Cellular and Molecular Changes in Hippocampal Glutamate Signaling and Alterations in Learning, Attention, and Impulsivity Following Prenatal Nicotine Exposure.

Over 70 million European pregnant women are smokers during their child-bearing years. Consumption of tobacco-containing products during pregnancy is associated with several negative behavioral outcomes for the offspring, including a higher susceptibility for the development of attention-deficit/hyperactive disorder (ADHD). In efforts to minimize fetal exposure to tobacco smoke, many women around the world switch to nicotine replacement therapies (NRTs) during the gestational period; however, prenatal nicotine exposure (PNE) in any form has been associated with alterations in cognitive processes, including learning, memory, and attention. These processes are controlled by glutamatergic signaling of hippocampal pyramidal neurons within the CA1 region, suggesting actions of nicotine on glutamatergic transmission in this region if present prenatally. Accordingly, we aimed to investigate hippocampal glutamatergic function following PNE treatment in NMRI mice employing molecular, cellular electrophysiology, and pharmacological approaches, as well as to evaluate cognition in the rodent continuous performance task (rCPT), a recently developed mouse task allowing assessment of learning, attention, and impulsivity. PNE induced increases in the expression levels of mRNA coding for different glutamate receptors and subunits within the hippocampus. Functional alterations in AMPA and NMDA receptors on CA1 pyramidal neurons of PNE mice were suggestive of higher GluA2-lacking and lower GluN2A-containing receptors, respectively. Finally, PNE was associated with reduced learning, attention, and enhanced impulsivity in the rCPT. Alterations in glutamatergic functioning in CA1 neurons parallel changes seen in the spontaneously hypertensive rat ADHD model and likely contribute to the lower cognitive performance in the rCPT.

Metabotropic Glutamate Receptor 2 and Dopamine Receptor 2 Gene Expression Predict Sensorimotor Gating Response in the Genetically Heterogeneous NIH-HS Rat Strain.

Disruption of sensorimotor gating causes "flooding" of irrelevant sensory input and is considered a congenital trait in several neurodevelopmental disorders. Prepulse inhibition of acoustic startle response (PPI) is the operational measurement and has a high translational validity. Pharmacological studies in rodents have linked alterations in serotonin, dopamine and glutamate signalling to PPI disruption. How PPI response is associated with gene expression levels of these receptors is unknown. PPI response was assessed in 39 genetically heterogeneous National Institutes of Health-Heterogeneous Stock (NIH-HS) rats. Animals were classified as high, medium or low PPI. Expression levels of glutamate metabotropic receptor 2 (Grm2), dopamine receptor D2 (Drd2), dopamine receptor D1 (Drd1), serotonin receptor 1A (Htr1a), serotonin receptor 2A (Htr2a) and homer scaffolding protein 1 (Homer1) were investigated in prefrontal cortex (PFC) and striatum (STR). When comparing the two extreme phenotypes, only Drd2 in STR showed increased expression in the low PPI group. A multinomial model fitting all genes and all groups indicated that Grm2 in PFC, and Grm2 and Drd2 in the STR predicted PPI group. This was corroborated by a linear relationship of Grm2 with PPI in PFC, and Drd2 with PPI in STR. An interaction between levels of H3K27 trimethylation, associated with transcriptional repression, and PPI phenotype was observed for Drd2 in STR. Gene set enrichment analysis on a microarray dataset on Lewis rats confirmed enrichment of Drd2 in PFC in relation to PPI. These findings contribute to the understanding of the genetic substrate behind alterations in sensorimotor gating, relevant for its linkage to neurodevelopmental disorders.

Differential expression of synaptic markers regulated during neurodevelopment in a rat model of schizophrenia-like behavior.

Schizophrenia is considered a neurodevelopmental disorder. Recent reports relate synaptic alterations with disease etiology. The inbred Roman High- (RHA-I) and Low- (RLA-I) Avoidance rat strains are a congenital neurobehavioral model, with the RHA-I displaying schizophrenia-related behaviors and serotonin 2A (5-HT2A) and metabotropic glutamate 2 (mGlu2) receptor alterations in the prefrontal cortex (PFC). We performed a comprehensive characterization of the RHA-I/RLA-I rats by real-time qPCR and Western blotting for 5-HT1A, 5-HT2A, mGlu2, dopamine 1 and dopamine 2 receptors (DRD1 and DRD2), AMPA receptor subunits Gria1, Gria2 and NMDA receptor subunits Grin1, Grin2a and Grin2b, as well as pre- and post-synaptic components in PFC and hippocampus (HIP). Besides corroborating decreased mGlu2 (Grm2) expression, we found increased mRNA levels for Snap25, Synaptophysin (Syp), Homer1 and Neuregulin-1 (Nrg1) in the PFC of the RHA-I and decreased expression of Vamp1, and Snapin in the HIP. We also showed alterations in Vamp1, Grin2b, Syp, Snap25 and Nrg1 at protein levels. mRNA levels of Brain Derived Neurotrophic Factor (BDNF) were increased in the PFC of the RHA-I rats, with no differences in the HIP, while BDNF protein levels were decreased in PFC and increased in HIP. To investigate the temporal dynamics of these synaptic markers during neurodevelopment, we made use of the open source BrainCloud™ dataset, and found that SYP, GRIN2B, NRG1, HOMER1, DRD1 and BDNF expression is upregulated in PFC during childhood and adolescence, suggesting a more immature neurobiological endophenotype in the RHA-I strain.