Integrins are transmembrane heterodimeric (αβ) receptors that transduce mechanical signals between the extracellular milieu and the cell in a bidirectional manner. Extensive research has shown that the integrin beta (β) family is widely expressed in the brain and that they control various aspects of brain development and function. Schizophrenia is a relatively common neurological disorder of unknown etiology and has been found to be closely related to neurodevelopment and neurochemicals in neuropathological studies of schizophrenia. Here, we review literature from recent years that shows that schizophrenia involves multiple signaling pathways related to neuronal migration, axon guidance, cell adhesion, and actin cytoskeleton dynamics, and that dysregulation of these processes affects the normal function of neurons and synapses. In fact, alterations in integrin β structure, expression and signaling for neural circuits, cortex, and synapses are likely to be associated with schizophrenia. We explored several aspects of the possible association between integrin β and schizophrenia in an attempt to demonstrate the role of integrin β in schizophrenia, which may help to provide new insights into the study of the pathogenesis and treatment of schizophrenia.

Although a great deal of biological research has been carried out on several psychiatric disorders, it is disappointing to see how little progress has been made in the field of the biology of personality. The authors underline the methodological problems that arise in the investigation of biological substrates of human personality and review both currently available and putative peripheral markers of the central nervous system that might be used in further human studies.

Affective disorders are widely distributed disorders with severe social and economic effects. Strong evidence underlines that effective treatment helps to restore function and quality of life. Unfortunately, patients with major affective disorders respond variably and, at times, unpredictably to different treatments, which underline the need of alternative approaches. Due to the action of most modern antidepressant drugs, serotonergic mechanisms have traditionally been suggested to play major roles in the pathophysiology. However, recent clinical evidence strongly suggests involvement of neurodegenerative pathology in the disease. Since there is accumulating evidence that the novel neurotransmitter NO acts as a neuromodulator, and participate in several sub-cellular processes, such as cellular memory and neuronal toxicity, nitrergic pathways may have an important role in hippocampal degenerative pathology and cognitive deficits seen in patients with affective disorders.

A few clinical and several pre-clinical studies, strongly suggests involvement of the nitric oxide (NO) signalling pathway in these disorders (Harvey 1996). Several of the conventional neurotransmitters, including serotonin, glutamate and GABA, are intimately regulated by NO (Wegener et al. 2000). Interestingly, distinct classes of antidepressants (Imipramine, Tianeptine, Citalopram and Paroxetine) have been found to modulate the NO level in the living rat hippocampus in clinically relevant doses (Wegener et al. 2003). Moreover, our recent work, using selective inhibitors of phosphodiesterase 5, indicate that the whole NO signalling pathway may play a major role in the behavioural and neurochemical effects observed.

The NO system is therefore a potential target for antidepressant and anxiolytic drug action in acute therapy as well as in prophylaxis.

Pentameric ligand-gated ion-channels rapidly transduce synaptic neurotransmitter signals to an electrical response in post-synaptic neuronal or muscle cells and control the neuromusculature of a majority of multicellular animals. A wide range of pharmaceuticals target these receptors including ethanol, nicotine, anti-depressants and other mood regulating drugs, compounds that control pain and mobility and are targeted by a majority of anthelmintic drugs used to control parasitic infection of humans and livestock. Major advances have been made in recent years to our understanding of the structure, function, activity and the profile of compounds that can activate specific receptors. It is becoming clear that these anthelmintic drug targets are not fixed, but differ in significant details from one nematode species to another. Here we review what is known about the evolution of the pentameric ligand-gated ion-channels, paying particular attention to the nematodes, how we can infer the origins of such receptors and understand the factors that determine how they change both over time and from one species to another. Using this knowledge provides a biological framework in which to understand these important drug targets and avenues to identify new receptors and aid the search for new anthelmintic drugs.

