Neonatal ventral hippocampal lesion (nVHL) in rats has been widely used as a neurodevelopmental model to mimic schizophrenia-like behaviors. Recently, we reported that nVHLs result in dendritic retraction and spine loss in prefrontal cortex (PFC) pyramidal neurons and medium spiny neurons of the nucleus accumbens (NAcc). Cerebrolysin (Cbl), a neurotrophic peptide mixture, has been reported to ameliorate the synaptic and dendritic pathology in models of aging and neurodevelopmental disorder such as Rett syndrome. This study sought to determine whether Cbl was capable of reducing behavioral and neuronal alterations in nVHL rats. The behavioral analysis included locomotor activity induced by novel environment and amphetamine, social interaction, and sensoriomotor gating. The morphological evaluation included dendritic analysis by using the Golgi-Cox procedure and stereology to quantify the total cell number in PFC and NAcc. Behavioral data show a reduction in the hyperresponsiveness to novel environment- and amphetamine-induced locomotion, with an increase in the total time spent in social interactions and in prepulse inhibition in Cbl-treated nVHL rats. In addition, neuropathological analysis of the limbic regions also showed amelioration of dendritic retraction and spine loss in Cbl-treated nVHL rats. Cbl treatment also ameliorated dendritic pathology and neuronal loss in the PFC and NAcc in nVHL rats. This study demonstrates that Cbl promotes behavioral improvements and recovery of dendritic neuronal damage in postpubertal nVHL rats and suggests that Cbl may have neurotrophic effects in this neurodevelopmental model of schizophrenia. These findings support the possibility that Cbl has beneficial effects in the management of schizophrenia symptoms.
BackgroundThe neurotrophin Brain-Derived Neurotrophic Factor (BDNF) influences nigral dopaminergic neurons via autocrine and paracrine mechanisms. The reduction of BDNF expression in Parkinson’s disease substantia nigra (SN) might contribute to the death of dopaminergic neurons because inhibiting BDNF expression in the SN causes parkinsonism in the rat. This study aimed to demonstrate that increasing BDNF expression in dopaminergic neurons of rats with one week of 6-hydroxydopamine lesion recovers from parkinsonism. The plasmids phDAT-BDNF-flag and phDAT-EGFP, coding for enhanced green fluorescent protein, were transfected using neurotensin (NTS)-polyplex, which enables delivery of genes into the dopaminergic neurons via neurotensin-receptor type 1 (NTSR1) internalization.ResultsTwo weeks after transfections, RT-PCR and immunofluorescence techniques showed that the residual dopaminergic neurons retain NTSR1 expression and susceptibility to be transfected by the NTS-polyplex. phDAT-BDNF-flag transfection did not increase dopaminergic neurons, but caused 7-fold increase in dopamine fibers within the SN and 5-fold increase in innervation and dopamine levels in the striatum. These neurotrophic effects were accompanied by a significant improvement in motor behavior.ConclusionsNTS-polyplex-mediated BDNF overexpression in dopaminergic neurons has proven to be effective to remit hemiparkinsonism in the rat. This BDNF gene therapy might be helpful in the early stage of Parkinson’s disease.
A neonatal basolateral-amygdala (nBLA) lesion in rats could be a potential animal model to study the early neurodevelopmental abnormalities associated with the behavioral and morphological brain changes observed in schizophrenia. Morphological alterations in pyramidal neurons from the prefrontal cortex (PFC) have been observed in postmortem schizophrenic brains, mainly because of decreased dendritic arbor and spine density. We assessed the effects of nBLA-lesion on the dendritic morphology of neurons from the PFC and the nucleus accumbens (NAcc) in rats. nBLA lesions were made on postnatal day 7 (PD7), and later, the dendritic morphology was studied by the Golgi-Cox stain procedure followed by Sholl analysis at PD35 (prepubertal) and PD60 (adult) ages. We also evaluated the effects of the nBLA-lesion on locomotor activity caused by a novel environment, apomorphine, and amphetamine. Adult animals with nBLA lesions showed a decreased spine density in pyramidal neurons from the PFC and in medium spiny cells from the NAcc. An increased locomotion in a novel environment and in amphetamine-treated adult animals with an nBLA-lesion was observed. Our results indicate that nBLA-lesion alters the neuronal dendrite morphology of the NAcc and PFC, suggesting a disconnection between these limbic structures. The locomotion paradigms support the idea that dopaminergic transmission is altered in the nBLA lesion model. This could help to understand the consequences of an earlier amygdala dysfunction in schizophrenia.
Apamin is a neurotoxin extracted from honey bee venom and is a selective blocker of small-conductance Ca²⁺-activated K⁺ channels (SK). Several behavioral and electrophysiological studies indicate that SK-blockade by apamin may enhance neuron excitability, synaptic plasticity, and long-term potentiation in the CA1 hippocampal region, and, for that reason, apamin has been proposed as a therapeutic agent in Alzheimer's disease treatment. However, the dendritic morphological mechanisms implied in such enhancement are unknown. In the present work, Golgi-Cox stain protocol and Sholl analysis were used to study the effect of apamin on the dendritic morphology of pyramidal neurons from hippocampus and the prefrontal cortex as well as on the medium spiny neurons from the nucleus accumbens and granule cells from the dentate gyrus (DG) of the hippocampus. We found that only granule cells from the DG and pyramidal neurons from dorsal and ventral hippocampus were altered in senile rats injected with apamin. Our research suggests that apamin may increase the dendritic morphology in the hippocampus, which could be related to the neuronal excitability and synaptic plasticity enhancement induced by apamin.
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