so may potentially reverse isolation-induced cognitive impairments. The aims of this study were to utilise protein microarray, immunohistochemical and glutamate microsensor techniques to further characterise isolationinduced hippocampal changes, and examine the ability of a 5-HT6 receptor antagonist, SB-399885, to reverse the neurochemical and behavioural alterations in this model. Male Lister hooded rats (University of Nottingham or Charles River UK) were weaned on post-natal day 21−24 and housed individually or in groups (3−4). Rats received minimal handling until assessment (starting 5−6 weeks later) of locomotor activity, NOD, and contextual and cue-mediated CER. Rats received i.p. vehicle (1% Tween 80, 1ml/kg) or 10mg/kg SB-399885 on six occasions (n = 11/housing-treatment combination) either 30min prior to testing or immediately after CER acquisition to preclude potential nociceptive/affective confounds. Rats were killed 24 h after the final injection and hippocampi collected for quantification of VGLUT1−3 expression using Western blots, cell proliferation using Ki67 immunohistochemistry and expression of intracellular signalling molecules using protein microarray. Glutamate signalling in hippocampal slices from separate groups of drug-free rats (n = 7/housing condition) was measured using enzyme-coated microsensors. Isolation-rearing prevented discrimination of the novel object during NOD (P> 0.05 versus familiar, whereas group-housed P 0.05 versus isolate and group vehicle controls in each case). Isolation also elevated Rac/CDC42 (Rho GTPases which regulate microtubule stabilisation and dendrite morphogenesis, and have been implicated in schizophrenia), while SB-399885 decreased TAK1 and pSTAT3 (members of the SAPK/JNK signalling cascade, whose stimulation via Rac/CDC42 reduces pSTAT3) in isolates only. Isolation tended to lower basal extracellular glutamate in hippocampal slices, from 4.32±1.40mM to 1.99±0.41mM (P= 0.0708), but the combination of 3mM SB-399885 and 120mM KCl stimulated glutamate release irrespective of housing. The 5-HT6 receptor antagonist reversed isolationinduced cognitive impairments and partially reversed deficits in hippocampal cell proliferation in this neurodevelopmental model of schizophrenia. These findings further support the use of 5-HT6 antagonists to treat cognitive dysfunction, and the value of isolation-reared rats to investigate the underlying neurobiology of schizophrenia and evaluate novel treatments for the cognitive symptoms.