminergic neurons and concomitant reduction in dopamine release. Several studies have suggested that the hypothesized reduction in dopamine release may not occur. perhaps due to impulse flow independent release. We examined impulse-dependent dopamine release during DI by infusing tetrodotoxin (‘ITX) was infused into the left medial forebrain bundle (MFB) of Sprague Dawley rats. 3-Methoxytyramine (3MT) accumulation 10 min after pargyline (75 m&g i.p.) was used as an index of dopamine release. Dose response and time course studies showed that lTX infusion consistently reduced left-sided striatal 3MT accumulation by 70% in the shiatum and 50% to 60% in the nucleus accumbens. Effects on prefrontal cortex were reduced by only 21% to 33%. For chronic studies, rats were treated with intraperitoneal injections of vehicle or haloperidol (0.4 mg/kg) for 21 days, and killed 1 hr after final injections. ‘ITX infusions (10 FM, 30 min before sacrifice), reduced left-sided striatal 3MT accumulation by approximately 70% in the striatum and 53% lo 59% in the accumbens after one or 21 daily injections of haloperidol. Slight reductions (16-32%) in the prefrontal cortex were not significant. These data suggest that there is no difference in the percent of dopamine release mediated by impulse flow after acute or chronic neuroleptic administration. This data does not support the notion that DI mediates the antipsychotic effects of neuroleptics by reducing total dopamine release or increasing impulse flow independent release. DI could reduce psychotic symptoms by altering the responsiveness of the dopamine system to external stimuli. Alternatively DI may normalize dopamine levels that are elevated during psychotic episodes.

RECEPTOR BINDING (Dl, D2, 5HT2, SHTlC) AFFINITIES FOR TYPICAL AND ATYPICAL ANTIPSYCHOTIC DRUGS IN CLONED RECEPTOR MEMBRANES D.L. Evans, G.S. Gill, P.G. Zaworski, M.W. Smith, R.M. Huff, R.A. Lahti*

for generous supUpjohn Laboratories,

Kalamazoo,

MI 49001, USA