Hippocampal morphometry in schizophrenia by high dimensional brain mapping

Theories of the pathophysiology of schizophrenia have implicated the hippocampus, but controversy remains regarding hippocampal abnormalities in patients with schizophrenia. In vivo studies of hippocampal anatomy using high resolution magnetic resonance scanning and manual methods for volumetric measurement have yielded inconclusive results, perhaps because of the normal variability in hippocampal volume and the error involved in manual measurement techniques. To resolve this controversy, high dimensional transformations of a computerized brain template were used to compare hippocampal volumes and shape characteristics in 15 matched pairs of schizophrenia and control subjects. The transformations were derived from principles of general pattern matching and were constrained according to the physical properties of fluids. The analysis and comparison of hippocampal shapes based on these transformations were far superior to the comparison of hippocampal volumes or other global indices of hippocampal anatomy in showing a statistically significant difference between the two groups. In the schizophrenia subjects, hippocampal shape deformations were found to be localized to subregions of the structure that send projections to prefrontal cortex. The results of this study demonstrate that abnormalities of hippocampal anatomy occur in schizophrenia and support current hypotheses that schizophrenia involves a disturbance of hippocampal–prefrontal connections. These results also show that comparisons of neuroanatomical shapes can be more informative than volume comparisons for identifying individuals with neuropsychiatric diseases, such as schizophrenia.     

Conditional calcineurin knockout mice exhibit multiple abnormal behaviors related to schizophrenia

Calcineurin (CN), a calcium- and calmodulin-dependent protein phosphatase, plays a significant role in the central nervous system. Previously, we reported that forebrain-specific CN knockout mice (CN mutant mice) have impaired working memory. To further analyze the behavioral effects of CN deficiency, we subjected CN mutant mice to a comprehensive behavioral test battery. Mutant mice showed increased locomotor activity, decreased social interaction, and impairments in prepulse inhibition and latent inhibition. In addition, CN mutant mice displayed an increased response to the locomotor stimulating effects of MK-801. Collectively, the abnormalities of CN mutant mice are strikingly similar to those described for schizophrenia. We propose that alterations affecting CN signaling could comprise a contributing factor in schizophrenia pathogenesis.     

The role of the hippocampus in feedback regulation of the hypothalamic-pituitary-adrenocortical axis

There is considerable, although not entirely consistent, evidence that the hippocampus inhibits most aspects of HPA activity, including basal (circadian nadir) and circadian peak secretion as well as the onset and termination of responses to stress. Although much of the evidence for these effects rests only on the measurement of corticosteroids, recent lesion and implant studies indicate that the hippocampus regulates adrenocortical activity at the hypothalamic level, via the expression and secretion of ACTH secretagogues. Such inhibition results largely from the mediation of corticosteroid feedback, although more work is required to determine whether the hippocampus supplies a tonic inhibitory input in the absence of corticosteroids. It must be noted that the hippocampus is not the only feedback site in the adrenocortical system, since removal of its input only reduces, but does not abolish, the efficacy of corticosteroid inhibition, and since other elements of the axis appear eventually to compensate for deficits in feedback regulation. The importance of other feedback sites is further suggested not only by the presence of corticosteroid receptors in other parts of the brain and pituitary, but also by the improved prediction of CRF levels by combined hypothalamic and hippocampal receptor occupancy. The likelihood of feedback mediated by nonhippocampal sites underscores the need for future work to characterize hippocampal influence on HPA activity in the absence of changes in corticosteroid secretion. However, despite the fact that the hippocampus is not the only feedback site, it is distinguished from most potential feedback sites, including the hypothalamus and pituitary, by its high content of both type I and II corticosteroid receptors. The hippocampus is therefore capable of mediating inhibition over a wide range of steroid levels. The low end of this range is represented by corticosteroid inhibition of basal (circadian nadir) HPA activity. The apparent type I receptor specificity of this inhibition and the elevation of trough corticosteroid levels after hippocampal damage support a role for hippocampal type I receptors in regulating basal HPA activity. It is possible that basal activity is controlled in part through hippocampal inhibition of vasopressin, since the inhibition of portal blood vasopressin correlates with lower levels of hippocampal receptor occupancy, and the expression of vasopressin by some CRF neurons is sensitive to very low corticosteroid levels. At the high end of the physiological range, stress-induced or circadian peak corticosteroid secretion correlates strongly with occupancy of the lower affinity hippocampal type II receptors.(ABSTRACT TRUNCATED AT 400 WORDS)     

