| Abstract No.: | C-C3112 |
| Country: | Canada |
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| Title: | REDUCED GABAERGIC INHIBITION AND ALTERED OSCILLATORY NETWORK ACTIVITY IN A MODEL OF SCHIZOPHRENIA: EFFECT OF PRENATAL IMMUNE CHALLENGE ON THE DEVELOPMENT OF THE HIPPOCAMPUS |
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| Authors/Affiliations: | 1 Guillaume Ducharme*; 1 Marc Danik; 1 Romain Goutagny; 1 Sylvain Williams;
1 McGill University, Douglas Hospital Research Center, Montreal, QC, Canada
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| Content: | Objectives: Numerous epidemiological studies have found that infection during pregnancy is an important risk factor for the development of schizophrenia in the offspring. The most striking of these studies has reported a 7 fold increase in schizophrenia in children from mothers who suffered an influenza infection during pregnancy.
One brain region that has been reported to be especially affected in schizophrenia is the hippocampus. This brain region is known to serve a variety of functions such as spatial/episodic memory and sensory integration which are known to be impaired in schizophrenia. More specifically, many post-mortem studies in human schizophrenics have demonstrated significant alteration in the GABAergic interneuron network of the hippocampus. These GABAergic interneurons are critical elements of hippocampal function since they control the excitability of principal neurons and as such are crucial for the generation of network oscillatory activity in the theta and gamma frequency range. These types of oscillations are known to be severely affected in schizophrenia. Leading theories on the function of these oscillations in the normal brain can explain many of the symptoms observed in schizophrenia. Given these observations, we investigated whether prenatal infection could alter the development of hippocampal interneurons and whether these changes have an effect on hippocampal rhythmogenesis.
Materials and Methods: We have exposed pregnant mice (at gestational day 9) to the viral mimetic polyriboinosinic-polyribocytidilic acid (PolyI:C) to trigger a strong inflammatory response characterized by significant hypothermia. We performed immunocytochemistry using several known interneuron markers (GAD, parvalbumin and somatostatin) to evaluate the state of the hippocampal inhibitory network in the offsprings at postnatal day 20. In addition, we conducted electrophysiological recordings in acute brain slices and in the intact hippocampus. We recorded miniature inhibitory post synaptic currents (mIPSC) in conventional hippocampal slices and measured spontaneous oscillations in whole septo-hippocampal preparation.
Results:
Using this combination of techniques in the poly I:C model, we found that prenatal infection early in pregnancy causes a severe reduction in the number of GAD positive neurons in the hippocampus (up to 40% in some subfields). This decrease in the number of inhibitory neurons was reflected at the synaptic level. Both the amplitude and frequency of miniature IPSCs were reduced in animals from poly I:C treated mothers, suggesting that both pre and post synaptic changes occurred. The effect of this decrease in inhibition was investigated at the level of the network where we found that spontaneous gamma oscillations in the intact septo-hippocampal preparation were significantly reduced, while theta oscillations were increased.
Conclusion: Prenatal and perinatal factors are increasingly being recognized as important factors in the etiology of schizophrenia. Our results show that the prenatal infection model captures essential features of the disease and as such can serve as a useful tool to investigate the synaptic mechanisms underlying the pathophysiology of schizophrenia
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