Genetic mouse models of schizophrenia -- Annie Bryant


Ayhan et al. developed a transgenic mouse model with tet-off inducible expression of the mutant human DISC1 (hDISC1), a protein linked to neuronal and synaptic development and implicated in schizophrenia pathophysiology. Side note -- I wonder how much can be gleaned from the function of a human transgene in a mouse setting? Nonetheless, selective prenatal expression of the transgene led to reduced brain volume and increased spine density in pyramidal cortical neurons, paralleling previous findings of decreased neuronal proliferation with DISC1 knockdown that gives rise to smaller brain volumes in adult mice. Notably, postnatal expression alone led to larger lateral ventricles and decreased cortical volume, which is in line with the hypothesis that gradual postnatal changes drive ventricular pathology in schizophrenia. It’s interesting that prenatal and postnatal expression both independently influenced GABA-ergic interneuron development. I liked the authors’ interpretation that mutant hDISC1 could affect different stages of interneuron development depending on when it is expressed, such as migration or final differentiation. This certainly lends credence to the idea of DISC1 as a protein that wears many hats throughout development.

Prenatal and postnatal expression together induced the most robust changes. Females exhibited increased depression and reduced hippocampal DA levels, which mirrors depression-related behaviors with DISC1 polymorphisms in humans. Males exhibited decreased social behavior and increased aggression and hyperlocomotive sensitivity to stimulants, potentially arising from the decreased DA and DOPAC content in the frontal cortex. Both males and females showed increased dendritic spine density in dentate gyrus neurons, which is somewhat incongruous with earlier findings of decreased cortical spine density in human psychiatric disorders and in other DISC1 mouse models. Ayhan et al. bring up a good point that they didn’t differentiate between immature vs mature spines, and since DISC1 knockdown increases spine density in young dentate gyrus neurons, the increased density here could be an artifact of immature non-functioning spines. If this is the case, I wonder how this abundance of non-functional spines affects learning and memory from an LTP perspective.

I was struck by the differences in behavioral readouts in male versus female transgenic mice, despite similar brain morphology and expression of mutant hDISC1, endogenous DISC1, and LIS1. I wonder if the differences in monoamine content in the hippocampus and cortex between the genders could account for this. I was also curious as to why Ayhan et al. only reported on males in the social interaction tests and females in the FST and TST assays. Did they only perform these experiments with one gender, or did they use both genders and only report significant findings? Either way, I think the male-female differences in this model are fascinating, and they warrant further investigation given the gender differences in schizophrenia manifestation in humans.

The metabotropic glutamate receptor 5 (mGlu5) interacts directly with NMDA-receptors (NMDARs) and is implicated schizophrenia. Burrows et al. investigated an mGlu5 knockout (KO) model, which has previously been shown to exhibit increased hyperlocomotion in response to PCP and MK-801, with impaired LTP in the CA1 as a result of impaired NMDAR-mediated plasticity. They also explored the effect of environment by comparing standard housing (SH) with environmental enrichment (EE), the latter of which upregulates NMDAR subunit expression and structural plasticity in WT mice. However, I had trouble supporting this paper because I had issues with their controls and the conclusions they quickly drew. To start, Figure 1 shows that both WT and KO mice exposed to EE exhibited reduced locomotor activity during habituation – the EE KO mice were even less active at 4 days than SH WT mice. However, this doesn’t line up with the results presented in Figure 4, showing that during habituation, there were no differences in locomotor activity between any group. Why was there different locomotor activity in one experiment and equivalent activity in another setting?

I thought findings from the Morris water maze were suspect, given that the SH WT mice didn’t show a significant preference for the target quadrant. The authors justify this with the explanation that some SH WT switched their search strategy, but since their most important control didn’t have reliable results, that precludes any reliable and meaningful conclusions. Burrows et al. conclude that EE ameliorated long-term spatial learning impairment in the Morris water maze but not short-term (novel object) memory in the Y-maze, and that the latter is resistant to environment-induced improvement. I’m not sure I’m sold on the conclusions about long-term memory due to the control issues. Burrows et al. do show that EE restores KO mice response to MK-801 in terms of both PPI and hyperlocomotion. This sounds kind of counterintuitive, since it’s restoring an impairment that wasn’t present in KO mice. Does this mean EE increased NMDAR expression in KO mice, offering more substrates upon which MK-801 can act and disrupt behavior?

For all my gripes with this paper, I definitely support the exploration of gene-environment interactions in complex psychiatric disorders, and I think this model could really be strengthened with a few changes. It’s bizarre that in WT mice, EE increased hippocampal dendritic branching and BDNF levels, yet it didn’t improve learning or memory. (Why did they bury these findings in the supplement? These seem like central plasticity-relevant findings). The authors attribute this to either a ceiling effect or task difficulty, but shouldn’t an environmental enrichment model intended to improve learning/memory actually accomplish that goal in controls? Perhaps either a different EE model or different learning/memory tasks are needed to stratify WT results to be able to more accurately compare findings with transgenic experimental cohorts. Furthermore, Burrows et al. point out that mGlu5 is important for experience-dependent plasticity and development in the visual and somatosensory cortex – they could include at least one of these areas to validate the enrichment model in terms of plasticity changes. Finally, they conclude that the beneficial effects of EE may be due at least in part to increase GluN2A-containing NMDARs; I wish they had at least stained for Glu2NA and/or NDMARs via IHC to examine relative expression between models.

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