Early ethanol exposure and vinpocetine treatment alter learning‐ and memory‐related proteins in the rat hippocampus and prefrontal cortex

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Fetal alcohol‐spectrum disorders (FASD) encompass a wide range of clinical features from subtle to dramatic changes in appearance, behavior, and cognition (May and Baete, 2015) and are caused by the maternal consumption of alcohol during pregnancy when the brain is most vulnerable (Jones, 2011). Learning and memory deficits are especially prevalent during childhood and adolescence in individuals with FASD (Kodituwakku, 2007; Willoughby et al., 2008). Other characteristics include visuospatial deficits, impairments in fine and gross motor skills, hyperactivity, depression, and drug dependence (Famy et al., 1998; O'Connor and Paley, 2009).
In humans, apoptotic or excitotoxic neuronal loss was thought to be the cause of the neuronal deficits in FASD (Ikonomidou et al., 2000). On average, the volume of brain areas, such as the hippocampus, was smaller (Joseph et al., 2014), and a decrease in cortical thickness was observed (Zhou et al., 2011) in patients with FASD. However, the functionality of the remaining cells remains unclear. Evidence from animal models suggests that neuronal plasticity deficits and impaired neurotransmission underlie the neurological deficits observed in children exposed to ethanol during the early stages of development (Krahe et al., 2010; Lantz et al., 2012). The heterogeneity of neuronal deficits observed in FASD depend on the pattern and level of ethanol exposure (Kleiber et al., 2013). Numerous animal models of FASD have been described (Patten et al., 2014). Rodents exposed to alcohol prenatally or during the early postnatal period have been shown to exhibit deficits in learning and memory (Filgueiras et al., 2010), depression‐like behavior and hyperactivity (Nunes et al., 2011; Brocardo et al., 2012; Brys et al., 2014), and a greater vulnerability to developing addiction‐like behaviors (Barbier et al., 2008). Brain‐derived neurotrophic factor (BDNF) and its signaling pathways, comprising, among others, mitogen‐activated protein kinase phosphatase (MKP‐1), extracellular signal‐regulated kinase 1/2 (ERK1/2), and glycogen synthase kinase 3 β (GSK3β) have all been implicated in developmental and learning and memory processes (Lee and Son, 2009; Schmitt et al., 2009; Peng et al., 2010; Goggin et al., 2014). Several studies have indicated changes in neurotrophins and their signaling pathways after early ethanol exposure (Barbier et al., 2008; DuPont et al., 2014; Goggin et al., 2014). This study investigates whether early postnatal ethanol‐induced changes in learning and memory and neural plasticity‐related proteins could be reversed by treatment with vinpocetine, a type 1 phosphodiesterase (PDE) inhibitor (Lantz et al., 2012), contextualized as a possible treatment for FASD. Vinpocetine has been shown to facilitate long‐term potentiation, enhance dendritic spine complexity, increase neuronal plasticity (Lantz et al., 2012), improve spatial learning in the Morris water maze (MWM; Filgueiras et al., 2010) and reduce hyperactivity in animal models of FASD (Nunes et al., 2011). We hypothesized that adolescent rats exposed to ethanol during the early postnatal period would take longer to find the hidden platform in the MWM and would have reduced levels of neural plasticity‐related proteins in the prefrontal cortex (PFC) and dorsal hippocampus (DH). These are key brain regions involved in cognitive function and learning and memory processes (Fanselow and Dong, 2010). Furthermore, treatment of rats exposed to early ethanol with vinpocetine would restore neural plasticity‐related proteins, thereby enabling rats to find the hidden platform in a time similar to that of controls. This study provides novel insight into the long‐term effects of ethanol and vinpocetine on neural plasticity‐related proteins in the rat brain.
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