CASPR2 Deficiency in Juvenile Rats Recapitulates the Broad Phenotypic Spectrum of CNTNAP2-Related Disorders

Background: CNTNAP2 mutations are associated with neurobehavioral and neuropsychiatric indications present in multiple conditions such as ASD, IDD, ADHD, schizophrenia and bipolar disorder. Mice completely lacking Cntnap2 have been used to model behavioral impairments, but these findings may not fully delineate the consequences of heterozygous deficiency predominantly reported in humans. Studies of adult Cntnap2 animals also raise the question of whether features would manifest earlier during a period that is relevant to disease onset in some CNTNAP2-related disorders.

Objectives: To evaluate the neurobehavioral and cellular deficits caused by the reduction or absence of CASPR2 in rats.

Methods: We profiled the neurobehavioral and cellular consequences of either haploinsufficiency or the complete loss of Cntnap2 in juvenile rats, given that we recently reported that the consequences of ASD/IDD-related gene deficiency may differ among divergent rodent species. A battery of behavioral evaluations were conducted from postnatal day 24 to 39 using both male and female Cntnap2^+/- and Cntnap2^-/- rats. In addition, molecular studies were conducted to confirm the nature of the targeted allele, as well as to identify whether cellular abnormalities previously reported in Cntnap2 mice were also present in this novel rat model.

Results: Juvenile Cntnap2^+/- and Cntnap2^-/- rats display obsessive-compulsive-like behaviors, increased play behavior, hyperactivity and an increased acoustic startle response. Impairments were dose-dependent in some cases. A limited number of behavioral impairments were altered as a function of both genotype and sex. Juvenile Cntnap2^-/- rats also showed decreased cortical interneuron number but not abnormal neuronal migration, and behavioral seizures were apparent as early as seven weeks of life.

Conclusions: A reduction or complete absence of CASPR2 results in strikingly different behavioral outcomes in rats compared with mice; however obsessive-compulsive-like behaviors, hyperactivity and some neuropathological alterations are shared between the two species. Taken together, these findings provide insight into the consequences of CASPR2 deficiency in a complementary rodent model, and identify the common features among Cntnap2 genetic tools that may serve as useful outcome measures for future preclinical studies.