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In neuropsychiatric diseases, such as major depression and anxiety, pathogenic vulnerability is partially dictated by a genetic predisposition. The search continues to define this genetic susceptibility and establish new genetic elements as potential therapeutic targets. The fibroblast growth factors (FGFs) could be interesting in this regard. This family of signaling molecules plays important roles in development while also functioning within the adult. This includes effects on aspects of brain function such as neurogenesis and synapse formation. Of this family, Fgf9 is expressed in the adult brain, but its functional role is less well defined. In this study, we examined the role of Fgf9 in different brain functions by analyzing the behavior of Fgf9 Y162C mutant mice, an Fgf9 allele without the confounding systemic effects of other Fgf9 genetic models. Here, we show that this mutation caused altered locomotor and exploratory reactivity to novel, mildly stressful environments. In addition, mutants showed heightened acoustic startle reactivity as well as impaired social discrimination memory. Notably, there was a substantial decrease in the level of adult olfactory bulb neurogenesis with no difference in hippocampal neurogenesis. Collectively, our findings indicate a role for the Fgf9 Y162C mutation in information processing and perception of aversive situations as well as in social memory. Thus, genetic alterations in Fgf9 could increase vulnerability to developing neuropsychiatric disease, and we propose the Fgf9 Y162C mutant mice as a valuable tool to study the predictive etiological aspects.

Phenotyping of inbred mouse strains and genetically modified mouse models for characteristics related to neuropsychiatric diseases includes assessing their anxiety-related behavior. A variety of tests have been developed to measure anxiety in laboratory rodents and these tests have been placed under scrutiny over the years concerning their validity. Here we describe the most widely used tests for anxiety in mice. The protocols we present are established methods used in the German Mouse Clinic (GMC), with which alterations in anxiety could successfully be discovered in mouse mutants. Moreover, since baseline anxiety levels in mice are easily influenced by a great variety of disturbances, we carefully outline the critical parameters that need to be considered.

Non-motor symptoms such as hyposmia and depression are often observed in Parkinson's disease (PD) and can precede the onset of motor symptoms for years. The underlying pathological alterations in the brain are not fully understood so far. Dysregulation of adult neurogenesis in the dentate gyrus of the hippocampus and the olfactory bulb has been recently suggested to be implicated in non-motor symptoms of PD. However, there is so far no direct evidence to support the relationship of non-motor symptoms and the modulation of adult neurogenesis following dopamine depletion and/or dopamine replacement. In this study, we investigated the long-term effects of l-DOPA and pramipexole, a dopamine agonist, in a mouse model of bilateral intranigral 6-OHDA lesion, in order to assess the impact of adult neurogenesis on non-motor behavior. We found that l-DOPA and pramipexole can normalize decreased neurogenesis in the hippocampal dentate gyrus and the periglomerular layer of the olfactory bulb caused by a 6-OHDA lesion. Interestingly, pramipexole showed an antidepressant and anxiolytic effect in the forced swim test and social interaction test. However, there was no significant change in learning and memory function after dopamine depletion and dopamine replacement, respectively.

Transgenic animal models of Alzheimer's disease (AD) are widely used to investigate mechanisms of pathophysiology and cognitive dysfunctions. A model with a very early development of parenchymal plaque load at the age of 2months is the 5xFAD mouse (Tg6799, Oakley et al. 2006). These 5xFAD mice over-express both human amyloid precursor protein (APP) and human presenilin 1 (PS1). Mice from this line have a high APP expression correlating with a high burden and an accelerated accumulation of the 42 amino acid species of amyloid-β (Aβ). The aim of this study was the behavioral and functional investigations of 5xFAD males because in most studies females of this strain were characterized. In comparison to literature of transgenic 5xFAD females, transgenic 5xFAD males showed decreased anxiety in the elevated plus maze, reduced locomotion and exploration in the open field and disturbances in learning performance in the Morris water maze starting at 9months of age. Electroencephalogram (EEG) recordings on 6month old transgenic mice revealed a decrease of delta, theta, alpha, beta and gamma frequency bands whereas the subdelta frequency was increased. EEG recordings during sleep showed a reduction of rapid eye movement sleep in relation to the amount of total sleep. Thus, 5xFAD males develop early functional disturbances and subsequently behavioral deficits and therefore they are a good mouse model for studying Alzheimer's disease.

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by the expansion of a CAG trinucleotide repeat in the HTT gene encoding huntingtin. The disease has an insidious course, typically progressing over 10-15 years until death. Currently there is no effective disease-modifying therapy. To better understand the HD pathogenic process we have developed genetic HTT CAG knock-in mouse models that accurately recapitulate the HD mutation in man. Here, we describe results of a broad, standardized phenotypic screen in 10-46 week old heterozygous HdhQ111 knock-in mice, probing a wide range of physiological systems. The results of this screen revealed a number of behavioral abnormalities in HdhQ111/+ mice that include hypoactivity, decreased anxiety, motor learning and coordination deficits, and impaired olfactory discrimination. The screen also provided evidence supporting subtle cardiovascular, lung, and plasma metabolite alterations. Importantly, our results reveal that a single mutant HTT allele in the mouse is sufficient to elicit multiple phenotypic abnormalities, consistent with a dominant disease process in patients. These data provide a starting point for further investigation of several organ systems in HD, for the dissection of underlying pathogenic mechanisms and for the identification of reliable phenotypic endpoints for therapeutic testing.