Background: STOP/MAP6 null (KO) mice recapitulate behavioral abnormalities related to positive and negative symptoms and cognitive deficits of schizophrenia. Here, we investigated whether decreased expression of STOP/MAP6 proteins in heterozygous mice (only one allele expressed) would result in abnormal behavior related to those displayed by STOP null mice. Methods: Using a comprehensive test battery, we investigated the behavioral phenotype of STOP heterozygous (Het) mice compared with STOP KO and wild type (WT) mice on animals raised either in standard conditions (controls) or submitted to maternal deprivation. Results: Control Het mice displayed prominent deficits in social interaction and learning, resembling KO mice. In contrast, they exhibited short-lasting locomotor hyperreactivity to acute mild stress and no impaired locomotor response to amphetamine, much like WT mice. Additionally, perinatal stress deteriorated Het mouse phenotype by exacerbating alterations related to positive symptoms such as their locomotor reactivity to acute mild stress and psychostimulant challenge. Conclusion: Results show that the dosage of susceptibility genes modulates their putative phenotypic contribution and that STOP expression has a high penetrance on cognitive abilities. Hence, STOP Het mice might be useful to investigate cognitive defects related to those observed in mental diseases and ultimately might be a valuable experimental model to evaluate preventive treatments.

Recently evidence has accumulated that schizophrenia can arise from primary synaptic defects involving structural proteins particularly, microtubule associated proteins. Previous experiments have demonstrated that a STOP (stable tubule only peptide) gene deletion in mice leads to a phenotype mimicking some aspects of positive symptoms classically observed in schizophrenic patients. In the current study, we determined if STOP null mice demonstrate behavioral abnormalities related to the social and cognitive impairments of schizophrenia. Compared with wild-type mice, STOP null mice exhibited deficits in the non-aggressive component of social recognition, short term working memory and social and spatial learning. As described in humans, learning deficits in STOP null mice were poorly sensitive to long term treatment with typical neuroleptics. Since social and cognitive dysfunction have consistently been considered as central features of schizophrenia, we propose that STOP null mice may provide a useful model to understand the neurobiological correlates of social and cognitive defects in schizophrenia and to develop treatments that better target these symptoms.

The ability to link events that are separated in time is important for extracting meaning from experiences and guiding behavior in the future. This ability likely requires the brain to continue representing events even after they have passed, a process that may involve the prefrontal cortex and takes the form of sustained, event-specific neuron activity. Here, we show that experimentally increasing the activity of excitatory neurons in the medial prefrontal cortex (mPFC) enables rats to associate two stimuli separated by a 750-ms long temporal gap. Learning is accompanied by ramping increases in prefrontal theta and beta rhythms during the interval between stimuli. This ramping activity predicts memory-related behavioral responses on a trial-by-trial basis but is not correlated with the same muscular activity during non-memory conditions. Thus, the enhancement of prefrontal neuron excitability extends the time course of evoked prefrontal network activation and facilitates the formation of associations of temporally disparate, but correlated, events.

Rat with excitotoxic neonatal ventral hippocampal lesions (NVHL rats) is considered as a heuristic neurodevelopmental model for studying schizophrenia. Extensive study of this model is limited by the lack of clear validity criteria of such lesions and because ascertaining of the lesions is realized postmortem with histological examination after completing experiments. Here, in a first experiment, by assessing the locomotor response to amphetamine in adult NVHL rats, we further specify that the lesions must be bilateral and confined to the ventral hippocampus to obtain the validated behavioral phenotype. We then show a longitudinal magnetic resonance imaging (MRI) protocol suitable for the detection of brain structural changes in NVHL rats. The T(2)-weighted images acquired in adult NVHL rats reveal the same structural changes as those appraised with histological protocol. Moreover, we demonstrate that the lesion status in adulthood can be accurately predicted from the T(2)-weighted images acquired in the juvenile period. As technical advantages, our MRI protocol makes possible to select animals according to lesion criteria as soon as in the juvenile period before long-lasting experiments and gives access in vivo to a quantitative parameter indicative of the lesion extent. Finally, we show that the lesion size increases only slightly between juvenile and adult periods. These latter results are discussed in the context of the specific postpubertal emergence of the behavioral deficits in NVHL rats.

The ability to capture the most relevant information from everyday experiences without constantly learning unimportant details is vital to survival and mental health. While decreased activity of the medial prefrontal cortex (mPFC) is associated with failed or inflexible encoding of relevant events in the hippocampus, mechanisms used by the mPFC to discern behavioral relevance of events are not clear. To address this question, we chemogenetically activated excitatory neurons in the mPFC of male rats and examined its impact on local network activity and differential associative learning dependent on the hippocampus. Rats were exposed to two neutral stimuli in two environments whose contingency with an aversive stimulus changed systematically across days. Over 2 weeks of differential and reversal learning, theta band activity began to ramp up toward the expected onset of the aversive stimulus, and this ramping activity tracked the subsequent shift of the set (stimulus modality to environment) predictive of the aversive stimulus. With chemogenetic mPFC activation, the ramping activity emerged within a few sessions of differential learning, which paralleled faster learning and stronger correlations between the ramping activity and conditioned responses. Chemogenetic mPFC activity, however, did not affect the adjustment of ramping activity or behavior during reversal learning or set-shifting, suggesting that the faster learning was not because of a general enhancement of attention, sensory, or motor processing. Thus, the dynamics of the mPFC network activation during events provide a relevance-signaling mechanism through which the mPFC exerts executive control over the encoding of those events in the hippocampus.

Anatomical and electrophysiological studies collectively suggest that the entorhinal cortex consists of several subregions, each of which is involved in the processing of different types of information. Consistent with this idea, we previously reported that the dorsolateral portion of the entorhinal cortex (DLE), but not the caudomedial portion, is necessary for the expression of a memory association between temporally discontiguous stimuli in trace eyeblink conditioning (Morrissey et al. (2012) J Neurosci 32:5356-5361). The present study examined whether memory acquisition depends on the DLE and what types of local neurotransmitter mechanisms are involved in memory acquisition and expression. Male Long-Evans rats experienced trace eyeblink conditioning, in which an auditory conditioned stimulus (CS) was paired with a mildly aversive electric shock to the eyelid (US) with a stimulus-free interval of 500 ms. Immediately before the conditioning, the rats received a microinfusion of neuroreactive substances into the DLE. We found that reversible inactivation of the DLE with GABAA receptor agonist, muscimol impaired memory acquisition. Furthermore, blockade of local muscarinic acetylcholine receptors (mACh) with scopolamine retarded memory acquisition while blockade of local NMDA receptors with APV had no effect. Memory expression was not impaired by either type of receptor blocker. These results suggest that the DLE is necessary for memory acquisition, and that acquisition depends on the integrity of local mACh receptor-dependent firing modulation, but not NMDA receptor-dependent synaptic plasticity.

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