The antipsychotic olanzapine reduces memory deficits and neuronal abnormalities in a male rat model of Autism.

The prevalence of autism spectrum disorder (ASD), a neurodevelopmental condition that impacts social interaction and sensory processing, is rising. Valproic acid (VPA) exposure during pregnancy causes autistic-like traits in offspring. Olanzapine (OLZ), an atypical antipsychotic, is used to treat ASD. We assessed the impact of OLZ on behavior, neuromorphology, and nitric oxide (NO) levels in the hippocampus using prenatal VPA treatment in rats. It is commonly known that ASD patients exhibit sensory abnormalities. As such, we utilized the tail flick test to validate the ASD model. In the novel object recognition test (NORT), VPA exposure reduces the discrimination index (DI) in the first introduction to the novel object. Moreover, OLZ and vehicle-treated rats perform differently in the second exposition to the DI of the novel object, suggesting that OLZ reverses VPA-induced deficits in recognition memory. The latency to find the hidden platform in the Morris water maze test of memory and learning improves in VPA-exposed rats after OLZ administration, indicating that OLZ improves spatial memory in these rats. Administration of prenatal VPA induces neuronal hypotrophy and reduces spine density in pyramidal neurons of the CA1 region of the hippocampus. Treatment with OLZ corrects the neuromorphological changes brought on by VPA. In the CA1 region of the hippocampus, VPA treatment increases the number of neurons, which normalizes with OLZ treatment. OLZ increases the NO levels in the dorsal hippocampus in control rats. In rats exposed to VPA, the second-generation antipsychotic OLZ reduces memory-related and neuroplastic alterations. The current findings support the use of OLZ in this illness and further validate the use of prenatal VPA as a model of ASD.

Cyclic changes and actions of progesterone and allopregnanolone on cognition and hippocampal basal (stratum oriens) dendritic spines of female rats.

Ovarian steroids modulate the neuronal structure and function during the estrous cycle, contrasting peak effects during the proestrus cycle and low effects during the metestrus cycle. An ovariectomy (OVX) decreases gonadal hormones and tests the effects of substitutive therapies. We studied female rats with a normal estrous cycle and we also studied the effects of systemic progesterone (P4, 4.0 mg/kg) or its reduced metabolite allopregnanolone (ALLO, 4.0 mg/kg, both for 10 days) in females who had had an OVX 16.5 weeks prior to the study (long-term OVX) with the novel object recognition test (NORT) for associative memory. The dendritic shape and spine density in Golgi-impregnated basal dendrites (stratum oriens) of hippocampal pyramidal neurons was also studied. Proestrus females had a better performance than metestrus or OVX females in short-term memory (tested 1 h after the acquisition phase). Proestrus and metestrus females showed better results than OVX females for long-term memory (24 h after the initial phase). Both P4 and ALLO recovered the cognitive impairment induced by long-term OVX. Also, proestrus females had a higher density of dendritic spines than metestrus females, OVX reduced the density of spines when compared to intact females, whereas both P4 and ALLO treatments increased the dendritic spine density, number of dendritic branches along the dendritic length, and branching order compared to vehicle. These data add the dendrites of the stratum oriens as an additional site for naturally occurring changes in spine density during the estrous cycle and evidence the actions of progestins in both behavioral recovery and the structural dendritic rearrangement of hippocampal pyramidal neurons in long-term OVX female rats.

Cerebrolysin prevents deficits in social behavior, repetitive conduct, and synaptic inhibition in a rat model of autism.

Autism spectrum disorder (ASD) is a syndrome of diverse neuropsychiatric diseases of growing incidence characterized by repetitive conduct and impaired social behavior and communication for which effective pharmacological treatment is still unavailable. While the mechanisms and etiology of ASD are still unknown, a consensus is emerging about the synaptic nature of the syndrome, suggesting a possible avenue for pharmacological treatment with synaptogenic compounds. The peptidic mixture cerebrolysin (CBL) has been successfully used during the last three decades in the treatment of stroke and neurodegenerative disease. Animal experiments indicate that at least one possible mechanism of action of CBL is through neuroprotection and/or synaptogenesis. In the present study, we tested the effect of CBL treatment (daily injection of 2.5 mL/Kg i.p. during 15 days) on a rat model of ASD. This was based on the offspring (43 male and 51 female pups) of a pregnant female rat injected with valproic acid (VPA, 600 mg/Kg) at the embryonic day 12.5, which previous work has shown to display extensive behavioral, as well as synaptic impairment. Comparison between saline vs. CBL-injected VPA animals shows that CBL treatment improves behavioral as well as synaptic impairments, measured by behavioral performance (social interaction, Y-maze, plus-maze), maximal response of inhibitory γ-amino butyric acid type A receptor (GABAA R)-mediated synaptic currents, as well as their kinetic properties and adrenergic and muscarinic modulation. We speculate that CBL might be a viable and effective candidate for pharmacological treatment or co-treatment of ASD patients. © 2017 Wiley Periodicals, Inc.

