Human Obesity Associated with an Intronic SNP in the Brain-Derived Neurotrophic Factor Locus.

Brain-derived neurotrophic factor (BDNF) plays a key role in energy balance. In population studies, SNPs of the BDNF locus have been linked to obesity, but the mechanism by which these variants cause weight gain is unknown. Here, we examined human hypothalamic BDNF expression in association with 44 BDNF SNPs. We observed that the minor C allele of rs12291063 is associated with lower human ventromedial hypothalamic BDNF expression (p < 0.001) and greater adiposity in both adult and pediatric cohorts (p values < 0.05). We further demonstrated that the major T allele for rs12291063 possesses a binding capacity for the transcriptional regulator, heterogeneous nuclear ribonucleoprotein D0B, knockdown of which disrupts transactivation by the T allele. Binding and transactivation functions are both disrupted by substituting C for T. These findings provide a rationale for BDNF augmentation as a targeted treatment for obesity in individuals who have the rs12291063 CC genotype.

A primate-specific, brain isoform of KCNH2 affects cortical physiology, cognition, neuronal repolarization and risk of schizophrenia.

Organized neuronal firing is crucial for cortical processing and is disrupted in schizophrenia. Using rapid amplification of 5' complementary DNA ends in human brain, we identified a primate-specific isoform (3.1) of the ether-a-go-go-related K(+) channel KCNH2 that modulates neuronal firing. KCNH2-3.1 messenger RNA levels are comparable to full-length KCNH2 (1A) levels in brain but three orders of magnitude lower in heart. In hippocampus from individuals with schizophrenia, KCNH2-3.1 expression is 2.5-fold greater than KCNH2-1A expression. A meta-analysis of five clinical data sets (367 families, 1,158 unrelated cases and 1,704 controls) shows association of single nucleotide polymorphisms in KCNH2 with schizophrenia. Risk-associated alleles predict lower intelligence quotient scores and speed of cognitive processing, altered memory-linked functional magnetic resonance imaging signals and increased KCNH2-3.1 mRNA levels in postmortem hippocampus. KCNH2-3.1 lacks a domain that is crucial for slow channel deactivation. Overexpression of KCNH2-3.1 in primary cortical neurons induces a rapidly deactivating K(+) current and a high-frequency, nonadapting firing pattern. These results identify a previously undescribed KCNH2 channel isoform involved in cortical physiology, cognition and psychosis, providing a potential new therapeutic drug target.

Genetic dissection of the role of catechol-O-methyltransferase in cognition and stress reactivity in mice.

The COMT (catechol-O-methyltransferase) gene has been linked to a spectrum of human phenotypes, including cognition, anxiety, pain sensitivity and psychosis. Doubts about its clinical impact exist, however, because of the complexity of human COMT polymorphism and clinical variability. We generated transgenic mice overexpressing a human COMT-Val polymorphism (Val-tg), and compared them with mice containing a null COMT mutation. Increased COMT enzyme activity in Val-tg mice resulted in disrupted attentional set-shifting abilities, and impaired working and recognition memory, but blunted stress responses and pain sensitivity. Conversely, COMT disruption improved working memory, but increased stress responses and pain sensitivity. Amphetamine ameliorated recognition memory deficits in COMT-Val-tg mice but disrupted it in wild types, illustrating COMT modulation of the inverted-U relationship between cognition and dopamine. COMT-Val-tg mice showed increased prefrontal cortex (PFC) calcium/calmodulin-dependent protein kinase II (CaMKII) levels, whereas COMT deficiency decreased PFC CaMKII but increased PFC CaMKKbeta and CaMKIV levels, suggesting the involvement of PFC CaMK pathways in COMT-regulated cognitive function and adaptive stress responses. Our data indicate a critical role for the COMT gene in an apparent evolutionary trade-off between cognitive and affective functions.

Cortical gene expression in the neonatal ventral-hippocampal lesion rat model.

Schizophrenia is a chronic, debilitating psychotic illness of unknown etiology that has been the subject of many genetic studies. We studied the neonatal ventral-hippocampal lesioned rat as an animal model of schizophrenia in order to identify novel candidate genes for schizophrenia. Temporal and frontal cortices were assessed using cDNA microarrays for differences in mRNA expression associated with the lesion, haloperidol treatment and in two rat strains with differential sensitivity to the behavioural effects of the lesion. Genes that had altered expression levels as a result of the lesion, that were normalized by haloperidol treatment, and that differed between rat strains were selected. The pattern of differential transcription was confirmed with quantitative PCR for all six candidate genes: large conductance calcium-activated potassium channel, subfamily M, beta member 1 (Kcnmb1); doublecortex (dcx); adenylyl cyclase-associated protein 1 (CAP1); adenosine monophosphate deaminase 2-isoform L (AMPD2); malic enzyme 3, NADP(+)-dependent, mitochondrial (Me3); and aspartylglucosaminidase (AGA). None of these genes has been extensively studied in schizophrenia, and further work with post-mortem tissue and genetic studies are ongoing.

Behavioral effects of neonatal and adult excitotoxic lesions of the mediodorsal thalamus in the adult rat.

We examined in the rat, the effects of neonatal (postnatal Day 7) and adult excitotoxic lesions of the mediodorsal thalamus (MDT), a brain area innervating the prefrontal cortex and implicated as a site of neuropathology in schizophrenia. Previous studies showed that rats with neonatal excitotoxic damage of the ventral hippocampus (VH), used as an animal model of this disorder, display in young adulthood a variety of abnormalities reminiscent of schizophrenia, including hyperactivity to stressful stimuli and amphetamine. It has been speculated that behavioral abnormalities of the neonatally VH lesioned animals are mediated through MDT projections to the prefrontal cortex. We tested if rats with ibotenic acid (1.5 microg per hemisphere in neonates, 2 microg in adults) lesions of MDT exhibited motor hyperactivity in the same experimental conditions (i.e. in response to novelty, saline injections and amphetamine administration) as rats with the VH lesions. We found that, in contrast to rats with VH lesions, neonatally lesioned MDT rats showed reduced vertical activity in response to amphetamine and no changes in locomotor activity to novelty, saline or amphetamine injections 7 weeks postlesion. Adult lesioned MDT rats exhibited no changes in motor activity as compared to controls at 7 weeks postlesion. These results indicate that neonatal or adult excitotoxic lesions of MDT do not produce behavioral changes analogous to those seen after neonatal VH lesions and do not appear to reproduce animal model-like features of schizophrenia.