Developmental microglial priming in postmortem autism spectrum disorder temporal cortex.

Microglia can shift into different complex morphologies depending on the microenvironment of the central nervous system (CNS). The distinct morphologies correlate with specific functions and can indicate the pathophysiological state of the CNS. Previous postmortem studies of autism spectrum disorder (ASD) showed neuroinflammation in ASD indicated by increased microglial density. These changes in the microglia density can be accompanied by changes in microglia phenotype but the individual contribution of different microglia phenotypes to the pathophysiology of ASD remains unclear. Here, we used an unbiased stereological approach to quantify six structurally and functionally distinct microglia phenotypes in postmortem human temporal cortex, which were immuno-stained with Iba1. The total density of all microglia phenotypes did not differ between ASD donors and typically developing individual donors. However, there was a significant decrease in ramified microglia in both gray matter and white matter of ASD, and a significant increase in primed microglia in gray matter of ASD compared to typically developing individuals. This increase in primed microglia showed a positive correlation with donor age in both gray matter and white of ASD, but not in typically developing individuals. Our results provide evidence of a shift in microglial phenotype that may indicate impaired synaptic plasticity and a chronic vulnerability to exaggerated immune responses.

Serotonergic Markers in Atopic Dermatitis.

Stress and anxiety may worsen atopic dermatitis (AD) through the serotonin system. Serotonergic expression was measured in 28 patients with AD in relation to extent of the disease (SCORing of Atopic Dermatitis; SCORAD), pruritus intensity (visual analogue scale; VAS), anxiety traits (Swedish Universities Scales of Personality; SSP) and depression (Montgomery-Åsberg Depression Rating Scale-Self assessment; MADRS-S). Biopsies were taken from lesional and non-lesional AD skin, and investigated for expression of serotonin, its receptors 5-HT1A and 5-HT2, and serotonin transporter protein (SERT), using immunohistochemistry. 5-HT1AR-immunoreactivity (ir) was higher in lesional skin in apical epidermis and in mast cell-like cells in dermis, and 5-HT2AR-ir in apical epidermis and on blood vessels. In contrast, a basement membrane 5-HT2AR-ir signal was higher in non-lesional skin. The distribution of SERT-ir in the basal epidermal layer was higher in lesional skin. Positive and negative correlations were found between serotonergic markers and SCORAD, inflammation, pruritus intensity, anxiety traits, and depression score, indicating that serotonergic mechanisms are involved in AD.

Contribution of olivofloccular circuitry developmental defects to atypical gaze in autism.

Individuals with autism demonstrate atypical gaze, impairments in smooth pursuit, altered movement perception and deficits in facial perception. The olivofloccular neuronal circuit is a major contributor to eye movement control. This study of the cerebellum in 12 autistic and 10 control subjects revealed dysplastic changes in the flocculus of eight autistic (67%) and two control (20%) subjects. Defects of the oculomotor system, including avoidance of eye contact and poor or no eye contact, were reported in 88% of autistic subjects with postmortem-detected floccular dysplasia. Focal disorganization of the flocculus cytoarchitecture with deficit, altered morphology, and spatial disorientation of Purkinje cells (PCs); deficit and abnormalities of granule, basket, stellate and unipolar brush cells; and structural defects and abnormal orientation of Bergmann glia are indicators of profound disruption of flocculus circuitry in a dysplastic area. The average volume of PCs was 26% less in the dysplastic region than in the unaffected region of the flocculus (p<0.01) in autistic subjects. Moreover, the average volume of PCs in the entire cerebellum was 25% less in the autistic subjects than in the control subjects (p<0.001). Findings from this study and a parallel study of the inferior olive (IO) suggest that focal floccular dysplasia combined with IO neurons and PC developmental defects may contribute to oculomotor system dysfunction and atypical gaze in autistic subjects.

Serotonin and its 5-HT1 receptor in human mastocytosis.