Neuregulin 1-ErbB4-PI3K signaling in schizophrenia and phosphoinositide 3-kinase-p110δ inhibition as a potential therapeutic strategy

Neuregulin 1 (NRG1) and ErbB4, critical neurodevelopmental genes, are implicated in schizophrenia, but the mediating mechanisms are unknown. Here we identify a genetically regulated, pharmacologically targetable, risk pathway associated with schizophrenia and with ErbB4 genetic variation involving increased expression of a PI3K-linked ErbB4 receptor (CYT-1) and the phosphoinositide 3-kinase subunit, p110δ (PIK3CD). In human lymphoblasts, NRG1-mediated phosphatidyl-inositol,3,4,5 triphosphate [PI(3,4,5)P3] signaling is predicted by schizophrenia-associated ErbB4 genotype and PIK3CD levels and is impaired in patients with schizophrenia. In human brain, the same ErbB4 genotype again predicts increased PIK3CD expression. Pharmacological inhibition of p110δ using the small molecule inhibitor, IC87114, blocks the effects of amphetamine in a mouse pharmacological model of psychosis and reverses schizophrenia-related phenotypes in a rat neonatal ventral hippocampal lesion model. Consistent with these antipsychotic-like properties, IC87114 increases AKT phosphorylation in brains of treated mice, implicating a mechanism of action. Finally, in two family-based genetic studies, PIK3CD shows evidence of association with schizophrenia. Our data provide insight into a mechanism of ErbB4 association with schizophrenia; reveal a previously unidentified biological and disease link between NRG1-ErbB4, p110δ, and AKT; and suggest that p110δ is a previously undescribed therapeutic target for the treatment of psychiatric disorders.     

Variation in DISC1 affects hippocampal structure and function and increases risk for schizophrenia

Disrupted-in-schizophrenia 1 (DISC1) is a promising schizophrenia candidate gene expressed predominantly within the hippocampus. We typed 12 single-nucleotide polymorphisms (SNPs) that covered the DISC1 gene. A three-SNP haplotype [hCV219779 (C)-rs821597 (G)-rs821616 (A)] spanning 83 kb of the gene was associated with schizophrenia in a family-based sample (P = 0.002). A common nonconservative SNP (Ser704Cys) (rs821616) within this haplotype was associated with schizophrenia (P = 0.004). Based on primary expression of DISC1 in hippocampus, we hypothesized that allelic variation at Ser704Cys would have a measurable impact on hippocampal structure and function as assayed via specific hippocampus-related intermediate phenotypes. In addition to overtransmission in schizophrenia, the Ser allele was associated with altered hippocampal structure and function in healthy subjects, including reduced hippocampal gray matter volume and altered engagement of the hippocampus during several cognitive tasks assayed with functional magnetic resonance imaging. These convergent data suggest that allelic variation within DISC1, either at Ser704Cys or haplotypes monitored by it, increases the risk for schizophrenia and that the mechanism of this effect involves structural and functional alterations in the hippocampal formation.     

Prevention of cerebral ischemia-induced memory deficits by inhibition of phosphodiesterase-4 in rats

