Handling prevents and reverses cognitive deficits induced by sub-chronic phencyclidine in a model for schizophrenia in rats.

Treatments for schizophrenia are not effective in ameliorating cognitive deficits. Therefore, novel therapies are needed to treat cognitive impairments associated with schizophrenia (CIAS), which are modelled in rats through administration of sub-chronic phencyclidine (scPCP). We have previously shown that enrichment via voluntary exercise prevents and reverses impairments in novel object recognition (NOR) in this model. The present study aimed to investigate if handling could prevent delay-induced NOR deficits and prevent and reverse scPCP-induced NOR deficits. Two cohorts of adult female Lister Hooded rats were used. In experiment one, handling (five minutes/day, five days/week for two weeks), took place before scPCP administration (2 mg/kg, i.p. twice-daily for seven days). NOR tests were conducted at two, four, and seven weeks post-handling with a one-minute inter-trial interval (ITI) and at five weeks post-dosing with a six-hour ITI. In experiment two, rats were handled after scPCP administration and tested immediately in the one-minute ITI NOR task and again at two weeks post-handling. In both handling regimens, the scPCP control groups failed to discriminate novelty, conversely the scPCP handled groups significantly discriminated in this task. In the 6 h ITI test, vehicle control and scPCP control failed to discriminate novelty; however, the vehicle handled and scPCP handled groups did significantly discriminate. Handling rats prevented and reversed scPCP-induced deficits and prevented delay-induced NOR deficits. These findings add to evidence that environmental enrichment is a viable treatment for cognitive deficits in rodent tests and models of relevance to schizophrenia, with potential to translate into effective treatments for CIAS.

Deletion of α-neurexin II results in autism-related behaviors in mice.

Autism is a common and frequently disabling neurodevelopmental disorder with a strong genetic basis. Human genetic studies have discovered mutations disrupting exons of the NRXN2 gene, which encodes the synaptic adhesion protein α-neurexin II (Nrxn2α), in two unrelated individuals with autism, but a causal link between NRXN2 and the disorder remains unclear. To begin to test the hypothesis that Nrxn2α deficiency contributes to the symptoms of autism, we employed Nrxn2α knockout (KO) mice that genetically model Nrxn2α deficiency in vivo. We report that Nrxn2α KO mice displayed deficits in sociability and social memory when exposed to novel conspecifics. In tests of exploratory activity, Nrxn2α KO mice displayed an anxiety-like phenotype in comparison with wild-type littermates, with thigmotaxis in an open field, less time spent in the open arms of an elevated plus maze, more time spent in the enclosure of an emergence test and less time spent exploring novel objects. However, Nrxn2α KO mice did not exhibit any obvious changes in prepulse inhibition or in passive avoidance learning. Real-time PCR analysis of the frontal cortex and hippocampus revealed significant decreases in the mRNA levels of genes encoding proteins involved in both excitatory and inhibitory transmission. Quantification of protein expression revealed that Munc18-1, encoded by Stxbp1, was significantly decreased in the hippocampus of Nrxn2α KO mice, which is suggestive of deficiencies in presynaptic vesicular release. Our findings demonstrate a causal role for the loss of Nrxn2α in the genesis of autism-related behaviors in mice.

Deficits of neuronal glutamatergic markers in the caudate nucleus in schizophrenia.

Abnormal glutamate neurotransmission has been implicated in the pathophysiology of schizophrenia. In the present study we investigated two potential neuronal glutamatergic markers, the Excitatory Amino Acid Transporter 3 (EAAT3) and the Vesicular Glutamate Transporter 1 (VGluT1), in post-mortem striatal tissue from control subjects and from subjects with schizophrenia (n = 15 per group). We also investigated the possible influence of chronic antipsychotic administration (typical and atypical) on striatal VGluT1 expression in the rat brain. We found deficits in EAAT3 in all striatal regions examined in schizophrenia when compared to controls. Following correction for confounding factors (post-mortem interval), these deficits only remained significant in the caudate nucleus (p = 0.019). We also found significant deficits in VGluT1 in the caudate nucleus (p = 0.009) in schizophrenia. There were no significant differences in VGluT1 in the striatum of antipsychotic treated rats when compared to their vehicle treated controls. The data provides additional evidence for a glutamatergic synaptic pathology in the caudate nucleus in schizophrenia and may reflect a loss of glutamatergic cortico-striatal pathways. The absence of an effect of antipsychotic administration on VGluT1 indicates that the deficits in schizophrenia are unlikely to be a consequence of pharmacotherapy and thus likely to be a correlate of the disease process.

