ABSTRACT
Perinatal exposure to alcohol (PEA) induces general developmental and specific neuropsychiatric disturbances. Ethanol affects amino acid neurotransmission and synaptic plasticity. We were interested in the transcriptional effects of ethanol on the expression of complexins I and II, two synaptic vesicle proteins (SVP) with relevance for cognition and memory. We exposed pregnant Wistar inbred rats (N=4) and their pups until postnatal day 8 (P8) in vapor chambers and performed in situ-hybridizations regarding complexins I and II at P8 as well as neurobehavioral testing in adult animals of the same litters. At P8, serum ethanol levels of 281+/-58 mg/dl were achieved. PEA animals presented a pronounced retardation of postnatal growth. Significantly lower expression levels of complexin I was observed in CA1, together with trends of reductions in other hippocampal and cortical regions. Complexin II was found reduced in anterior cingulate, prefrontal and fronto-parietal cortex. Adult rats of exposed litters showed worse performance in hippocampus-dependent learning (Morris water maze). The observed suppression of complexins I and II reveals disturbed synaptic plasticity and corresponds with long lasting, ethanol-induced deficits of learning and memory. Further investigations should focus on other synaptic vesicle protein genes in order to unravel the molecular basis of ethanol-induced neurocognitive disabilities.
Subject(s)
Adaptor Proteins, Vesicular Transport/metabolism , Alcohol-Related Disorders/genetics , Ethanol/toxicity , Gene Expression/drug effects , Nerve Tissue Proteins/metabolism , Pregnancy Complications , Prenatal Exposure Delayed Effects/genetics , Administration, Inhalation , Alcohol-Related Disorders/blood , Alcohol-Related Disorders/psychology , Animals , Animals, Newborn , Brain/drug effects , Brain/metabolism , Ethanol/administration & dosage , Ethanol/blood , Female , Male , Maternal Exposure , Maze Learning/drug effects , Pregnancy , Prenatal Exposure Delayed Effects/psychology , RNA, Messenger/metabolism , Rats , Rats, WistarABSTRACT
Glutamatergic neurotransmission is critically involved into the pathogenesis of schizophrenic psychosis, in particular regarding cognitive and negative symptoms. The reported molecular mechanisms include increased glutamate transporter expression and antipsychotic agents such as clozapine were found able to suppress the expression of these genes. So far, the effects of the partial dopaminergic and serotonergic agonist aripiprazole on glutamatergic neurotransmission were never investigated. In a rat animal model of long-term antipsychotic treatment, we analyzed the expression of glutamate transporter genes after treatment with aripiprazole. Groups of 6 male Sprague-Dawley rats were treated for 4 weeks or 4 months with daily oral doses of 10 or 40mg aripiprazole per kg. Using semi-quantitative in situ-hybridization, we assessed the expression of pre- and post-synaptic glutamate transporter genes. Compared to control animals, differential expression levels were found in several cortical and hippocampal regions. The astroglial excitatory amino acid transporter genes EAAT1 and EAAT2 as well as the neuronal transporter EAAT3 were suppressed, while the presynaptic vesicular glutamate transporter vGluT1 was transiently induced in hippocampal subregions and EAAT4 was transiently suppressed in frontocortical areas. These transcriptional effects exerted by aripiprazole may counteract a glutamatergic deficit state and strengthen the neurotransmission of glutamate with positive consequences on cognitive and negative symptoms of schizophrenia.
