QTL replication and targeted association highlight the nerve growth factor gene for nonverbal communication deficits in autism spectrum disorders.
Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Autism Spectrum Disorder (ASD) has a heterogeneous etiology that is genetically complex.
It is defined by deficits in communication and social skills and the presence of restricted and repetitive behaviors. Genetic analyses of heritable quantitative traits that correlate with ASD may reduce heterogeneity.
With this in mind, deficits in nonverbal communication (NVC) were quantified based on items from the Autism Diagnostic Interview Revised. Our previous analysis of 228 families from the Autism Genetics Research Exchange (AGRE) repository reported 5 potential quantitative trait loci (QTL).
Here we report an NVC QTL replication study in an independent sample of 213 AGRE families. One QTL was replicated (P<0.0004). It was investigated using a targeted-association analysis of 476 haplotype blocks with 708 AGRE families using the Family Based Association Test (FBAT). Blocks in two QTL genes were associated with NVC with a P-value of 0.001. Three associated haplotype blocks were intronic to the Nerve Growth Factor (NGF) gene (P=0.001, 0.001, 0.002), and one was intronic to KCND3 (P=0.001).
Individual haplotypes within the associated blocks drove the associations (0.003, 0.0004 and 0.0002) for NGF and 0.0001 for KCND3.
Using the same methods, these genes were tested for association with NVC in an independent sample of 1517 families from an Autism Genome Project (AGP). NVC was associated with a haplotype in an adjacent NGF block (P=0.0005) and one 46 kb away from the associated block in KCND3 (0.008). These analyses illustrate the value of QTL and targeted association studies for genetically complex disorders such as ASD.
NGF is a promising risk gene for NVC deficits.
Further Readings of Interest
Environmental enrichment attenuates hippocampal neuroinflammation and improves cognitive function during influenza infection.
Neuroscience Program, University of Illinois, Urbana, IL 61801, USA. firstname.lastname@example.org
Recent findings from our lab have shown that peripheral infection of adult mice with influenza A/PR/8/34 (H1N1) virus induces a neuroinflammatory response that is paralleled by loss of neurotrophic and glial regulatory factors in the hippocampus, and deficits in cognitive function.
Environmental enrichment has been shown to exert beneficial effects on the brain and behavior in many central nervous system (CNS) disorders, but its therapeutic potential during peripheral viral infection remains unknown.
Therefore, the objective of the present study was to determine if long-term continuous exposure to environmental enrichment could prevent and/or attenuate the negative effects of influenza infection on the hippocampus and spatial cognition.
Mice were housed in enriched or standard conditions for 4 months, and continued to live in their respective environments throughout influenza infection. Cognitive function was assessed in a reversal learning version of the Morris water maze, and changes in hippocampal expression of proinflammatory cytokines (IL-1β, IL-6, TNF-α, IFN-α), neurotrophic (BDNF, NGF), and immunomodulatory (CD200, CX3CL1) factors were determined.
We found that environmental enrichment reduced neuroinflammation and helped prevent the influenza-induced reduction in hippocampal CD200. These changes were paralleled by improved cognitive performance of enriched mice infected with influenza when compared to infected mice in standard housing conditions.
Collectively, these data are the first to demonstrate the positive impact of environmental enrichment on the brain and cognition during peripheral viral infection, and suggest that enhanced modulation of the neuroimmune response may underlie these beneficial effects.
Influenza infection induces neuroinflammation, alters hippocampal neuron morphology, and impairs cognition in adult mice.
Influenza is a common and highly contagious viral pathogen, yet its effects on the structure and function of the CNS remain largely unknown.
Although there is evidence that influenza strains that infect the brain can lead to altered cognitive and emotional behaviors, it is unknown whether a viral strain that is not neurotropic (A/PR/8/34) can result in a central inflammatory response, neuronal damage, and neurobehavioral effects.
We hypothesized that neuroinflammation and alterations in hippocampal neuron morphology may parallel cognitive dysfunction following peripheral infection with live influenza virus.
Here, we show that influenza-infected mice exhibited cognitive deficits in a reversal learning version of the Morris water maze. At the same time point in which cognitive impairment was evident, proinflammatory cytokines (IL-1β, IL-6, TNF-α, IFN-α) and microglial reactivity were increased, while neurotrophic (BDNF, NGF) and immunomodulatory (CD200, CX3CL1) factors were decreased in the hippocampus of infected mice.
In addition, influenza induced architectural changes to hippocampal neurons in the CA1 and dentate gyrus, with the most profound effects on dentate granule cells in the innermost portion of the granule cell layer.
Overall, these data provide the first evidence that neuroinflammation and changes in hippocampal structural plasticity may underlie cognitive dysfunction associated with influenza infection.
In addition, the heightened inflammatory state concurrent with reduced neurotrophic support could leave the brain vulnerable to subsequent insult following influenza infection. A better understanding of how influenza impacts the brain and behavior may provide insight for preventing inflammation and neuronal damage during peripheral viral infection.