CONTEXT: Human mastocytosis is a rare disease, in which the serotonergic system may be involved. OBJECTIVE: The objective of the present study was to examine the possible presence of serotonin (5-HT) and its 5-HT1A receptor (R) in the skin of patients with mastocytosis. In addition, the effect of the 5-HT1AR was tested on human mastocytosis cells, cultured in vitro. MATERIALS AND METHODS: The expression of 5-HT and 5-HT1AR in patients with urticaria pigmentosa and mastocytoma was studied using immunohistochemistry. The effects of 8-OH-DPAT, an agonist of 5-HT1AR, on the proliferation (cell number), viability, apoptosis, spontaneous release of histamine, as well as a possible 5-HT metabolism, in the human HMC-1 mast cell line, were investigated. RESULTS: Both 5-HT and 5-HT1AR were expressed in the mast cells in biopsies of mastocytoma and urticaria pigmentosa, as well as in HMC-1 cells. However, no metabolism of 5-HT by the cell line could be detected by the methodology used. The 5-HT1AR agonist had no significant effect on the viability and number of HMC-1 cells, and was without effect on the apoptosis. At concentrations of 10⁻6 mol/L and 10⁻8-10⁻¹° mol/L (i.e. also at physiological concentrations), the agonist inhibited histamine release by these cells by as much as 30%. CONCLUSION: These findings indicate that 5-HT and its 5-HT1AR are expressed in human mastocytosis and that an agonist of the 5-HT1AR might be of value in the treatment of these patients.

Clozapine functions through the prefrontal cortex serotonin 1A receptor to heighten neuronal activity via calmodulin kinase II-NMDA receptor interactions.

Aberrant dopamine release in the prefrontal cortex (PFC) is believed to underlie schizophrenia, but the mechanistic pathway through which a widely used antipsychotic, clozapine (Clz), evokes neurotransmitter-releasing electrical stimulation is unclear. We analyzed Clz-evoked regulation of neuronal activity in the PFC by stimulating axons in layers IV and V and recording the electrical effect in the post-synaptic pyramidal cells of layers II and III. We observed a Clz-evoked increase in population spike (PS), which was mediated by serotonin 1A receptor (5-HT(1A)-R), phospholipase Cß, and Ca(2+)/calmodulin-dependent protein kinase II (CaMKII). Immunoblotting demonstrated that the Clz-activation of CaMKII was 5-HT(1A)-R-mediated. Intriguingly, the NMDA receptor (NMDA-R) antagonist (±)2-amino-5-phosphonovaleric acid (APV) eliminated the Clz-mediated increase in PS, suggesting that the 5-HT(1A)-R, NMDA-R and CaMKII form a synergistic triad, which boosts excitatory post-synaptic potential (EPSP), thereby enhancing PS. In corroboration, Clz as well as NMDA augmented field EPSP (fEPSP), and WAY100635 (a 5-HT(1A)-R antagonist), APV, and a CaMKII inhibitor eliminated this increase. As previously shown, CaMKII binds to the NMDA-R 2B (NR2B) subunit to become constitutively active, thereby inducing α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptor recruitment to the post-synaptic membrane and an increase in fEPSP. Co-immunoprecipitation demonstrated that Clz potentiates interactions among CaMKII, NR2B, and 5-HT(1A)-R, possibly in the membrane rafts of the post-synaptic density (PSD), because pretreatment with methyl-ß-cyclodextrin (MCD), an agent that disrupts rafts, inhibited both co-immunoprecipitation as well as fEPSP. In summary, Clz functions in the PFC by orchestrating a synergism among 5-HT(1A)-R, CaMKII, and NMDA-R, which augments excitability in the PFC neurons of layers II/III.

Dystrophic serotonin axons in postmortem brains from young autism patients.

Autism causes neuropathological changes in varied anatomical loci. A coherent neural mechanism to explain the spectrum of autistic symptomatology has not been proposed because most anatomical researchers focus on point-to-point functional neural systems (e.g., auditory and social networks) rather than considering global chemical neural systems. Serotonergic neurons have a global innervation pattern. Disorders Research Program, AS073234, Program Project (JW). Their cell bodies are found in the midbrain but they project their axons throughout the neural axis beginning in the fetal brain. This global system is implicated in autism by animal models and by biochemical, imaging, pharmacological, and genetics studies. However, no anatomical studies of the 5-HT innervation of autistic donors have been reported. Our review presents immunocytochemical evidence of an increase in 5-HT axons in postmortem brain tissue from autism donors aged 2.8-29 years relative to controls. This increase is observed in the principle ascending fiber bundles of the medial and lateral forebrain bundles, and in the innervation density of the amygdala and the piriform, superior temporal, and parahippocampal cortices. In autistic donors 8 years of age and up, several types of dystrophic 5-HT axons were seen in the termination fields. One class of these dystrophic axons, the thick heavily stained axons, was not seen in the brains of patients with neurodegenerative diseases. These findings provide morphological evidence for the involvement of serotonin neurons in the early etiology of autism, and suggest new therapies may be effective to blunt serotonin's trophic actions during early brain development in children.