Unilateral injection of Aß25-35 in the hippocampus reduces the number of dendritic spines in hyperglycemic rats.

Alzheimer's disease (AD) is a neurodegenerative process exacerbated by several risk factors including impaired glucose metabolism in the brain that could cause molecular and neurochemical alterations in cognitive regions such as the hippocampus (Hp). Consequently, this process could cause neuronal morphological changes; however, the mechanism remains elusive. We induced chronic hyperglycemia after streptozotocin (STZ) administration. Then, we examined spatial learning and memory using the Morris water maze test and evaluated neuronal morphological changes using the Golgi-Cox stain procedure in hyperglycemic rats that received a Aß25-35 unilateral injection into the Hp. Our results demonstrate that STZ combined with Aß25-35 induced significant deficits in the spatial memory. In addition, we observed a significant reduction in the number of dendritic spines of pyramidal neurons in the dorsal Hp of rats with STZ plus Aß25-35 . In conclusion, the reduced spine density of pyramidal neurons in the CA1 dorsal Hp could produce the spatial memory deficit observed in these animals. These results suggest that hyperglycemia can trigger Aß-induced neurodegeneration and thus the appearance of AD symptoms would be accelerated. Synapse 68:585-594, 2014. © 2014 Wiley Periodicals, Inc.

Prefrontal cortex, hippocampus, and basolateral amygdala plasticity in a rat model of autism spectrum.

We aimed to investigate the effect of prenatal administration of valproic acid (VPA) (500 mg/kg) at embryonic day 12.5 on the anatomical properties of the prefrontal cortex, hippocampus, and basolateral amygdala, at three different ages: immediately after weaning (postnatal day 21 [PD21]), prepubertal (PD35), and postpubertal (PD70) ages in a rat model of autistic spectrum disorder. Quantitative analysis of the thickness of the prefrontal cortex revealed a reduced size at all study ages in the cingulate 1 area of the prefrontal cortex and CA1 of the dorsal hippocampus in prenatally exposed animals compared to controls. At the level of the basolateral amygdala, a reduction in the size was observed at PD35 and PD70 in the VPA group. In addition, a reduced thickness was observed in the prelimbic region of the prefrontal cortex in VPA animals at PD35. Interestingly, no differences in cortical thickness were observed between control and VPA animals in the infralimbic region of the prefrontal at any age. Our results suggest that prenatal exposure to VPA differentially alters cortical limbic regions anatomical parameters, with implication in the autistic spectrum disorder.

Clozapine administration reverses behavioral, neuronal, and nitric oxide disturbances in the neonatal ventral hippocampus rat.

Clozapine is widely used in the treatment of schizophrenia; however its complete mechanism of action is not fully established. The neonatal ventral hippocampal lesion (nVHL) has emerged as a model of schizophrenia-related behavior. Our group has previously shown hyperresponsiveness to novel environment, neuronal atrophy in prefrontal cortex (PFC) and nucleus accumbens (NAcc) neurons as well as abnormal levels of nitric oxide (NO) in the PFC of the nVHL rat. In the present study, we aimed to investigate the role of repeated clozapine administration (2 mg/kg/day for 21 days) in a novel environment, neuronal rearrangement in PFC, NAcc and basolateral amygdala (BLA) as well as NO levels in this model. Clozapine administration reversed the hyperlocomotion observed in a novel environment in the nVHL rat with no effect on locomotion in sham animals. Quantitative morphological analysis demonstrated a retracted neuronal arborization and decreased spinogenesis in the NAcc, PFC and BLA in nVHL rat. Interestingly, clozapine administration also rescued neuronal atrophy in these brain regions. The nVHL also displayed increased NO levels in PFC, striatum and occipital cortex. Clozapine administration selectively reversed these abnormal levels of NO in striatum in nVHL rat while NO levels were increased in the PFC of sham animals. Our results further extend the usefulness of the nVHL as a model of schizophrenia-related behavior and suggest that clozapine reverses behavioral deficits in these animals by modulating neuronal reorganization and NO levels in the brain.

Neonatal ventral hippocampus lesion induces increase in nitric oxide [NO] levels which is attenuated by subchronic haloperidol treatment.

Haloperidol is a potent dopamine receptor antagonist and used to treat psychotic disorders, such as schizophrenia. Recent clinical and preclinical studies demonstrated the overactivity of the nitric oxide (NO) system in schizophrenia. Neonatal ventral hippocampal (nVH) lesions in rats have been widely used as a neurodevelopmental model that mimics schizophrenia-like behaviors. Here, we investigate first whether the nVH lesion causes changes in NO levels in different limbic brain regions in young adults, postnatal day (PD) 81, and second, whether haloperidol treatment from PD60 to PD81 reverses these changes, by determining the accumulation of nitrites. The results show that NO levels at the level of the prefrontal cortex, occipital cortex, and cerebellum are higher in the nVH lesion animals, and that the haloperidol, in part, attenuates these altered NO levels. The NO levels observed in the nVH lesion animals with and without haloperidol treatment may be relevant to behaviors observed in schizophrenia.