Evidence for decreased DARPP-32 in the prefrontal cortex of patients with schizophrenia.

Background: The neurotransmitters dopamine and glutamate have been implicated in the prefrontal dysfunction associated with schizophrenic illness. Studies suggest that the D1 subclass of dopamine receptor and the N-methyl-D-aspartate subclass of glutamate receptor are involved in this prefrontal dysfunction. These 2 receptors regulate, in opposing directions, the amount of phosphorylated activated DARPP-32, a potent inhibitor of protein phosphatase 1 that modulates the activity of several classes of receptors and ion channels.

Brain-derived neurotrophic factor is essential for opiate-induced plasticity of noradrenergic neurons.

Chronic opiate exposure induces numerous neurochemical adaptations in the noradrenergic system, including upregulation of the cAMP-signaling pathway and increased expression of tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine biosynthesis. These adaptations are thought to compensate for opiate-mediated neuronal inhibition but also contribute to physical dependence, including withdrawal after abrupt cessation of drug exposure. Little is known about molecules that regulate the noradrenergic response to opiates.

Neurotrophin-3 promotes cell death induced in cerebral ischemia, oxygen-glucose deprivation, and oxidative stress: possible involvement of oxygen free radicals.

To explore the role of neurotrophin-3 (NT-3) during cerebral ischemia, NT-3-deficient brains were subjected to transient focal ischemia. Conditional mutant brains produced undetectable amounts of NT-3 mRNA, whereas the expression of the neurotrophin, BDNF, the NT-3 receptor, TrkC, and the nonselective, low-affinity neurotrophin receptor p75NTR, were comparable to wild-type. Baseline absolute blood flow, vascular and neuroanatomical features, as well as physiological measurements were also indistinguishable from wild-type.

Expression pattern of the Rett syndrome gene MeCP2 in primate prefrontal cortex.

Dysfunction of the prefrontal cortex may contribute to the autistic features and mental retardation of Rett syndrome, a neuropsychiatric condition caused by mutations of the gene encoding methyl-CpG-binding protein 2 (MeCP2). Because nothing is known about the expression of MeCP2 and other chromatin-associated factors in primate brain, we studied in monkey prefrontal cortex and murine cerebral cortex expression patterns of MeCP2 and of macrohistone H2A (MacroH2A), which like MeCP2 is associated with transcriptionally silent chromatin. In both species, MeCP2 and MacroH2A appeared to be ubiquitously expressed by cortical neurons, including projection neurons and GABAergic interneurons.

Neurotrophin-3 modulates noradrenergic neuron function and opiate withdrawal.

Somatic symptoms and aversion of opiate withdrawal, regulated by noradrenergic signaling, were attenuated in mice with a CNS-wide conditional ablation of neurotrophin-3. This occurred in conjunction with altered cAMP-mediated excitation and reduced upregulation of tyrosine hydroxylase in A6 (locus coeruleus) without loss of neurons. Transgene-derived NT-3 expressed by noradrenergic neurons of conditional mutants restored opiate withdrawal symptoms.

Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice.

Mecp2 is an X-linked gene encoding a nuclear protein that binds specifically to methylated DNA (ref. 1) and functions as a general transcriptional repressor by associating with chromatin-remodeling complexes. Mecp2 is expressed at high levels in the postnatal brain, indicating that methylation-dependent regulation of gene expression may have a crucial role in the mammalian central nervous system.

Maldistribution of interstitial neurons in prefrontal white matter of the brains of schizophrenic patients.

Background: The cortical subplate is a transitory structure involved in the formation of connections in developing cerebral cortex. Interstitial neurons, normally present in subcortical white matter (WM) of the adult brain, have escaped the programmed cell death that eliminates most subplate neurons. Previous investigations indicated a maldistribution of one population of interstitial neurons in the WM of brains of schizophrenic patients, suggesting a defect of the subplate during brain development.

Selective alterations in gene expression for NMDA receptor subunits in prefrontal cortex of schizophrenics.

NMDA receptor antagonists can induce a schizophrenia-like psychosis, but the role of NMDA receptors in the pathophysiology of schizophrenia remains unclear. Expression patterns of mRNAs for five NMDA receptor subunits (NR1/NR2A-D) were determined by in situ hybridization in prefrontal, parieto-temporal, and cerebellar cortex of brains from schizophrenics and from neuroleptic-treated and nonmedicated controls. In the cerebral cortex of both schizophrenics and controls, mRNAs for NR1, NR2A, NR2B, and NR2D subunits were preferentially expressed in layers II/III, Va, and VIa, with much higher levels in the prefrontal than in the parieto-temporal cortex.