Increased serotonin axons (immunoreactive to 5-HT transporter) in postmortem brains from young autism donors.

Imaging studies of serotonin transporter binding or tryptophan retention in autistic patients suggest that the brain serotonin system is decreased. However, treatment with drugs which increase serotonin (5-HT) levels, specific serotonin reuptake inhibitors (SSRIs), commonly produce a worsening of the symptoms. In this study we examined 5-HT axons that were immunoreactive to a serotonin transporter (5-HTT) antibody in a number of postmortem brains from autistic patients and controls with no known diagnosis who ranged in age from 2 to 29 years. Fine, highly branched, and thick straight fibers were found in forebrain pathways (e.g. medial forebrain bundle, stria terminalis and ansa lenticularis). Many immunoreactive varicose fine fibers were seen in target areas (e.g. globus pallidus, amygdala and temporal cortex). Morphometric analysis of the stained axons at all ages studied indicated that the number of serotonin axons was increased in both pathways and terminal regions in cortex from autism donors. Our findings provide morphological evidence to warrant caution when using serotonin enhancing drugs (e.g. SSRIs and receptor agonist) to treat autistic children. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'.

Different serotonergic expression in nevomelanocytic tumors.

The neuromediator serotonin (5-hydroxytryptamine; 5-HT) has been proposed to play a role in tumor progression. Thus, the aim of the present investigation was to determine whether alterations in the serotonergic system occur in nevomelanocytic tumors. For this purpose, paraffin-embedded biopsies of superficial spreading malignant melanoma (SSM), dysplastic compound nevi (DN) and benign compound nevi (BCN) were characterized with regard to their expression of 5-HT, the 5-HT1A and 5-HT2A receptors, and the serotonin transporter protein (SERT), by immunohistochemical analysis. Melanocytes in the region surrounding the tumor were found to express both the 5-HT1A and 5-HT2A receptors. Tumor cells that immunostained positively for the different serotonergic markers were observed in the suprabasal epidermis of DN tissue and, to an even greater extent, in the case of SSM. Furthermore, some of these latter cells expressed both 5-HT1AR and 5-HT2AR. The level of expression of 5-HT1AR at the junctional area was lower for SSM than for DN or BCN. As the degree of atypia increased, the intensity of tumor cell staining in the dermis for 5-HT1AR and SERT declined. Vessel immunoreactivity for 5-HT2A was more intense in SSM than in BCN tissue. Round-to-dendritic cells that expressed both SERT and 5-HT1AR were seen to infiltrate into the dermal region of the tumor, this infiltration being more evident in the case of DN and SSM. These latter cells were also tryptase-positive, indicating that they are mast cells. Thus, alterations in serotonergic system may be involved in nevomelanocytic tumors and mast cells may play an important role in this connection.

Dystrophic serotonergic axons in neurodegenerative diseases.

Neurodegenerative diseases such as Parkinson's disease (PD), frontal lobe dementia (FLD) and diffuse Lewy-body dementia (DLBD) have diverse neuropathologic features. Here we report that serotonin fibers are dystrophic in the brains of individuals with these three diseases. In neuropathologically normal (control) brains (n=3), serotonin axons immunoreactive (IR) with antibodies against the serotonin transporter (5-HTT) protein were widely distributed in cortex (entorhinal and dorsolateral prefrontal), hippocampus and rostral brainstem. 5-HTT-IR fibers-of-passage appeared thick, smooth, and unbranched in medial forebrain bundle, medial lemniscus and cortex white matter. The terminal branches were fine, highly branched and varicose in substantia nigra, hippocampus and cortical gray matter. In the diseased brains, however, 5-HTT-IR fibers in the forebrain were reduced in number and were frequently bulbous, splayed, tightly clustered and enlarged. Morphometric analysis revealed significant differences in the size distribution of the 5-HTT-IR profiles in dorsolateral prefrontal area between neurodegenerative diseases and controls. Our observations provide direct morphologic evidence for degeneration of human serotonergic axons in the brains of patients with neurodegenerative diseases despite the limited size (n=3 slices for each region (3) from each brain (4), total slices was n=36) and the lack of extensive clinical characterization of the analyzed cohort. This is the first report of dystrophic 5-HTT-IR axons in postmortem human tissue.

