Schizophrenia Research Trends

72Guy Sandnerand the cause of the disconnection? Concerning the nature and cause of the disconnection, itcould be no more than a loss of synchrony among action potentials. This would be difficult toobserve directly [91], but some predictions about its consequence on the global brain activitycould be checked [12, 68]. It could also correspond to a diffuse micro-anatomical orbiochemical alteration. Some recent speculations have opened the possibility of a diffuse glialfunctional deficit or a neuronal cytoskeleton weakness. But for testing these ideas, studies onlower animal models are needed.ForewordMODELS OF SCHIZOPHRENIA USING LOWER ANIMALSProducing schizophrenia in rats (or in any other lower animal) and being able to observeall its manifestations is obviously impossible. Models are only expected to provideexplanations for some manifestations of the disease and to offer means to test drugs [79]. Forbuilding a model, two aspects have to be considered. First, the animal’s brain has to bemodified (independent variable of the experimental approach). Second, one or severalrelevant behavioral criteria have to be tested (dependent variables). The validity of a model isdocumented either on a theoretical ground (construct validity), on the observation of themodeled feature in patients (face validity), or on the reversibility of any property of the brainby drugs used to attenuate the manifestations of the disease in humans (predictive validity)[188]. It is very difficult to find out whether a specific modification of behavior in humans orlower animals is directly related to the cause of the disease, because of the adaptability of thebrain and of the behavior. The reaction to a modification may hide the basic modification.This may reflect an anatomo-functional reorganization or a neuro-psychological substitutionof the altered function. Therefore, even if we knew the cause of the disease, its experimentalreproduction in an animal would seldom produce a similar phenotypic expression as inhumans. We will briefly consider in turn, some classical and more speculative behavioralcriteria, and then some means to produce their modification.Neurobiological and Behavioral Models1) Prepulse inhibition of the startle reflex and P50: Prepulse inhibition (PPI) refers to thereducing effect of a weak stimulus, called prepulse, on the subsequent startling effect of astrong stimulus, called pulse. Most often, the prepulse is a tone, sometimes a tactile stimulus,and the pulse, a noise or an air-puff. P50 gating also corresponds to a reducing effect of anauditory prepulse on the response to a pulse, the response being assessed using the amplitudeof a positive evoked potential, following by 50 ms the pulse. In PPI, the optimum intervalbetween prepulse and pulse is 100 ms and in P50, 500 ms. They were interpreted as “preattentive”filtering mechanisms and were found deficient in patients, unfortunately notspecifically in schizophrenia [17, 60]. My favorite alternate explanation is that the changesobserved in such basic reflexes result from a perturbation of the tonic top-down glutamatergic