Cytokines (e.g. various interleukins and subfamily members, tumor necrosis factors, interferons, chemokines and growth factors) act in the brain as immunoregulators and neuromodulators. Over a decade ago, the integrative article ‘Immunoregulators in the Nervous System’ (Neurosci Biobehav Rev 1991; 15: 185–215) provided a comprehensive framework of pivotal issues on cytokines and the nervous system that recently have been extensively studied. Cytokine profiles in the brain, including cytokine generation and action, have been studied in multiple models associated with neuropathophysiological conditions. These include: (1) acute conditions and disorders such as stroke (cerebral ischemia or infarction and intracranial hemorrhage), traumatic brain injury, spinal cord injury and acute neuropathies; (2) chronic neurodegenerative disorders and chronic conditions, including Alzheimer's disease, Parkinson's disease, neuropathic pain, epilepsy and chronic neuropathies; (3) brain infections, including bacterial meningitis and encephalitis; (4) brain tumors; (5) neuroimmunological disorders per se, such as multiple sclerosis; (5) psychiatric disorders, including schizophrenia and depression; (6) neurological and neuropsychiatric manifestations associated with non- central nervous system (CNS) disorders such as peripheral cancer, liver, kidney and metabolic compromise, and peripheral infectious and inflammatory conditions; and (7) cytokine immunotherapy, which can be accompanied by neuropsychiatric manifestations when administered either via peripheral or brain routes. Cytokine profiles have also been studied in multiple animal models challenged with inflammatory, infectious, chemical, malignant and stressor insults. Essentially data show that cytokines play a pivotal role in multiple neuropathophysiological processes associated with different types of disorders and insults. Cytokine expression and action in the brain shows a different profile across conditions, but some similarities exist. Under a defined temporal sequence, cytokine involvement in neuroprotection or the induction of a deleterious pathophysiological cascade and in resolution/healing is proposed depending on the type of cytokine. In the brain, functional interactions among cytokines, balance between pro-inflammatory and anti-inflammatory cytokines and functional interactions with neurotransmitters and neuropeptides play a pivotal role in the overall cytokine profile, pattern of neuropathophysiological cascades, and quality and magnitude of neuropsychiatric manifestations. In this brief review various selected cytokine-related issues with relevance to the brain are discussed.

The bird visual system includes a substantial projection, of unknown function, from a midbrain nucleus to the contralateral retina. Every centrifugal, or efferent, neuron originating in the midbrain nucleus makes synaptic contact with the soma of a single unique amacrine cell, the target cell (TC). By labeling efferent neurons in the midbrain, we have been able to identify their terminals in retinal slices and make patch-clamp recordings from TCs. TCs generate Na+-based action potentials (APs) triggered by spontaneous EPSPs originating from multiple classes of presynaptic neurons. Exogenously applied glutamate elicited inward currents having the mixed pharmacology of NMDA, kainate, and inward rectifying AMPA receptors. Exogenously applied GABA elicited currents entirely suppressed by GABAzine and therefore mediated by GABAA receptors. Immunohistochemistry showed the vesicular glutamate transporter, vGluT2, to be present in the characteristic synaptic boutons of efferent terminals, whereas the GABA synthetic enzyme, GAD, was present in much smaller processes of intrinsic retinal neurons. Extracellular recording showed that exogenously applied GABA was directly excitatory to TCs and, consistent with this, NKCC, the Cl− transporter often associated with excitatory GABAergic synapses, was identified in TCs by antibody staining. The presence of excitatory retinal input to TCs implies that TCs are not merely slaves to their midbrain input; instead, their output reflects local retinal activity and descending input from the midbrain.

Tritiated neurotransmitter candidates were unilaterally injected in visual cortical regions with abundant corpus callosum connections. D-aspartate (Asp) or gamma-aminobutyric acid (GABA) was injected along the area 17/18 border in cat, and the area 17/18a and 17/18b borders in rat. Retrograde Asp label was found contralaterally in supragranular and infragranular laminae in areas 17, 18, 19, PMLS, and PLLS in cat, and in areas 29, 18b, 17, and 18a in rat. No contralateral GABA label was found in cat or rat. Thus, the cat and rat corpus callosum may use Asp or a related substance as a neurotransmitter.

γ-aminobutyric acid (GABA) has been reported to be an important neurotransmitter in the retinas of many species. This immunocytochemical study detailed the localization of antigens resembling GABA and glutamic acid decarboxylase (GAD, an enzyme involved in the synthesis of GABA), in retinal neurons in the turtle, Pseudemys scripta elegans. GABA-like immunoreactivity was present within somata in the inner and outer regions of the inner nuclear layer, within somata in the ganglion cell layer, and in processes in the outer plexiform layer, inner plexiform layer, and ganglion cell axon layer. GAD-like immunoreactivity was found in somata in the inner and outer regions of the inner nuclear layer and in processes in the inner and outer plexiform layers. Cell counts indicated more somata with GABA-like than GAD-like immunoreactivity in the inner nuclear layer. Double-label studies showed that every somata in the inner nuclear layer which had GAD-like immunoreactivity also had GABA-like immunoreactivity, but that many somata had only GABA-like immunoreactivity.