Inhibition of phosphodiesterase-4 (PDE4) by rolipram, a prototypical PDE4 inhibitor, reverses memory impairment produced pharmacologically or genetically. Comparably, much less is known about the effect of rolipram on cerebral ischemia-induced memory deficits. The objective of this study was to determine the effects of rolipram on ischemia-induced memory deficit, neuronal damage, and alteration of PDE4 activity in the hippocampus. Memory was examined using Morris water-maze and step-through passive avoidance tests in rats subjected to global cerebral ischemia with or without repeated treatment with rolipram (0.3 or 1 mg/kg, i.p.); neuronal damage in the hippocampus and PDE4 activity in hippocampal tissues were determined using Nissl staining and HPLC, respectively. In the water-maze test, cerebral ischemia significantly increased the escape latency to reach the platform during acquisition training and decreased the exploration time in the target quadrant in the probe trial test; these were blocked by rolipram in a dose-dependent manner. Rolipram also reduced the distracted platform searches induced by cerebral ischemia. In the passive avoidance test, ischemia decreased the 24-h latency to the dark compartment, which was also blocked by rolipram treatment. In addition, Nissl staining revealed ischemia-induced neuron loss in hippocampal CA1; this was blocked by rolipram. Further, cerebral ischemia led to increases in activity of PDE, primarily PDE4, in the hippocampus, which also was antagonized by rolipram. These results suggest that rolipram prevents cerebral ischemia-induced memory deficits via inhibition of increased PDE4 activity and attenuation of hippocampal, neuronal damages induced by ischemia. PDE4 may be a target for treatment of cognitive disorders associated with cerebral ischemia.     

Dysbindin-1 mutant mice implicate reduced fast-phasic inhibition as a final common disease mechanism in schizophrenia

DTNBP1 (dystrobrevin binding protein 1) is a leading candidate susceptibility gene in schizophrenia and is associated with working memory capacity in normal subjects. In schizophrenia, the encoded protein dystrobrevin-binding protein 1 (dysbindin-1) is often reduced in excitatory cortical limbic synapses. We found that reduced dysbindin-1 in mice yielded deficits in auditory-evoked response adaptation, prepulse inhibition of startle, and evoked γ-activity, similar to patterns in schizophrenia. In contrast to the role of dysbindin-1 in glutamatergic transmission, γ-band abnormalities in schizophrenia are most often attributed to disrupted inhibition and reductions in parvalbumin-positive interneuron (PV cell) activity. To determine the mechanism underlying electrophysiological deficits related to reduced dysbindin-1 and the potential role of PV cells, we examined PV cell immunoreactivity and measured changes in net circuit activity using voltage-sensitive dye imaging. The dominant circuit impact of reduced dysbindin-1 was impaired inhibition, and PV cell immunoreactivity was reduced. Thus, this model provides a link between a validated candidate gene and an auditory endophenotypes. Furthermore, these data implicate reduced fast-phasic inhibition as a common underlying mechanism of schizophrenia-associated intermediate phenotypes.     

N-desmethylclozapine, an allosteric agonist at muscarinic 1 receptor, potentiates N-methyl-D-aspartate receptor activity

The molecular and neuronal substrates conferring on clozapine its unique and superior efficacy in the treatment of schizophrenia remain elusive. The interaction of clozapine with many G protein-coupled receptors is well documented but less is known about its biologically active metabolite, N-desmethylclozapine. Recent clinical and preclinical evidences of the antipsychotic activity of the muscarinic agonist xanomeline prompted us to investigate the effects of N-desmethylclozapine on cloned human M1-M5 muscarinic receptors. N-desmethylclozapine preferentially bound to M1 muscarinic receptors with an IC50 of 55 nM and was a more potent partial agonist (EC50, 115 nM and 50% of acetylcholine response) at this receptor than clozapine. Furthermore, pharmacological and site-directed mutagenesis studies suggested that N-desmethylclozapine preferentially activated M1 receptors by interacting with a site that does not fully overlap with the acetylcholine orthosteric site. As hypofunction of N-methyl-d-aspartate (NMDA) receptor-driven neuronal ensembles has been implicated in psychotic disorders, the neuronal activity of N-desmethylclozapine was electrophysiologically investigated in hippocampal rat brain slices. N-desmethylclozapine was shown to dose-dependently potentiate NMDA receptor currents in CA1 pyramidal cells by 53% at 100 nM, an effect largely mediated by activation of muscarinic receptors. Altogether, our observations provide direct evidence that the brain penetrant metabolite N-desmethylclozapine is a potent, allosteric agonist at human M1 receptors and is able to potentiate hippocampal NMDA receptor currents through M1 receptor activation. These observations raise the possibility that N-desmethylclozapine contributes to clozapine's clinical activity in schizophrenics through modulation of both muscarinic and glutamatergic neurotransmission.     

