Glutamic acid decarboxylase 67 haplodeficiency in mice: consequences of postweaning social isolation on behavior and changes in brain neurochemical systems.

Reductions of glutamate acid decarboxylase (GAD67) and subsequent GABA levels have been consistently observed in neuropsychiatric disorders like schizophrenia and depression, but it has remained unclear how GABAergic dysfunction contributes to different symptoms of the diseases. To address this issue, we investigated male mice haplodeficient for GAD67 (GAD67+/GFP mice), which showed a reduced social interaction, social dominance and increased immobility in the forced swim test. No differences were found in rotarod performance and sensorimotor gating. We also addressed potential effects of social deprivation, which is known, during early life, to affect GABAergic function and induces behavioral abnormalities similar to the symptoms found in psychiatric disorders. Indeed, social isolation of GAD67+/GFP mice provoked increased rearing activity in the social interaction test and hyperlocomotion on elevated plus maze. Since GABA closely interacts with the dopaminergic, serotonergic and cholinergic neurotransmitter systems, we investigated GAD67+/GFP and GAD67+/+ mice for morphological markers of the latter systems and found increased tyrosine hydroxylase (TH)-IR fiber densities in CA1 of dorsal hippocampus. By contrast, no differences in numbers and densities of TH-positive neurons of the midbrain dopamine regions, serotonin (5-HT) neurons of the raphe nuclei, or choline acetyltransferase (ChAT)-expressing neurons of basal forebrain and their respective terminal fields were observed. Our results indicate that GAD67 haplodeficiency impairs sociability and increases vulnerability to social stress, provokes depressive-like behavior and alters the catecholaminergic innervation in brain areas associated with schizophrenia. GAD67+/GFP mice may provide a useful model for studying the impact of GABAergic dysfunction as related to neuropsychiatric disorders.

Electric stimulation of the medial forebrain bundle influences sensorimotor gaiting in humans.

BACKGROUND: Prepulse inhibition (PPI) of the acoustic startle response, a measurement of sensorimotor gaiting, is modulated by monoaminergic, presumably dopaminergic neurotransmission. Disturbances of the dopaminergic system can cause deficient PPI as found in neuropsychiatric diseases. A target specific influence of deep brain stimulation (DBS) on PPI has been shown in animal models of neuropsychiatric disorders. In the present study, three patients with early dementia of Alzheimer type underwent DBS of the median forebrain bundle (MFB) in a compassionate use program to maintain cognitive abilities. This provided us the unique possibility to investigate the effects of different stimulation conditions of DBS of the MFB on PPI in humans. RESULTS: Separate analysis of each patient consistently showed a frequency dependent pattern with a DBS-induced increase of PPI at 60 Hz and unchanged PPI at 20 or 130 Hz, as compared to sham stimulation. CONCLUSIONS: Our data demonstrate that electrical stimulation of the MFB modulates PPI in a frequency-dependent manner. PPI measurement could serve as a potential marker for optimization of DBS settings independent of the patient or the examiner.

Effects of neonatal excitotoxic lesions in ventral thalamus on social interaction in the rat.

The role of the thalamus in schizophrenia has increasingly been studied in recent years. Deficits in the ventral thalamus have been described in only few postmortem and neuroimaging studies. We utilised our previously introduced neurodevelopmental animal model, the neonatal excitotoxic lesion of the ventral thalamus of Sprague-Dawley rats (Wolf et al., Pharmacopsychiatry 43:99-109, 22). At postnatal day (PD7), male pubs received bilateral thalamic infusions with ibotenic acid (IBA) or artificial cerebrospinal fluid (control). In adulthood, social interaction of two animals not familiar to each other was studied by a computerised video tracking system. This study displays clear lesion effects on social interaction of adult male rats. The significant reduction of total contact time and the significant increase in distance between the animals in the IBA group compared to controls can be interpreted as social withdrawal modelling a negative symptom of schizophrenia. The significant increase of total distance travelled in the IBA group can be hypothesised as agitation modelling a positive symptom of schizophrenia. Using a triple concept of social interaction, the percentage of no social interaction (Non-SI%) was significantly larger, and inversely, the percentage of passive social interaction (SI-passive%) was significantly smaller in the IBA group when compared to controls. In conclusion, on the background of findings in schizophrenic patients, the effects of neonatal ventral thalamic IBA lesions in adult male rats support the hypothesis of face and construct validity as animal model of schizophrenia.

