Prenatal immune challenge induces behavioral deficits, neuronal remodeling, and increases brain nitric oxide and zinc levels in the male rat offspring.

Schizophrenia is a severe mental disorder with numerous etiological susceptibilities. Maternal infection is a key risk factor for schizophrenia. Prenatal lipopolysaccharide (LPS) infection stimulates cytokine production that affects brain development. In the present study, we aimed to investigate the effect of prenatal LPS injection at gestational day (GD) 14-16 on behavioral paradigms, and neuronal morphology in the prefrontal cortex (PFC), basolateral amygdala (BLA), nucleus accumbens (NAcc) and ventral hippocampus (VH) at two critical ages of development: pre-pubertal (postnatal day 35, PD35) and post-pubertal (PD60) age in male rats. We also evaluated the effects of LPS on nitric oxide (NO) and zinc (Zn) levels in seven brain areas (PFC, VH, amygdala, brainstem, striatum and dorsal hippocampus) at PD35 and PD60. LPS induced hyperlocomotion in a novel environment and reduced social contact as well as increased the levels of NO and Zn in the PFC, brainstem and amygdala as observed in other animal models of schizophrenia-related behavior. Furthermore, we found that LPS-treated rats presented post-pubertal neuronal hypertrophy in the PFC and BLA and decreased spine density in the NAcc. The neuronal morphology of neurons in the VH in LPS-treated rats remained unaltered. Interestingly, the anxiogenic-related behavior correlated with neuronal hypertrophy observed in the BLA. Our findings suggest that the behavioral and neural modifications observed in our model could be mediated by the long-lasting alterations in Zn and NO levels in the brain.

Acute mechanisms underlying antibody effects in anti-N-methyl-D-aspartate receptor encephalitis.

OBJECTIVE: A severe but treatable form of immune-mediated encephalitis is associated with antibodies in serum and cerebrospinal fluid (CSF) against the GluN1 subunit of the N-methyl-D-aspartate receptor (NMDAR). Prolonged exposure of hippocampal neurons to antibodies from patients with anti-NMDAR encephalitis caused a reversible decrease in the synaptic localization and function of NMDARs. However, acute effects of the antibodies, fate of the internalized receptors, type of neurons affected, and whether neurons develop compensatory homeostatic mechanisms were unknown and are the focus of this study. METHODS: Dissociated hippocampal neuron cultures and rodent brain sections were used for immunocytochemical, physiological, and molecular studies. RESULTS: Patient antibodies bind to NMDARs throughout the rodent brain, and decrease NMDAR cluster density in both excitatory and inhibitory hippocampal neurons. They rapidly increase the internalization rate of surface NMDAR clusters, independent of receptor activity. This internalization likely accounts for the observed decrease in NMDAR-mediated currents, as no evidence of direct blockade was detected. Once internalized, antibody-bound NMDARs traffic through both recycling endosomes and lysosomes, similar to pharmacologically induced NMDAR endocytosis. The antibodies are responsible for receptor internalization, as their depletion from CSF abrogates these effects in hippocampal neurons. We find that although anti-NMDAR antibodies do not induce compensatory changes in glutamate receptor gene expression, they cause a decrease in inhibitory synapse density onto excitatory hippocampal neurons. INTERPRETATION: Our data support an antibody-mediated mechanism of disease pathogenesis driven by immunoglobulin-induced receptor internalization. Antibody-mediated downregulation of surface NMDARs engages homeostatic synaptic plasticity mechanisms, which may inadvertently contribute to disease progression.

[Depression and neuroplasticity. Interaction of nervous, endocrine and immune systems]. / Depresión y neuroplasticidad. Interacción de los sistemas nervioso, endocrino e inmune.

