Long-Term Effects of Early Postnatal Administration of R-Baclofen on Neuronal Properties in the Cntnap2 Knockout Rat

Contactin-associated protein-like 2 (Cntnap2) is a highly expressed gene during development, coding for the cell adhesion molecule CASPR2. Loss-of-function of Cntnap2 leads to a neurodevelopmental disorder that presents with the core symptoms of autism. One prominent theory to explain autism symptoms is an imbalance of excitatory and inhibitory neurotransmitters, which leads to hyper-excitability in the autistic brain. R-baclofen, a γ-aminobutyric acid (GABA_B) receptor agonist, has been shown to acutely improve autism-like symptoms in rat models of autism, including exaggerated acoustic reactivity. However, the cellular basis and long-term impact of R-baclofen treatment during development are unknown. In the present study, we explored the impact of acute R-baclofen treatment on auditory cortical neurons and whether there are lasting changes in cell excitability and synaptic signaling following time-restricted R-baclofen administration during the critical period of auditory development.

R-baclofen or saline were injected daily on postnatal days (PND) 14-21 and whole-cell patch clamp recordings were performed on pyramidal neurons in brain slices of the auditory cortex of juvenile (PND25-33) and adult (PND70-90) Cntnap2 wild-type and knockout rats.

While acute R-baclofen application led to the expected reduction in cell excitability, early-life exposure to R-baclofen induced lasting changes in neuronal membrane properties and excitability. However, these effects were not uniformly beneficial, as in some instances they exacerbated the knockout phenotype and induced unwanted effects in wild-type neurons.

The study shows that drug exposure in early age can change the developmental trajectory of the auditory system, indicating both opportunities and risks when considering early drug intervention.