Implications of Animal Research for Clinical Interventions in Autism
Below I have pasted the last section of a review I wrote for Neuropsychopharmacology.
In conclusion, genetic studies combined with studies primarily in mouse models of the candidate gene defects have contributed to our understanding of the underlying mechanisms of NDDs. Although, much work is still needed, it is apparent that, at least for a subset of NDDs, deficits during development have a significant impact on synapse assembly and function, and consequently on behavior. Much work still needs to be carried out. The number of mouse models of candidate genes needs to be expanded to gain a more complete picture of the underlying molecular mechanisms of NDDs. Existing mouse models, or perhaps even zebrafish with high-throughput capacity (Tropepe and Sive, 2003), can be systematically tested for pharmacological rescue of behavioral deficits, thereby generating lead drug candidates for treatment studies. In addition, it will be important to study whether candidate gene function is absolutely necessary during development of the synapse or whether some aspects of synaptic function can be regained in the adult.
Although determining whether a genetic defect primarily affects development of synapses rather than mature synapse function may seem, at first glance, an esoteric endeavor, this difference has important implications for therapy. With the advent of viral-based gene therapy applications almost a realistic possibility in humans (Witt and Marks, 2011), it will be important to know where and also when an intervention is critical for a successful outcome. For example, if a synaptic deficit can be overcome in the adult, then this provides hope for many adults with this form of ASD. In contrast, when it is known that a developmental synaptic deficit is hardwired into the mature CNS, it advocates for an intervention as early as possible. Although the genetic critical periods are not the only deciding factors in the ability to treat a deficit, especially by pharmacological means, information on when and where a gene product’s function is necessary will certainly give insight into windows of opportunity.
To date, only a few of the NDD candidate genes have been studied with temporal requirements in mind. These kinds of experiments are difficult, requiring either the ‘rescue’ of deficits with viruses in a known location during development and in the adult, or the generation of conditional mutations, allowing for genetic rescue at given times. Such studies have been performed for Mecp2 and Nlgn3, and for Nlgn1 overexpression, but are necessary for more models of NDDs.
The most striking temporal rescue was demonstrated using a floxed STOP allele of the Mecp2 gene in mice. Re-expression of Mecp2 protein starting at 10 weeks after birth ameliorated neurological symptoms and promoted survival of male null mice many weeks beyond their null littermates that did not re-express Mecp2 (Guy et al., 2007). These experiments conclusively demonstrated that Rett-like defects in mice can be rectified in adult mice. Similarly, late expression (P30) of Nlgn3 in a null background rescued an ectopic synapse formation phenotype in the cerebellum (Baudouin et al., 2012). Nlgn3 knock-out mice demonstrate a motor coordination phenotype that is rescued by re-expression during development. Amelioration of the motor coordination phenotype was not tested in the juvenile rescue experiment (Baudouin et al., 2012). It is also important to note that pharmacological intervention has been successful in improving synaptic and social deficits in adult mice. Shank2 deficient mice, which have the same microdeletion as seen in cases of ASD, manifest decreased NMDA receptor function, reduced social interaction and reduced ultrasonic vocalization (Won et al., 2012). Treatment of adult mice with D-cycloserine, a partial NMDA receptor agonist, or CDPPB, a positive allosteric modulator of the metabotropic glutamate receptor 5 (mGluR5, which modulates NMDA receptor function) reversed the synaptic deficits and enhanced social interaction (Won et al., 2012).
To contrast these examples of juvenile/adult rescue of neuronal and neurological deficits, adult reduction of Neuroligin1 overexpression did not rescue synaptic or behavioral symptoms (Hoy et al., 2013). Neuroligin1 overexpression in the hippocampus results in increased spine head size and reduced learning and memory behavior. When overexpression was turned off at 2 months of age, spine heads remained larger in size and repeated testing with the novel object recognition test showed no improvement of memory for up to 4 weeks (Hoy et al., 2013). In contrast, four weeks of overexpression that began in the adult did lead to decreased novel object recognition. This study suggests that overexpression of Neuroligin1 is sufficient to hardwire synapses into a pathological state during development, and that this state can not be reversed by reducing expression levels in the adult. It is, however, possible that a pharmacological intervention might be successful in improving the behavioral deficits.
Given the heterogeneity of results from these models, i.e. that Neuroligin1 overexpression deficits can not be rescued after development (Hoy et al., 2013), whereas MeCP2, Neuroligin3 and SHANK2 deletions can (Baudouin et al., 2012; Guy et al., 2007; Won et al., 2012) , it is imperative that we widen these types of studies to other genetic models. It is tempting to hypothesize that overexpression can generally not be rescued, while lack of expression can. However, this general rule does not seem to be the case as the increased number of synapses driven by SynCAM1 overexpression during development can only be maintained by continuous SynCAM1 overexpression in the adult (Robbins et al., 2010). As rescue is not equally possible in developing and adult mice, it seems that each individual mutation may have a defined critical period and will have to be experimentally determined in each case.
With the advent of personalized medicine, we can expect to see prenatal genomic profiling to become increasingly routine. Genomic data will need to be supplemented with a basic understanding of (1) the genes involved in NDDs, (2) the parts of these genes that are essential for synaptic function, and (3) the critical periods for the function of each gene. It is difficult to extrapolate genetic critical periods from mouse studies to humans, and much work is necessary to confirm these trends in human patients. However, an integration of these studies with an individual’s genome sequence may eventually allow personalized interventions, such as gene therapy and/or pharmaceutical treatments for the most severe cases of NDDs.