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S002-3

The CRC for Mental Health Psychoses Biomarker Discovery Program

Brian Dean

NHMRC Senior Research Fellow The Florey Insititute of Neuroscience and Mental Health Director, The Victorian
Brain bank Network The University of Melbourne, Australia

Background/Objective: Treatment resistance remains a significant problem in the clinical
management of schizophrenia but there is now increasing evidence that targeting specific muscarinic
receptors with agonists or allosteric modulators can reduce the severity of symptoms associated with
the disorder.

Method: Our previous findings have identified a subgroup of muscarinic receptor deficit
schizophrenia (MRDS). Along this line of evidence, we aimed to better understand the changes in
muscarinic receptors in the caudate putamen from subjects with schizophrenia and whether the
sub-group of individuals with MRDS were identifiable by a marked loss of [3H]pirenzepine binding
in that central nervous system region. Hence, we measured levels of [3H]pirenzepine binding and
[3H]AF-DX 384 binding to caudate putamen from subjects with schizophrenia which contained
tissue from subjects with MRDS and caudate putamen from age / sex matched subjects with no
history of psychiatric disorders (controls). In addition, we measured binding of [3H]4DAMP using a
methodology that made that radioligand highly selective for the muscarinic M3 receptor. Further, to
determine if changes in radioligand binding may be due to loss of pre- or post-synaptic neurons we
measured levels of 25 kilodalton synaptosomal-associated protein (SNAP25) and postsynaptic
density protein 95 (PSD95), respectively.

Result: We also measured levels of glial fibrillary acidic protein (GFAP) 41 and 43 as a surrogate
measure of astrocytic number. In this talk, we will present the findings of lower levels of
[3H]pirenzepine and [3H]AF-DX 384, but unchanged [3H]4DAMP, binding to caudate putamen
from subjects with schizophrenia which is predominantly due to a lower binding to that tissue from a
sub-set of subjects defined by their loss of cortical muscarinic receptors.

Conclusion: In addition we will report higher levels of PSD 95 in caudate putamen from subjects
with schizophrenia which appeared more prominent in subjects with MRDS. Levels of SNAP 25 and
GFAP 41 and 43 were unchanged.