Deficits in parvalbumin and calbindin immunoreactive cells in the hippocampus of isolation reared rats.

Post-mortem studies have provided evidence for abnormalities of the gamma-aminobutyric acid (GABA)-ergic system in schizophrenia. The calcium-binding proteins (CBPs), parvalbumin (PV), calbindin (CB) and calretinin (CR) can be used as markers for specific subpopulations of GABAergic neurons in the brain. Isolation rearing of rats is a non-pharmacological, non-lesion manipulation that leads to deficits in prepulse inhibition of the startle reflex (PPI) and other behavioural and neurochemical alterations reminiscent of schizophrenia. Female rats were reared in social housing (groups of three) or singly for 11 weeks post weaning and PPI was measured. Brains were removed and hippocampal CBP- containing neurons determined following immunocytochemical staining. Compared to socially housed rats, isolated rats exhibited PPI deficits and reductions in PV and CB-immunoreactive cells in the hippocampus, with no significant change in CR. These findings demonstrate selective abnormalities of sub-populations of GABAergic interneurons in the hippocampus of isolation reared rats, which resemble the neuronal deficits seen in this region in schizophrenia.

The neuronal pathology of schizophrenia: molecules and mechanisms.

There is an accumulation of evidence for abnormalities in schizophrenia of both the major neurotransmitter systems of the brain - those of GABA (gamma-aminobutyric acid) and glutamate. Initial studies have found deficits in the putative neuronal marker, N-acetylaspartate, in a number of brain regions in schizophrenia. The animal models have provided some interesting correlates and discrepancies with these findings. The deficit in inhibitory interneurons within structures implicated in schizophrenic symptomatology may well have direct functional relevance, and can be induced by animal models of the disease such as subchronic phencyclidine administration or social isolation. Their association with these animal models suggests an environmental involvement. A loss of glutamatergic function in schizophrenia is supported by decreases in markers for the neuronal glutamate transporter in striatal structures that receive cortical glutamatergic projections. Deficits in the VGluT1 (vesicular glutamate transporter-1) in both striatal and hippocampal regions support this observation, and the association of VGluT1 density with a genetic risk factor for schizophrenia points to genetic influences on these glutamatergic deficits. Further studies differentiating neuronal loss from diminished activity and improved models allowing us to determine the temporal and causal relationships between GABAergic and glutamatergic deficits will lead to a better understanding of the processes underlying the neuronal pathology of schizophrenia.

Increased N-acetylaspartate in rat striatum following long-term administration of haloperidol.

N-acetylaspartate (NAA) is present in high concentrations in the CNS and is found primarily in neurons. NAA is considered to be a marker of neuronal viability. Numerous magnetic resonance spectroscopy (MRS) and postmortem studies have shown reductions of NAA in different brain regions in schizophrenia. Most of these studies involved patients chronically treated with antipsychotic drugs. However, the effect of chronic antipsychotic treatment on NAA remains unclear. In the present study, we measured NAA in brain tissue taken from 43 male Long-Evans rats receiving 28.5 mg/kg haloperidol decanoate i.m. every 3 weeks for 24 weeks and from 21 controls administered with vehicle. Determination of tissue concentrations of NAA was achieved by HPLC of sections of frozen tissue from several brain regions with relevance to schizophrenia. Chronic administration of haloperidol was associated with a significant increase (+23%) in NAA in the striatum (p<0.05) when compared to controls, with no significant changes in the other regions investigated (frontal and temporal cortex, thalamus, hippocampus, amygdala, and nucleus accumbens). NAA appears to be selectively increased in the striatum of rats chronically receiving haloperidol. This increase may reflect a hyperfunction of striatal neurons and relate to the reported increase in somal size of these cells and/or the increase in synaptic density seen in this region following antipsychotic administration. The lack of effect in other regions indicates that the well-documented NAA deficits seen in chronically treated schizophrenia patients is not an effect of antipsychotic medication and may in fact be related to the disease process.