The skin as a mirror of the soul: exploring the possible roles of serotonin.

Serotonin (5-hydroxytryptamine; 5-HT) is an important mediator of bidirectional interactions between the neuroendocrine system and the skin. The rate of synthesis of 5-HT from l-tryptophan can be enhanced by brain-derived neuronal growth factor, cytokines, exposure to ultraviolet light and steroids. The major source of 5-HT in the skin are platelets, which, upon aggregation, release this biogenic amine. Moreover, the epidermal and dermal skin express the enzymes required for the transformation of tryptophan to 5-HT, and certain skin cells, such as melanocytes, have been demonstrated to produce 5-HT. In addition, rodent mast cells produce 5-HT, but human mast cells have not yet been fully examined in this respect. Skin cells express functionally active, membrane-bound receptors for 5-HT, as well as proteins that transport 5-HT. The interactions of 5-HT with these various proteins determines the nature, magnitude and duration of serotonergic responses. The immune and vasculature systems in the skin are traditional targets for bioregulation by 5-HT. Moreover, recent findings indicate that keratinocytes, melanocytes and dermal fibroblasts also respond to this amine in various ways. Thus, mammalian skin is both a site for the production of and a target for bioregulation by 5-HT. This indicates that agonists and antagonists directed towards specific 5-HT receptors could be useful in connection with treatment of skin diseases. Based on our increasing knowledge concerning these receptors and their plasticity, future research will focus on the development of serotonergic drugs that exert metabotrophic effects on the cells of the skin without affecting the central nervous system.

Cajal and brain plasticity: insights relevant to emerging concepts of mind.

The main legacies of Cajal are his drawings of brain structure and their connections, and his ideas of brain plasticity, not only in the mature brain but also during development and after brain injury. As the 21st century begins, many scientists are asking an old question: "how does the brain express the mind?" Although most models of mind incorporate the brain connections produced by Cajal, his ideas of plasticity are largely ignored. The purpose of this chapter is to review how some of Cajal's ideas can be useful in understanding the expression of the mind. I have also introduced several concepts and facts not available during Cajal's life. I cover the concept of homeostasis, the global projections of the monoamine neurons, and the actions of "mind-expanding" drugs. The global projecting neurons, because their monoamine transmitters have such a long history, are considered 1st order systems. The point-to-point connections are considered 2nd order systems. Their importance in theories of functional localization studies is briefly reviewed. Finally, a new model is presented called "Plastic Homeostasis," which incorporates the plastic interactions between 1st and 2nd order neurons. It is hoped that this review will encourage others to study the ideas presented by Cajal when considering functions of the brain. The emerging models of the mind would be well served by a review of the theoretical writing of Cajal.

Serotonergic mechanisms in human allergic contact dermatitis.

Expression of serotonin (5-hydroxytryptamine; 5-HT), 5-HT receptors 1A (5-HT1AR) and 2A, and serotonin transporter protein (SERT) was studied in positive epicutaneous reactions to nickel sulphate in nickel-allergic patients, at 72 h post-challenge with the antigen. In addition, the effects of 5-HT2AR agonist 2,5-dimethoxy-4-iodoamphetamine (DOI), and the selective serotonin reuptake inhibitors (SSRIs) citalopram and fluoxetine, were tested on nickel-stimulated peripheral blood mononuclear cells from nickel-allergic patients, regarding their proliferation and interleukin (IL)-2 production, as well as the effect of these SSRIs on a murine Langerhans' cell-like line (XS52), regarding its IL-1beta production. Serotonin-positive platelets were increased in the inflamed skin compared with control skin. A decrease (p <0.01) in 5-HT1AR-positive mononuclear cells was evident in the eczematous skin compared with control skin, whereas 5-HT2AR- and SERT-positive cells were increased (p <0.001 for both) in the eczematous skin. Treatment of nickel-stimulated peripheral blood mononuclear cells with 5x10(-5) mol/l of DOI inhibited (p <0.01) the proliferation of nickel-stimulated peripheral blood mononuclear cells, while no effect was found regarding IL-2 production. Citalopram at 10(-6) mol/l tended to inhibit the production of IL-1beta by the XS52 cell line. These results indicate the implication of the serotonergic system in the contact allergic reaction.

