We have previously identified reductions in mean pyramidal cell somal volume in deep layer 3 of BA 41 and 42 and reduced axon terminal density in deep layer 3 of BA 41. In other brain regions demonstrating similar deficits, reduced dendritic spine density has also been identified, leading us to hypothesize that dendritic spine density would also be reduced in BA 41 and 42. Because dendritic spines and their excitatory inputs are regulated in tandem, we further hypothesized that spine density would be correlated with axon terminal density. We used stereologic methods to quantify a marker of dendritic spines, spinophilin-immunoreactive (SP-IR) puncta, in deep layer 3 of BA 41 and 42 of 15 subjects with schizophrenia, each matched to a normal comparison subject. The effect of long-term haloperidol exposure on SP-IR puncta density was evaluated in nonhuman primates. SP-IR puncta density was significantly lower by 27.2% in deep layer 3 of BA 41 in the schizophrenia subjects, and by 22.2% in deep layer 3 of BA 42. In both BA 41 and 42, SP-IR puncta density was correlated with a marker of axon terminal density, but not with pyramidal cell somal volume. SP-IR puncta density did not differ between haloperidol-exposed and control monkeys. Lower SP-IR puncta density in deep layer 3 of BA 41 and 42 of subjects with schizophrenia may reflect concurrent reductions in excitatory afferent input. This may contribute to impairments in auditory sensory processing that are present in subjects with schizophrenia.

Reductions in dendritic arbor length and complexity are among the most consistently replicated changes in neuronal structure in post mortem studies of cerebral cortical samples from subjects with schizophrenia, however, the underlying molecular mechanisms have not been identified. This study is the first to identify an alteration in a regulatory protein which is known to promote both dendritic length and arborization in developing neurons, Kalirin-9. We found Kalirin-9 expression to be paradoxically increased in schizophrenia. We followed up this observation by overexpressing Kalirin-9 in mature primary neuronal cultures, causing reduced dendritic length and complexity. Kalirin-9 overexpression represents a potential mechanism for dendritic changes seen in schizophrenia.

Psychosis in Alzheimer disease differentiates a subgroup with more rapid decline, is heritable, and aggregates within families, suggesting a distinct neurobiology. Evidence indicates that greater impairments of cerebral cortical synapses, particularly in dorsolateral prefrontal cortex, may contribute to the pathogenesis of psychosis in AD phenotype. Soluble β-amyloid induces loss of dendritic spine synapses through impairment of long term potentiation. In contrast, the Rho GEF kalirin is an essential mediator of spine maintenance and growth in cerebral cortex. We therefore hypothesized that psychosis in AD would be associated with increased soluble β-amyloid and reduced expression of kalirin in the cortex. We tested this hypothesis in postmortem cortical gray matter extracts from fifty-two AD subjects with and without psychosis. In subjects with psychosis, the β-amyloid1-42/β-amyloid1-40 ratio was increased, due primarily to reduced soluble β-amyloid1-40, and kalirin-7, -9, and -12 were reduced. These findings suggest that increased cortical β-amyloid1-42/β-amyloid1-40 ratio and decreased kalirin expression may both contribute to the pathogenesis of psychosis in AD.

Alzheimer disease with LB is associated with selective alterations in dopamine receptor density, which may contribute to the distinct clinical profile of this group. The D3 receptor may be an important target of neuroleptic treatment of psychosis in AD.

Suicide has been associated with decreased serotonin transmission. Measurement of concentrations of serotonin, its precursors tryptophan (TRY) and 5-hydroxytryptophan (5-HTP) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA), have been used as indices of serotonin activity, and with serotonin transporter binding, are indices of the integrity of serotonin nerve terminals. Most previous studies have not distinguished high affinity transporter binding from a very similar nontransporter binding site, where binding is not dependent on Na+ or Cl- and that does not have a known functional role. We therefore, assayed binding kinetics in prefrontal (PFC) and temporal cortex (TC) in matched pairs of suicide victims and controls using the selective ligand 3H-paroxetine, and employing 1 microM sertraline to define specific binding to the transporter and 10 microM sertraline which also displaces binding to the high affinity, nontransporter site. In addition, we measured concentrations of TRY, 5-HTP, serotonin and 5-HIAA in the same brain areas. The total number of 3H-paroxetine transporter and nontransporter binding sites (Bmax), was lower in the suicide group compared to controls in both Brodmann area 9 (prefrontal cortex; p = 0.02) and in Brodmann area 38 (temporal cortex, p = 0.01). In contrast, no differences were found in the number of high affinity transporter binding sites and concentrations of serotonin, 5-HIAA, 5-HTP or TRY (p > 0.05). We conclude that the number of serotonin transporter sites is not altered in Brodmann area 9 in suicide, and that fewer 3H-paroxetine and 3H-imipramine binding sites found in this region of cerebral cortex of suicides may be explained by a reduction in the nontransporter binding sites.