Interneuron precursor transplants in adult hippocampus reverse psychosis-relevant features in a mouse model of hippocampal disinhibition

GABAergic interneuron hypofunction is hypothesized to underlie hippocampal dysfunction in schizophrenia. Here, we use the cyclin D2 knockout (Ccnd2^−/−) mouse model to test potential links between hippocampal interneuron deficits and psychosis-relevant neurobehavioral phenotypes. Ccnd2^−/− mice show cortical PV⁺ interneuron reductions, prominently in hippocampus, associated with deficits in synaptic inhibition, increased in vivo spike activity of projection neurons, and increased in vivo basal metabolic activity (assessed with fMRI) in hippocampus. Ccnd2^−/− mice show several neurophysiological and behavioral phenotypes that would be predicted to be produced by hippocampal disinhibition, including increased ventral tegmental area dopamine neuron population activity, behavioral hyperresponsiveness to amphetamine, and impairments in hippocampus-dependent cognition. Remarkably, transplantation of cells from the embryonic medial ganglionic eminence (the major origin of cerebral cortical interneurons) into the adult Ccnd2^−/− caudoventral hippocampus reverses these psychosis-relevant phenotypes. Surviving neurons from these transplants are 97% GABAergic and widely distributed within the hippocampus. Up to 6 mo after the transplants, in vivo hippocampal metabolic activity is lowered, context-dependent learning and memory is improved, and dopamine neuron activity and the behavioral response to amphetamine are normalized. These findings establish functional links between hippocampal GABA interneuron deficits and psychosis-relevant dopaminergic and cognitive phenotypes, and support a rationale for targeting limbic cortical interneuron function in the prevention and treatment of schizophrenia.Precursors of most γ-aminobutyric acid (GABA)-releasing interneurons of the cerebral cortex and the hippocampus originate in the embryonic medial ganglionic eminence (MGE) (1–3). A subpopulation of MGE-derived cells differentiates into fast-spiking, parvalbumin-expressing (PV⁺) interneurons that tightly regulate the activity and synchronization of cortical projection neurons (2, 4). Structural and functional deficits in PV⁺ interneurons are hypothesized as a pathophysiological mechanism in schizophrenia and psychotic disorders (4–6).Although psychotic disorders are clearly heterogeneous in etiology, disinhibition within temporolimbic cortical circuits is postulated as a core pathophysiology underlying positive symptoms (e.g., delusions and hallucinations) and a subset of cognitive disturbances that manifest with psychosis (4, 5, 7). Postmortem studies of brains from individuals with psychotic disorders show reduced molecular markers of the number and/or function of PV⁺ interneurons in the hippocampus (6, 8). Consistent with these observations, basal metabolic activity in the hippocampus, as measured with functional magnetic resonance imaging (fMRI), is increased in schizophrenia, a phenotype that predicts psychosis and positive symptom severity (5, 7). This abnormal resting activity is postulated to underlie abnormal recruitment of hippocampal circuits during cognitive performance (5, 9). Striatal dopamine (DA) release capacity is also increased and correlated with positive symptoms in schizophrenia and its risk states (10, 11). Importantly, hippocampal hyperactivity may contribute to DA dysregulation (12), because rodent studies show that caudoventral hippocampal (in the primate, anterior hippocampal) efferents regulate the activity of DA neurons and medial striatal DA release (13, 14).Thus, converging evidence implicates hippocampal disinhibition in the abnormal striatal DA transmission and cognitive impairment in schizophrenia. However, the role of hippocampal inhibitory interneurons in psychosis-relevant circuitry remains to be established. To this end, we used the cyclin D2 (Ccnd2) knockout mouse model (15), which displays a relatively selective deficit in cortical PV⁺ interneurons, and transplantation of interneuron precursors from the MGE to elucidate relationships between reduced hippocampal GABA interneuron function and multiple psychosis-relevant phenotypes, and to explore a novel treatment strategy for psychosis.     