Antagonist-induced increase in 5-HT1A-receptor expression in adult rat hippocampus and cortex.

Many receptor antagonists function as reverse agonists on the signaling transduction pathway, but little is known about the action of these drugs on the regulation of receptor expression. Serotonin 1A (5-HT1A) receptor expression in 5-HT and serum-free fetal hippocampal cultures is increased in the presence of a specific 5-HT1A-receptor antagonist N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl) cyclohexane carboxamide (WAY 100635). To study the plasticity of postsynaptic 5-HT1A receptors in the presence of antagonist in vivo, adult Sprague Dawley rats were injected i.p. either once or twice daily with a dose of WAY 100635 (3 mg/kg) over a period of 3 days. The 5-HT1A receptor expression was detected by immunocytochemistry and light microscopy, and the receptor immunoreactivity (IR) in hippocampus subregions was quantitatively assessed by using a comparative computer-assisted morphometric analysis. Following the daily injections of WAY 100635, a significant increase in 5-HT1A receptor labeling in hippocampal neurons was recorded. This marked increase in 5-HT1A receptor expression, which occurred within 4 h after a single injection of WAY 100635, is evident on the somata membrane and dendritic processes of hippocampal and cortex layer V neurons. By contrast, no increase in 5-HT1A receptor-IR was observed after multiple daily injections at a low dose (1 mg/kg) of WAY 100635. Our study shows that a single or multiple daily injections of WAY 100635 can result in an increase in 5-HT1A receptor-IR. This increase in labeling is consistent with an enhanced expression of the receptor protein. The action of this "inverse agonist" may have clinical importance in disorders such as depression, epilepsy, and Alzheimer's disease in which 5-HT1A receptor levels are deficient.

Expression of serotonergic receptors in psoriatic skin.

Psoriasis appears to be influenced by stress, which causes release of adrenal hormones. Serotonin, or hormonal actions on serotonin and serotonin receptors, may have a role in psoriasis. Distribution of serotonin receptors was studied in involved and noninvolved skin in patients with psoriasis and compared to normal skin, by using immunohistochemistry and antibodies to 5-HT1A, 5-HT2A and 5-HT3 receptors (R). There was a decreased (P<0.001) number of 5-HT1AR positive cells, the majority being tryptase positive, in involved and noninvolved psoriatic papillary dermis, compared to normal skin. 5-HTlAR expression was also found in the upper part of the epidermis, on vessel walls and on melanocytes. 5-HT2AR expressing papillary mononuclear cells, CD3 positive, were increased (P<0.001 and P<0.01, respectively) in involved and noninvolved psoriatic skin, compared to normal skin, an increase (P<0.01) also being found in the involved compared to noninvolved skin. Expression of 5-HT3R could be found in the basal epidermal layer of noninvolved but not in the involved skin of psoriasis, where it was only found in the acrosyringium. The present findings are compatible with the 5-HT1A and 5-HT2A receptors having antagonistic functions, and raise the possibility of using receptor specific drugs in the treatment of psoriasis.

Gender-specific 5-HT1A receptor changes in BrdU nuclear labeling patterns in neonatal dentate gyrus.

The actions of 5-HT1A receptors on cell proliferation in the rat neonatal dentate gyrus are unknown. We injected a 5-HT1A receptor agonist (ipsapirone) or antagonist (Way 100635) 1 h before injections of BrdU in neonates of both genders between days 2-4, a peak time of dentate gyrus granule cell proliferation. The BrdU immunoreactive (IR) nuclei in the granule cell layer and subgranular zone were examined after 2 weeks. The BrdU-IR nuclear staining patterns were classified as being either diffuse (homogenous dark BrdU-staining throughout the nucleus) or punctate (multiple distinct small stained spots within the nucleus). Most BrdU-labeled nuclei with a diffuse pattern were seen in the subgranular zone while the punctate pattern nuclei were seen within the granular cell layer of the dentate gyrus. 5-HT1A antagonist showed no overall change in absolute number or pattern of labeled nuclei compared to control animals. After a 5-HT1A agonist, there was also no differences in the total number of BrdU-IR nuclei (punctate and diffuse pattern). However, in both genders, the proportion of the BrdU-labeled nuclei showing a punctate compared to diffuse pattern increased: 33% in females and 18% in males. In females, the 5-HT1A receptor agonist increased the number of nuclei showing a punctate pattern by 41%, while in males the 5-HT1A receptor agonist decreased the number of nuclei showing a diffuse pattern by 29%. These results indicate gender-specific 5-HT1A receptor action on the state of nuclear DNA in the cells of the dentate gyrus, without increasing the total number of BrdU-labeled nuclei.