Clinical depression is a physical and psychic disease that has neuropathological basis, although the clear understanding of its ethiopathology is still missing. There is evidence of a genetic component in depression, however, the participation of environment is crucial. Stress plays an essential role in the onset of depression. The interaction and the response of the endocrine system with the immune and nervous system are altered in depression. The observation of the effect of antidepressants on monoaminergic transmitters leads to the hypothesis of monoamines. However this hypothesis cannot explain many of the mechanisms involved in the action of antidepressants. The new hypothesis proposed to explain the action of antidepressant is the neuro-plasticity hypothesis. This hypothesis suggests that the effects of antidepressants on nervous, immune and endocrine systems are able to induce neuroadaptative changes in the brain. The neuroplasticity have been described as the ability of the brain to reorganize itself and form new neuronal connections throughout life. It is proposed that antidepressants influence neuroplasticity inducing improvements in the symptoms of this illness.

Role of mast cell- and non-mast cell-derived inflammatory mediators in immunologic induction of synaptic plasticity.

We have previously discovered a long-lasting enhancement of synaptic transmission in mammal autonomic ganglia caused by immunological activation of ganglionic mast cells. Subsequent to mast cell activation, lipid and peptide mediators are released which may modulate synaptic function. In this study we determined whether some mast cell-derived mediators, prostaglandin D2 (PGD2; 1.0 microM), platelet aggregating factor (PAF; 0.3 microM) and U44619 (a thromboxane analogue; 1.0 microM), and also endothelin-1 (ET-1; 0.5 microM) induce synaptic potentiation in the guinea pig superior cervical ganglion (SCG), and compared their effects on synaptic transmission with those induced by a sensitizing antigen, ovalbumin (OVA; 10 micrograms/ml). The experiments were carried out on SCGs isolated from adult male guinea pigs (200-250 g) actively sensitized to OVA, maintained in oxygenated Locke solution at 37 degrees C. Synaptic potentiation was measured through alterations of the integral of the post-ganglionic compound action potential (CAP). All agents tested caused long-term (LTP; duration > or = 30 min) or short-term (STP; < 30 min) potentiation of synaptic efficacy, as measured by the increase in the integral of the post-ganglionic CAP. The magnitude of mediator-induced potentiation was never the same as the antigen-induced long-term potentiation (A-LTP). The agent that best mimicked the antigen was PGD2, which induced a 75% increase in CAP integral for LTP (antigen: 94%) and a 34% increase for STP (antigen: 91%). PAF-, U44619-, and ET-1-induced increases in CAP integral ranged for LTP from 34 to 47%, and for STP from 0 to 26%. These results suggest that the agents investigated may participate in the induction of A-LTP.

Role of mast cell- and non-mast cell -derived inflammatory mediators in immunologic induction of synaptic plasticity

We have previously discovered a long-lasting enhancement of synaptic transmission in mammal autonomic ganglia caused by immunological activation of ganglionic mast cells. Subsequent to mast cell activation, lipid and peptide mediators are released which may modulate synpatic function. In this study we determined whether some mast cell-derived mediators, prostaglandin D2 (PGD2; 1.0 muM), platelet aggregating factor (PAF; 0.3 muM) and U44619 (a thromboxane analogue; 1.0 muM), and also endothelin-1 (ET-1; 0.5 muM) induce synaptic potentiation in the guinea pig superior cervical ganglion (SCG), and compared their effects on synaptic transmission with those induced by a sensitizing antigen, ovalbumin (OVA; 10 mug/ml). The experiments were carried out on SCGs isolated from adult male guinea pigs (200-250 g) actively sensitized to OVA, maintained in oxygenated Locke solution at 37 graus Celsius. Synaptic potentiation was measured through alterations of the integral of the post-ganglionic compound action potential (CAP). All agents tested caused long-term (LTP; duration = 30 min) or short-term (STP; <30 min) potentiation of synaptic efficacy, as measured by the increase in the integral of the post-ganglionic CAP. The magnitude of mediator-induced potentiation was never the same as the antigen-induced long-term potentiation (A-LTP). The agent that best mimicked the antigen was PGD2, which induced a 75 per cent increase in CAP integral for LTP (antigen: 94 per cent) and a 34 per cent increase for STP (antigen: 91 per cent). PAF-, U44619-, and ET-1 induced increases in CAP integral ranged for LTP from 34 to 47 per cent, and for STP from 0 to 26 per cent. These results suggest that the agents investigated may participate in the induction of A-LTP.