An epigenetic mouse model for molecular and behavioral neuropathologies related to schizophrenia vulnerability

Reelin and glutamic acid decarboxylase (GAD)67 expressed by cortical gamma-aminobutyric acid-ergic interneurons are down-regulated in schizophrenia. Because epidemiological studies of schizophrenia fail to support candidate gene haploinsufficiency of Mendelian origin, we hypothesize that epigenetic mechanisms (i.e., cytosine hypermethylation of CpG islands present in the promoter of these genes) may be responsible for this down-regulation. Protracted l-methionine (6.6 mmolkg for 15 days, twice a day) treatment in mice elicited in brain an increase of S-adenosyl-homocysteine, the processing product of the methyl donor S-adenosyl-methionine, and a marked decrease of reelin and GAD67 mRNAs in both WT and heterozygous reeler mice. This effect of l-methionine was associated with an increase in the number of methylated cytosines in the CpG island of the reelin promoter region. This effect was not observed for GAD65 or neuronal-specific enolase and was not replicated by glycine doses 2-fold greater than those of l-methionine. Prepulse inhibition of startle declined at a faster rate as the prepulsestartle interval increased in mice receiving l-methionine. Valproic acid (2 mmolkg for 15 days, twice a day) reverted l-methionine-induced down-regulation of reelin and GAD67 in both WT and heterozygous reeler mice, suggesting an epigenetic action through the inhibition of histone deacetylases. The same dose of valproate increased acetylation of histone H3 in mouse brain nearly 4-fold. This epigenetic mouse model may be useful in evaluating drug efficacy on schizophrenia vulnerability. Hence the inhibition of histone deacetylases could represent a pharmacological intervention mitigating epigenetically induced vulnerability to schizophrenia in individuals at risk.     

Enhancement of CA3 hippocampal network activity by activation of group II metabotropic glutamate receptors

Impaired function or expression of group II metabotropic glutamate receptors (mGluRIIs) is observed in brain disorders such as schizophrenia. This class of receptor is thought to modulate activity of neuronal circuits primarily by inhibiting neurotransmitter release. Here, we characterize a postsynaptic excitatory response mediated by somato-dendritic mGluRIIs in hippocampal CA3 pyramidal cells and in stratum oriens interneurons. The specific mGluRII agonists DCG-IV or LCCG-1 induced an inward current blocked by the mGluRII antagonist LY341495. Experiments with transgenic mice revealed a significant reduction of the inward current in mGluR3(-/-) but not in mGluR2(-/-) mice. The excitatory response was associated with periods of synchronized activity at theta frequency. Furthermore, cholinergically induced network oscillations exhibited decreased frequency when mGluRIIs were blocked. Thus, our data indicate that hippocampal responses are modulated not only by presynaptic mGluRIIs that reduce glutamate release but also by postsynaptic mGluRIIs that depolarize neurons and enhance CA3 network activity.     

The PIDDosome mediates delayed death of hippocampal CA1 neurons after transient global cerebral ischemia in rats

A brief period of global brain ischemia, such as that induced by cardiac arrest or cardiopulmonary bypass surgery, causes cell death in vulnerable hippocampal CA1 pyramidal neurons days after reperfusion. Although numerous factors have been suggested to account for this phenomenon, the mechanisms underlying it are poorly understood. We describe a cell death signal called the PIDDosome, a protein complex of p53-induced protein with a death domain (PIDD), receptor-interacting protein-associated ICH-1/CED-3 homologous protein with a death domain (RAIDD), and procaspase-2. We induced 5 min of transient global cerebral ischemia (tGCI) using bilateral common carotid artery occlusion with hypotension. Western blot analysis showed that expression of twice-cleaved fragment of PIDD (PIDD-CC) increased in the cytosolic fraction of the hippocampal CA1 subregion and preceded procaspase-2 activation after tGCI. Caspase-2 cleaved Bid in brain homogenates. Co-immunoprecipitation and immunofluorescent studies demonstrated that PIDD-CC, RAIDD, and procaspase-2 were co-localized and bound directly, which indicates the formation of the PIDD death domain complex. Furthermore, we tested inhibition of PIDD expression by using small interfering RNA (siRNA) treatment that was initiated 48 h before tGCI. Administration of siRNA against PIDD decreased not only expression of PIDD-CC, but also activation of procaspase-2 and Bid, resulting in a decrease in histological neuronal damage and DNA fragmentation in the hippocampal CA1 subregion after tGCI. These results imply that PIDD plays an important role in procaspase-2 activation and delayed CA1 neuronal death after tGCI. We propose that PIDD is a hypothetical molecular target for therapy against neuronal death after tGCI.     