The stratification of immunoreactivity within the inner plexiform layer was analyzed using a scanning densitometer. We described the strata within the inner plexiform layer such that S0 represented the inner nuclear layer/inner plexiform layer border and S100 represented the inner plexiform layer/ganglion cell layer border. Analysis of GAD-like labeling yielded seven distinct strata with peak densities at positions S8, S19, S28, S42, S59, S75, and S93. GABA-like labeling provided five distinct strata with peak densities at positions S17, S28, S67, S84, and S95. The strata with peaks of GABA-like immunoreactivity at S17 and S28 were in statistically identical locations to corresponding strata with GAD-like immunoreactivity. The strata with GABA-like immunoreactivity at S67, S84, and S95 did not have statistically identical peaks of correlated GAD-like immunoreactivity, although there were corresponding strata with GAD-like immunoreactivity nearby. Antiserum directed against GABA failed to produce labeled strata at positions corresponding to the strata with GAD-like immunoreactivity at S8 and S42.

In summary, our results indicated that the antisera we used, which were directed against GABA and GAD, produced significantly different labeling in the inner nuclear layer, inner plexiform layer, and the ganglion cell body and axon layers of the turtle retina. Until the physiological significance of these differences is resolved, studies employing these markers to investigate the function of GABA in the turtle retina should be interpreted with caution.

A class 1 aldehyde dehydrogenase (ALDH) catalyzes oxidation of retinaldehyde to retinoic acid in bovine retina. We used immunocytochemistry and in situ hybridization to localize this enzyme in adult and fetal bovine retinas. Specific ALDH immunoreactivity was present in the cytoplasm of wide-field amacrine cells restricted in distribution to the dorsal part of the adult retina. The somata diameters ranged from ∼8 μ to ∼15 μ, and the cells increased in density from ∼125 cells/mm2 near the horizontal meridian to ∼425 cells/mm2 in the superior far periphery. The ALDH-positive cells had somata on both sides of the inner plexiform layer (IPL) and processes in two IPL strata. The majority of ALDH-positive cells were unreactive with antibodies against known amacrine cell enzymes and neurotransmitters, including GABA and glycine. The ALDH-positive amacrine cells also did not react with anti-cellular retinoic acid-binding protein, which was present in a subset of GABA-positive amacrine cells. In flat-mounted retinas processed by in situ hybridization, the larger ALDH-positive amacrine cells tended to be more heavily labeled. In addition to amacrine cells, Müller cell processes in the inner retina were weakly immunoreactive for ALDH; however, these glial cells did not contain ALDH mRNA. The pattern of ALDH expression in fetal bovine retinas was documented by immunocytochemistry. No ALDH reactivity was found before 5.5 months; for the remainder of the fetal period, ALDH immunoreactivity was present in amacrine cells similar to those in adult retina. The ALDH-positive amacrine cells in bovine retina are novel, being limited in distribution to the dorsal retina and unlabeled with other amacrine cell-specific markers. Identification of ALDH in amacrine cells provides additional evidence that cells of the inner retina are involved in retinoid metabolism.

The inhibitory amino-acid neurotransmitter, gamma-aminobutyric acid (GABA), was localized in the pure cone retina of the lizard Anolis carolinensis by autoradiographic and immunocytochemical techniques. Uptake of [3H]-GABA labeled horizontal cells, amacrine cells, numerous cells in the ganglion cell layer, both plexiform layers, and the nerve fiber layer. Label in the inner plexiform layer showed distinct lamination.

The pattern of GABA immunoreactivity was similar to the pattern of [3H]-GABA uptake, although some differences, particularly in labeling of amacrine and ganglion cells, were observed. Immunocytochemistry revealed endogenous stores of GABA in a set of horizontal cells, amacrine cells, and cells in the ganglion cell layer. Both plexiform layers were labeled by the GABA antisera. Labeling in the inner plexiform layer (IPL) was highly stratified and GABA-immunoreactive strata were present in both sublaminae a and b. Six subtypes of conventionally placed GABA-immunoreactive amacrine cells and one displaced amacrine cell subtype were identified. Three of the six conventional amacrine cell subtypes were of pyriform morphology and three subtypes were of multipolar morphology. GABA-immunoreactive interstitial cells also were observed.