Editing for an AMPA receptor subunit RNA in prefrontal cortex and striatum in Alzheimer's disease, Huntington's disease and schizophrenia.

Animal studies and cell culture experiments demonstrated that posttranscriptional editing of the transcript of the GluR-2 gene, resulting in substitution of an arginine for glutamine in the second transmembrane region (TM II) of the expressed protein, is associated with a reduction in Ca2+ permeability of the receptor channel. Thus, disturbances in GluR-2 RNA editing with alteration of intracellular Ca2+ homeostasis could lead to neuronal dysfunction and even neuronal degeneration. The present study determined the proportions of edited and unedited GluR-2 RNA in the prefrontal cortex of brains from patients with Alzheimer's disease, in the striatum of brains from patients with Huntington's disease, and in the same areas of brains from age-matched schizophrenics and controls, by using reverse transcriptase-polymerase chain reaction, restriction endonuclease digestion, gel electrophoresis and scintillation radiometry.

GABAA receptor subunit gene expression in human prefrontal cortex: comparison of schizophrenics and controls.

The prefrontal cortex of schizophrenics is hypoactive and displays changes related to inhibitory, GABAergic neurons, and GABAergic synapses. These changes include decreased levels of glutamic acid decarboxylase (GAD), the enzyme for GABA synthesis, upregulation of muscimol binding, and downregulation of benzodiazepine binding to GABAA receptors. Studies in the visual cortex of nonhuman primates have demonstrated that gene expression for GAD and for several GABAA receptor subunit polypeptides is under control of neuronal activity, raising the possibility that similar mechanisms in the hypoactive prefrontal cortex of schizophrenics may explain the abnormalities in GAD and in GABAA receptor regulation.

Developmental and regional expression pattern of a novel NMDA receptor-like subunit (NMDAR-L) in the rodent brain.

A novel NMDA receptor-like (NMDAR-L) cDNA was isolated that contained an open reading frame coding for a predicted polypeptide of 1115 amino acids that shares approximately 27% identity with NMDA receptor subunits. In situ hybridization experiments indicated that NMDAR-L mRNA was expressed in the developing rodent CNS. On postnatal day 1 (P1), NMDAR-L mRNA expression was pronounced in the entorhinal cortex, the subiculum and the thalamus, in layer V of the developing neocortex, in the superior and inferior colliculi, and various regions of the hindbrain, excluding the cerebellum.

Gene expression for glutamic acid decarboxylase is reduced without loss of neurons in prefrontal cortex of schizophrenics.

Background: Up-regulation of gamma-aminobutyric acidA (GABAA) receptors and decreased GABA uptake in the cerebral cortex of schizophrenics suggest altered GABAergic transmission, which could be caused by primary disturbance of GABA synapses or by decreased production of the transmitter. Decreased production could be due to a shutdown in GABA production or to loss of GABA neurons caused by cell death or their failure to migrate to the cortex during brain development.

Methods: To discriminate between these possibilities, we quantified levels of messenger RNA (mRNA) for the 67-kd isoform of glutamic acid decarboxylase (GAD), the key enzyme in GABA synthesis, and the number and laminar distribution of GAD mRNA--expressing neurons in the dorsolateral prefrontal cortex (DLPFC) of schizophrenics and matched controls, using in situ hybridization-histochemistry, densitometry, and cell-counting methods.

Corticofugal connections between the cerebral cortex and brainstem vestibular nuclei in the macaque monkey.

The distribution of cortical efferent connections to brainstem vestibular nuclei was quantitatively analysed by means of retrograde tracer substances injected into different electrophysiologically identified parts of the brainstem vestibular nuclear complex of five Java monkeys (Macaca fascicularis). Three polysensory vestibular areas were found to have a substantial projection to the vestibular nuclei: area 2v located at the tip of the intraparietal sulcus, the parietoinsular vestibular cortex (PIVC) covering the most occipital part of the granular insula (Ig) and the retroinsular area (Ri or reipt), and the dorsolateral part of the somatosensory area 3a ("area 3aV" neck/trunk region). From physiological recording experiments, these three cortical fields were known to contain many neurons responding to stimulation of semicircular canals as well as to optokinetic (area 2v, PIVC) and somatosensory stimuli (PIVC, area 3a).