Protein kinase D regulates the adiponectin gene expression through phosphorylation of AP-2: a common pathway to the ABCA1 gene regulation

Expression of the activator protein (AP) 2β is closely associated with type-2 diabetes and negatively regulates expression of the adiponectin gene. We previously demonstrated that AP-2α negatively regulates the ATP-binding cassette A1 (ABCA1) gene through its Ser-phosphorylation by protein kinase (PK) D. The phosphorylation site of AP-2α located in the basic domain, a critical site for its DNA binding, is conserved among species and five subtypes of AP-2. We therefore investigated the involvement of PKD in regulation of the adiponectin gene expression. Knockdown of PKD by its siRNA led to the increase in the mRNA and the promoter activity of adiponectin, and resulted in increase of adiponectin secretion and decrease of fat accumulation in cultured cells. PKD activators decreased expression of the adiponectin gene, and its inhibition by PKD siRNA and by a selective inhibitor G?6983 canceled this effect. ChIP analysis demonstrated that inhibition of PKD activity decreased the DNA binding of AP-2β to the adiponectin promoter. Finally, G?6983 increased adiponectin expression in mice. PKD is thus a common modulator of the DNA binding activity of AP-2α and AP-2β through their phosphorylation for negative regulation of the ABCA1 and adiponectin genes expression, respectively.     

Differentiation of cyclooxygenase 1- and 2-derived prostanoids in mouse kidney and aorta

Accumulating evidence indicates cyclooxygenase (COX) 1 and COX2 differentially regulate cardiovascular and renal function. We have demonstrated previously in mice that COX2 inhibition enhances angiotensin II-induced hypertension, and COX1 inhibition attenuates the pressor effect of angiotensin II. To further elucidate the mechanism underlying the functional difference of COX1 versus COX2 inhibition, the present studies examined the prostaglandin (PG) profiles derived in COX1- or COX2-inhibited mouse kidney and aorta using gas chromatographic/mass spectrometric assays. PGE2 is the most abundant prostanoid in both renal cortex and medulla in normal C57BL/6J mice, followed by PGI2, PGF2alpha and thromboxane A2. In contrast PGI2 was most abundant in aorta followed by thromboxane A2, PGE2, and PGF2alpha. PGD2 was undetectable in control kidney or aorta. At baseline, inhibition of COX1 decreased total prostaglandins in renal cortex, medulla, and aorta, whereas COX2 inhibition decreased total prostaglandins only in renal medulla. Angiotensin II infusion significantly increased COX2-dependent/COX1-independent PGE2 and PGI2 in renal cortex and medulla. Angiotensin II also significantly increased renal PGF2alpha in cortex, but not in medulla, through both COX1- and COX2-dependent mechanisms. These studies demonstrate that although COX1 primarily contributes to basal prostanoid production in the kidney and aorta, angiotensin II increases renal vasodilator prostanoids predominately via COX2 activity. These effects may contribute to the specific effect of COX2 inhibitors to increase blood pressure.     