Under certain conditions the GABA antiserum labeled the cones. Etching the resin eliminated cone labeling, suggesting that GABA in the cones is present in a labile pool, unlike GABA in horizontal or amacrine cells, or the observed labeling was not due to endogenous GABA. Cones did not demonstrate [3H]-GABA uptake.

Neurons likely to utilize glycine (GLY) as a neurotransmitter were identified immunocytochemically in the “all-cone” lizard retina and the basic anatomical organization of the retinal GLY and gamma-aminobutyric acid (GABA) systems was compared. Four types of GLY-immunoreactive (GLY-IR) neurons were identified. Most GLY-IR cells were amacrine cells, which comprised at least two types. GLY-IR interplexiform cells and ganglion cells also were identified. The first GLY-IR amacrine cell type was characterized by a small pyriform soma, located distal to the border of the inner plexiform layer (IPL), and fine dendrites. Most GLY-IR amacrine cells were of this type and several subtypes may exist within this group. The second amacrine cell type was characterized by a large, distally located soma and a large descending process. This amacrine cell type showed colocalization of GLY-IR and GABA-IR and comprised about 4% of the total GLY-IR amacrine cell population.

Comparison of GLY-IR and GABA-IR on serial sections showed that GLY and GABA were present in largely separate neuronal populations. Generally, GLY-IR amacrine cells were smaller, more distally located in the inner nuclear layer and had finer dendrites than GABA-IR amacrine cells. Distribution of GLY-IR and GABA-IR in the outer plexiform layer and the inner plexiform layer differed considerably.

Based on the segregated distribution of GLY-IR and GABA-IR in the synaptic layers of the lizard retina, GLY and GABA may have fundamentally different roles in retinal processing.

Immunocytochemical and autoradiographic methods were used to identify neurons in the pure cone retina of the lizard (Anolis carolinensis) that are likely to employ glutamate (GLU) or aspartate (ASP) as a neurotransmitter.

GLU immunocytochemistry demonstrated high levels of endogenous GLU in all cone types and numerous bipolar cells. Moderate GLU levels were found in horizontal and ganglion cells. Müller cells and most amacrine cells had very low GLU levels. GLU immunoreactivity (GLU-IR) in the cones was present from the inner segment to the synaptic pedicle. A large spherical cell type with moderate GLU-IR was identified in the proximal inner plexiform layer (IPL). These cells also contain ASP and have been tentatively identified as amacrine cells. Uptake of [3H]-L-GLU labeled all retinal layers. All cone types and Müller cells sequestered [3H]-D-ASP, a substrate specific for the GLU transporter.

Anti-ASP labeling was observed in cones, horizontal cells, amacrine cells, and cells in the ganglion cell layer. ASP immunoreactivity (ASP-IR) in the cones was confined to the inner segment. One ASP-containing pyriform amacrine cell subtype ramifying in IPL sublamina b was identified.

Analysis of GLU-IR, ASP-IR, and GABA-IR on serial sections indicated that there were two distinct populations of horizontal cells in the Anolis retina: one containing GABA-IR, GLU-IR, and ASP-IR; and another type containing only GLU-IR and ASP-IR. Light GLU-IR was frequently found in GABA-containing amacrine cells but ASP-IR was not.

The distinct distributions of GLU and ASP may indicate distinctly different roles for these amino acids. GLU, not ASP, is probably the major neurotransmitter in the cone-biploar-ganglion cell pathway of the Anolis retina. Both GLU and ASP are present in horizontal cells and specific subpopulations of amacrine cells, but it is unclear if GLU or ASP have a neurotransmitter role in these cells.

Immunocytochemical methods were used to visualize glutamate immunoreactivity in the cat retina and to compare its localization with that of aspartate, GABA, and glycine. The cellular and subcellular distribution of glutamate was analyzed at the light-microscopic level by optical densitometry and at the electron-microscopic level by immunogold quantification. The findings were consistent with the proposed role for glutamate as the neurotransmitter of photoreceptors and bipolar cells as particularly high concentrations of staining were found in synaptic terminals of these cells. Ganglion cells were also consistently stained. Aspartate was totally colocalized with glutamate in neuronal cell bodies but the synaptic levels of aspartate were much lower than for glutamate. In addition to the staining of photoreceptor, bipolar, and ganglion cells, glutamate immunoreactivity was also observed in approximately 60% of the amacrine cells. These cells exhibited colocalization with either GABA or glycine. The elevated levels of Glu in amacrine cells may reflect its role as a transmitter precursor in GABAergic cells and as an energy source for mitochondria in glycinergic cells.