Corticofugal projections to the vestibular nuclei in squirrel monkeys: further evidence of multiple cortical vestibular fields.

Single- and multiple-unit recordings were made from nerve cells located in the different nuclei of the brainstem vestibular nuclear complex (VNC) of anaesthetized squirrel monkeys (Saimiri sciureus) by conventional stereotaxic techniques. After neurons responding to semicircular canal stimulation in a yaw, roll, or pitch direction or to otholith stimulation were identified, small amounts of retrograde tracer substances were deposited at the recording sites. Up to three different tracers were administered to different parts of the VNC in the same animal (Fast Blue, HRP-WGA, and Rhodamine-dextranes).

Distorted distribution of nicotinamide-adenine dinucleotide phosphate-diaphorase neurons in temporal lobe of schizophrenics implies anomalous cortical development.

The distribution of neurons expressing the enzyme nicotinamide-adenine dinucleotide phosphate-diaphorase (NADPH-d) in the lateral and medial temporal lobes of schizophrenic and matched control brains was investigated in a systematic blind analysis. Schizophrenics had significantly lower numbers of NADPH-d neurons in the hippocampal formation and in the neocortex of the lateral temporal lobe but significantly greater numbers of NADPH-d neurons in the white matter of the lateral temporal lobe and a tendency toward greater numbers in parts of the parahippocampal white matter. The distorted distribution of NADPH-d neurons in the lateral temporal lobe, which may be explained by developmental disturbances, such as impaired neuronal migration or an alteration in the death cycle of transitory subcortical neurons, is similar to that found in the prefrontal cortex of schizophrenics.

Altered distribution of nicotinamide-adenine dinucleotide phosphate-diaphorase cells in frontal lobe of schizophrenics implies disturbances of cortical development.

Epidemiological and anatomical studies support the theory that disturbances of brain development may play a contributory role in the etiology of schizophrenia. Anatomical findings suggest that the normal pattern of neuronal migration during development of the cerebral cortex may be affected in the brains of schizophrenics, with the implication that cortical connectivity and associative function will be disrupted. In the present investigation in matched schizophrenic and control brains, we examined a particular population of neurons found in the prefrontal cortex and underlying white matter and characterized by histochemical staining for the enzyme nicotinamide-adenine dinucleotide phosphate-diaphorase.

Thalamic connections of the vestibular cortical fields in the squirrel monkey (Saimiri sciureus).

The afferent thalamic connections to cortical fields important for control of head movement in space were analysed by intracortical retrograde tracer injections. The proprioceptive/vestibular area 3aV, the neck-trunk region of area 3a, receives two thirds of its thalamic projections from the oral and superior ventroposterior nucleus (VPO/VPS), which is considered as the proprioceptive relay of the ventroposterior complex (Kaas et al., J.

Cortico-cortical connections and cytoarchitectonics of the primate vestibular cortex: a study in squirrel monkeys (Saimiri sciureus).

The cortical connections of two vestibular fields [parieto-insular vestibular cortex (PIVC) and area 3aV] were studied in the squirrel monkey (Saimiri sciureus) by means of retrograde tracer techniques. Small iontophoretic or pressure injections of horseradish peroxidase (HRP), wheat-germ-HRP, Nuclear Yellow, and Fast Blue were administered to the cytoarchitectonic areas Ri (PIVC), 3aV, the parieto-temporal association area T3, the granular insula (Ig), and the rostral part of area 7 (7ant). The injection sites were physiologically characterized by means of microelectrode recordings and vestibular, optokinetic, or somatosensory stimulation: Area Ri is the region of the parieto-insular vestibular cortex (PIVC) as defined in macaques.

Responses of single neurons in the parietoinsular vestibular cortex of primates.

1. Neurons activated by stimulation of the horizontal and/or vertical vestibular semicircular canals were recorded in the parietoinsular vestibular cortex in four awake Java monkeys (Macaca fascicularis) and three squirrel monkeys (Saimiri sciureus). Steady tilt in darkness or during illumination of a vertically striped cylinder or of the normal laboratory surroundings did not lead to a significant change in PIVC neuron activity.