Chronic gliosis induced by loss of S-100B: knockout mice have enhanced GFAP-immunoreactivity but blunted response to a serotonin challenge.

Serotonin (5-HT) can induce a release of intraglial S-100B and produce a change in glial morphology. Because S-100B can inhibit polymerization of glial fibrillary acidic protein (GFAP), we hypothesize that glial reactivity may reflect the loss of intraglial S-100B. Adult male transgenic S-100B homozygous knockout (-/-) mice (KO) and wild-type CD-1 (WT) mice were studied. S-100B-immunoreactivity (IR) was seen in the brain tissue of WT (CD-1) but not S-100B KO (-/-) mice. GFAP-IR was seen in both WT (CD-1) and S-100B KO (-/-) glia cells, but S-100B KO (-/-) GFAP-IR cells appeared larger, darker, and more branched than in WT (CD-1). To compare the response of GFAP-IR cells to 5-HT in S-100B KO (-/-) and WT (CD-1) mice, we injected animals with para-chloroamphetamine (PCA) over 2 days (5 and 10 mg/ml). PCA is a potent 5-HT releaser which can induce gliosis in the rodent brain. In WT (CD-1) mice, the size, branching, and density of GFAP-IR cells were significantly increased after PCA injections. No increase in GFAP-IR activation was seen in the S-100B KO (-/-) after PCA injections. Cell-specific densitometry (set at a threshold of 0-150 based on a scale of 255) in these animals statistically showed an increase in GFAP-IR after PCA injections in WT (CD-1) but not S-100B KO (-/-) mice. These results are consistent with the hypothesis that 5-HT may modulate glial morphology by inducing a release of intracellular S-100B, and this pathway is inoperable in the S-100B KO (-/-).

Differential effects on somatic and reflex development by chronic clomipramine treatment.

The developmental effect of altered 5-HT and NE levels is a subject that requires more attention, especially when considering the increased demand for antidepressive dual reuptake inhibitors. Serotonin and norepinephrine are bioamines that differentially influence the nervous tissue growth. This study investigated the somatic maturation and the ontogeny of reflexes in neonate rats treated from the 1st to the 21st postnatal day (PND) with clomipramine (20 mg/kg sc, daily), a potent monoamine reuptake inhibitor. Indicators of both general body growth (body weight, axis of the head and body lengths) and physical maturation (ear unfolding, auditory conduit opening, eruption of the lower incisors and eye opening) were appraised. Ontogeny of motor and sensory reflexes (righting, free-fall righting--acceleration, negative geotaxis, cliff avoidance, auditory startle response and vibrissa placing) was also observed. The results demonstrated that chronic neonatal treatment with clomipramine alters the somatic growth. However, it did not interfere with the onset time of many physical features and reflexes. These results provide insights into the consequences of dual transmitter during early development.

Serotonin1A receptors at the axon initial segment of prefrontal pyramidal neurons in schizophrenia.

OBJECTIVE: Inhibition mediated by gamma-aminobutyric acid at the axon initial segment of pyramidal neurons appears to be altered in the prefrontal cortex in schizophrenia. This study examined the densities and laminar distribution of axon initial segments labeled with an antibody against the serotonin(1A) (5-HT(1A)) receptor, which also mediates inhibitory regulation of pyramidal neurons, in subjects with schizophrenia. METHOD: The densities and laminar distribution of axon initial segments with 5-HT(1A)-like immunoreactivity were assessed in postmortem tissue from the prefrontal cortex (Brodmann's area 46) of 14 matched triads of subjects with schizophrenia, subjects with major depressive disorder, and comparison subjects with no psychiatric disorder. RESULTS: The relative densities of the labeled axon initial segment in both the superficial and the deep cortical layers did not differ across the three subject groups. CONCLUSIONS: The findings do not support a role for altered serotonin transmission by means of the 5-HT(1A) receptor in dysfunction of prefrontal cortex pyramidal neurons in schizophrenia.