Decreased sensitivity to glucocorticoid fast feedback in chronically stressed rats

A number of changes in anterior pituitary corticotrophs occur after chronic footshock. These include increased ACTH and beta-endorphin content and a loss of glucocorticoid negative feedback on corticotropin-releasing hormone (CRH)-stimulated ACTH and beta-endorphin secretion, without changes in sensitivity to ovine CRH examined in vitro. The present studies were undertaken to determine whether the in vitro changes were reflected by similar changes in vivo. We developed a fast feedback paradigm using a 5-min swim stress as challenge, with injection of saline or corticosterone immediately prior to swim. Corticosterone reliably decreased ACTH and beta-endorphin responses to swim over the 30-min period studied. This feedback inhibition did not occur in rats that were either exposed to 30 min of chronic footshock for 7 or 14 days or in rats that were treated with corticosterone daily for 14 days in a regimen that has been reported to decrease hippocampal glucocorticoid receptors. By contrast, in rats exposed to the less intense stimulus of 30 min swim for 14 days, the fast feedback action of corticosterone was intact. These results suggest that both fast and delayed feedback corticosterone-inhibitory mechanisms may be blocked by relatively high levels of chronic stress or by chronic treatment with corticosterone, possibly as a consequence of decreased hippocampal glucocorticoid receptor number.     

Does maternal body mass index during pregnancy influence risk of schizophrenia in the adult offspring?

Maternal obesity in pregnancy has been linked with several adverse outcomes in offspring including schizophrenia. The rising prevalence of obesity may contribute to an increase in the number of schizophrenia cases in the near future; therefore, it warrants further exploration. We reviewed current evidence regarding maternal body mass index (BMI) in pregnancy and risk of schizophrenia in adult offspring. We searched PubMed and Embase databases and included studies that were based on large and representative population-based datasets. A qualitative review was undertaken due to heterogeneity between studies. Four studies with 305 cases of schizophrenia and 24,442 controls were included. Maternal obesity (pre-pregnant BMI over 29 or 30 compared with mothers with low or average BMI) was associated with two- to threefold increased risk of schizophrenia in the adult offspring in two birth cohorts. High maternal BMI at both early and late pregnancy also increased risk of schizophrenia in the offspring. Discrepant findings from one study could be attributable to sample characteristics and other factors. The area needs more research. Future studies should take into account obstetric complications, diabetes, maternal infections and immune responses that might potentially mediate this association.     

Increased serum growth hormone and somatic growth in adult hamsters with hippocampal transections.

Somatic, endocrine, and behavioral correlates of growth and levels of voluntary running activity were measured in adult hamsters with hippocampal transections (HIPPO cuts) or in controls with transections of overlying cortex. Significant increase in serum concentration of growth hormone (GH) and decrease in pituitary concentration of GH were measured in HIPPO hamsters with a homologous radioimmunoassay method for hamster GH. HIPPO hamsters had increased: serum insulin concentration in fed state, food consumption, ponderal and linear growth, and percentage of body fat, and decreased levels of voluntary activity. Similarities between growth acceleration after HIPPO cuts and lesions of rostral medial septum suggest that fibers interconnecting, or passing through, the hippocampal formation and septum inhibit growth in adult hamsters.     

Serotonergic control of the hippocampus via local inhibitory interneurons.

Information flow and processing in hippocampal neuronal networks is determined by a wide range of inhibitory mechanisms [e.g., feedforward or feedback, gamma-aminobutyrate (GABA) A or B receptor-mediated, perisomatic shunting, or distal dendritic inhibition], each subserving specialized functions. These forms of local inhibition are mediated by morphologically and neurochemically well-defined, mostly GABA-containing, interneurons, which control large populations of principal cells through their extensive axonal arborizations. These neurons can serve as ideal targets for subcortical pathways, such as those originating in the septum or raphe, which exercise a global control over hippocampal activity. This intriguing possibility prompted us to study whether the profound effect of the serotonergic raphe-hippocampal pathway is mediated by inhibitory interneurons or whether a direct diffuse action on the principal cells is dominant. We demonstrate that axons of this pathway form multiple synaptic contacts with hippocampal GABAergic interneurons. Interestingly, the serotonergic afferents selectively innervate the somata and dendritic trees of GABAergic neurons that contain the 28-kDa calcium-binding protein calbindin D28K, but never those that contain another calcium-binding protein, parvalbumin. These results show that the mechanism by which the serotonergic pathway may exert a powerful influence on hippocampal function involves the modulation of local inhibitory circuits. Furthermore, the selectivity in the choice of target GABAergic interneurons suggests a strong functional specialization among inhibitory circuits, as well as among the subcortical input pathways originating in the septum and raphe.