ABSTRACT
Transient prenatal vitamin D deficiency is considered a neurodevelopmental animal model in schizophrenia research. Vitamin D deficiency in female rats causes morphological, cellular and molecular changes in the brain and alters behaviour and nerve growth factors expression in their offspring. Prenatal depleted animals showed a significant impairment of latent inhibition, a feature often associated with schizophrenia and of hole board habituation. Interestingly, memory consolidation of brightness discrimination was improved. Possible functional effects of altered brain development that results from prenatal vitamin D deficiency were characterized by investigation of potentiation phenomena in the hippocampus in freely moving rats. Transient prenatal vitamin D deficiency induced an enhancement of long-term potentiation (LTP) using either weak tetanic or strong tetanic stimulation, whereas the response to test stimuli was not changed. The classic neuroleptic drug haloperidol (Hal) and the atypical neuroleptic risperidone (Ris) in doses, which normalized behavioural disturbances in prenatal vitamin D-deficient animals without any side effects on the normal behaviour decreased the enhanced LTP in the experimental group to control level. Interestingly, the effect of the substances was different in experimental and control rats. The LTP was enhanced in control animals by the low doses of the drugs effective in our behavioural experiments. It can be suggested, that changes in brain development induced by prenatal vitamin D deficiency lead to specific functional alterations in hippocampal synaptic plasticity. LTP is considered a cellular correlate of learning and memory. The better retention performance in brightness discrimination seems in accordance with enhanced potentiation level.
Subject(s)
Dentate Gyrus/physiopathology , Neuronal Plasticity/drug effects , Neuronal Plasticity/physiology , Vitamin D Deficiency/physiopathology , Animals , Dentate Gyrus/drug effects , Female , Haloperidol/pharmacology , Long-Term Potentiation/drug effects , Long-Term Potentiation/physiology , Male , Pregnancy , Rats , Rats, Sprague-Dawley , Risperidone/pharmacology , Time FactorsABSTRACT
Focal ischaemia in the cerebral cortex affects the inducibility of long-term potentiation (LTP) in the hippocampus. This impairment of hippocampal function may result from excessive activation of cortico-hippocampal afferents and subsequent perturbation of hippocampal LTP-relevant transmitter systems, which include opioids. Here, we tested if permanent focal ischaemia and electrical afferent stimulation influence the expression of the mu-opioid receptor (MOR) in the rat hippocampus. In the applied ischaemia model, the entire ipsilateral cortical hemisphere and hippocampus experienced sustained excitation as indicated by a long-lasting increase in the expression of arg 3.1/arc (ARG) mRNA, a marker for neuronal activity. Expression of MOR mRNA and protein was strongly increased in granule cells, which contain very low MOR levels under normal conditions, but not in gamma-aminobutyric acid (GABA)ergic neurons, which express the MOR constitutively. In the molecular layer, which contains the dendrites of granule cells, focal ischaemia caused a redistribution of MOR-like immunoreactivity. In contrast to the dentate gyrus, MOR expression was unaltered in the hippocampus proper and in non-infarcted cortical areas. Repetitive high-frequency stimulation of cortico-hippocampal perforant path afferents induced strong MOR mRNA expression throughout the granular layer. However, weak tetanization sufficient to induce LTP and ARG expression did not influence MOR mRNA levels. Taken together, we provide direct evidence for the induction of MOR expression in granule cells experiencing sustained excitation by cortical afferents. In activated, MOR-expressing granule cells, inhibitory opioids may counter-regulate glutamatergic excitation by the perforant path.
Subject(s)
Brain Ischemia/pathology , Entorhinal Cortex/radiation effects , Gene Expression Regulation/physiology , Hippocampus/pathology , Neurons/metabolism , Perforant Pathway/physiology , Receptors, Opioid, mu/metabolism , Animals , Brain Ischemia/etiology , Brain Ischemia/metabolism , Cytoskeletal Proteins/genetics , Cytoskeletal Proteins/metabolism , Diagnostic Imaging/methods , Disease Models, Animal , Dose-Response Relationship, Radiation , Electric Stimulation/methods , Entorhinal Cortex/physiopathology , Functional Laterality/physiology , Gene Expression Regulation/radiation effects , Glutamate Decarboxylase/metabolism , Immunohistochemistry/methods , In Situ Hybridization/methods , Infarction, Middle Cerebral Artery/complications , Long-Term Potentiation/physiology , Long-Term Potentiation/radiation effects , Male , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Neurons/radiation effects , Perforant Pathway/radiation effects , RNA, Messenger/metabolism , Rats , Receptors, Opioid, mu/genetics , Reverse Transcriptase Polymerase Chain Reaction/methodsABSTRACT
The present work analyzed the changes in evoked field potentials of freely moving rats after kindling induced by a convulsant inverse agonist of the GABA(A)-benzodiazepine receptor complex, methyl beta-carboline-3-carboxylate (beta-CCM). Two doses of beta-CCM (2 mg/kg and 4 mg/kg) were used. In kindled and control animals, a stimulating electrode was implanted in the perforant pathway and a recording electrode in the dentate gyrus. Results showed that, after an acutely injected dose of 20 mg/kg pentylenetetrazol (PTZ), all kindled animals showed a decrease in population spike amplitude after 20 min. After 60 min, only fully kindled rats showed a long-lasting potentiation, also visible up to 24 h later, as compared to controls or nonkindled animals. Changes in glutamate and GABA receptor binding measured in previous experiments may explain this potentiation effect observed in fully kindled rats.