A Jacob/Nsmf Gene Knockout Results in Hippocampal Dysplasia and Impaired BDNF Signaling in Dendritogenesis.

Jacob, the protein encoded by the Nsmf gene, is involved in synapto-nuclear signaling and docks an N-Methyl-D-Aspartate receptor (NMDAR)-derived signalosome to nuclear target sites like the transcription factor cAMP-response-element-binding protein (CREB). Several reports indicate that mutations in NSMF are related to Kallmann syndrome (KS), a neurodevelopmental disorder characterized by idiopathic hypogonadotropic hypogonadism (IHH) associated with anosmia or hyposmia. It has also been reported that a protein knockdown results in migration deficits of Gonadotropin-releasing hormone (GnRH) positive neurons from the olfactory bulb to the hypothalamus during early neuronal development. Here we show that mice that are constitutively deficient for the Nsmf gene do not present phenotypic characteristics related to KS. Instead, these mice exhibit hippocampal dysplasia with a reduced number of synapses and simplification of dendrites, reduced hippocampal long-term potentiation (LTP) at CA1 synapses and deficits in hippocampus-dependent learning. Brain-derived neurotrophic factor (BDNF) activation of CREB-activated gene expression plays a documented role in hippocampal CA1 synapse and dendrite formation. We found that BDNF induces the nuclear translocation of Jacob in an NMDAR-dependent manner in early development, which results in increased phosphorylation of CREB and enhanced CREB-dependent Bdnf gene transcription. Nsmf knockout (ko) mice show reduced hippocampal Bdnf mRNA and protein levels as well as reduced pCREB levels during dendritogenesis. Moreover, BDNF application can rescue the morphological deficits in hippocampal pyramidal neurons devoid of Jacob. Taken together, the data suggest that the absence of Jacob in early development interrupts a positive feedback loop between BDNF signaling, subsequent nuclear import of Jacob, activation of CREB and enhanced Bdnf gene transcription, ultimately leading to hippocampal dysplasia.

Identification and Characterization of GABAergic Projection Neurons from Ventral Hippocampus to Amygdala.

GABAergic local circuit neurons are critical for the network activity and functional interaction of the amygdala and hippocampus. Previously, we obtained evidence for a GABAergic contribution to the hippocampal projection into the basolateral amygdala. Using fluorogold retrograde labeling, we now demonstrate that this projection indeed has a prominent GABAergic component comprising 17% of the GABAergic neurons in the ventral hippocampus. A majority of the identified GABAergic projection neurons are located in the stratum oriens of area CA1, but cells are also found in the stratum pyramidale and stratum radiatum. We could detect the expression of different markers of interneuron subpopulations, including parvalbumin and calbindin, somatostatin, neuropeptide Y, and cholecystokinin in such retrogradely labeled GABA neurons. Thus GABAergic projection neurons to the amygdala comprise a neurochemically heterogeneous group of cells from different interneuron populations, well situated to control network activity patterns in the amygdalo-hippocampal system.

Complex encounters: nanoparticles in whole blood and their uptake into different types of white blood cells.

AIM: A whole blood assay for evaluating the uptake of nanoparticles into white blood cells in order to close the gap between basic studies in cell culture and pharmacokinetic studies in animals was developed. MATERIALS & METHODS: After drawing peripheral blood into standard blood collection vials with different anticoagulants, amino- and carboxy-functionalized polymeric styrene nanoparticles were added and uptake was evaluated by flow cytometry. RESULTS: By counterstaining surface markers of leukocytes (e.g., monocytes, neutrophil granulocytes, B or T lymphocytes), investigations of different cell types can be conducted in a single run by flow cytometry. The authors demonstrated that anticoagulation should be done with heparin, and not EDTA, in order to prevent hampering of uptake mechanisms. CONCLUSION: By using heparinized whole blood, the authors demonstrated differences and usefulness of this assay for screening cellular uptake as it should occur in the bloodstream. Nevertheless, animal studies are warranted for final assessment of the nanoparticles.