The Role of the Neurokinin Receptor 3 in the Striatum During Development

Abstract

Early postnatal development underlies the proper function of the mature brain, and alterations to neural activity during this period contribute to neurodevelopmental pathophysiology. However, the molecular control of early brain activity is poorly understood. The neurokinin receptor 3 (Nk3r) is a potent neuromodulator involved in cell physiology, network responses to stress, and cognition. Yet, its influence on the activity of the maturing brain has not been defined. This research aimed to understand the function of Nk3r throughout early postnatal stages using the mouse striatum as a model structure. We first wanted to understand the expression and activation of Nk3r at different stages of development. We identified a higher expression of Nk3r in the first ten postnatal days of life (P0-P10) compared to adult mice; a critical stage for striatal maturation. Nk3r had the highest expression in cholinergic interneurons (CINs), cells responsible for controlling striatal output. Furthermore, activation of the receptor had a larger influence over CINs’ firing early in postnatal development compared to adult, coinciding with its increased expression in the striatum. Ergo, we postulated that Nk3r had an essential function during this period. To test this, we manipulated Nk3r throughout P0-P10 to understand its effect on the development of the CINs. We found that the chronic pharmacological blockade of the receptor with the specific antagonist Osanetant significantly altered CIN intrinsic properties and reduced tonic firing frequency through changes to voltage-gated sodium, voltage-gated potassium, and hyperpolarisation-activated cyclic nucleotidegated channels. Furthermore, this treatment decreased the frequency of spontaneous excitatory inputs and increased the frequency of spontaneous inhibitory inputs onto CINs. These data indicate that Nk3r’s developmental activity modulates the intrinsic state of CINs and helps balance inhibition and excitation within the maturing striatal network. In support of this, both the chronic blockade with Osanetant and a striatumspecific knockout of Nk3r led to drastic changes in CIN-related behaviours, including decreased sociability and increased repetitive behaviours such as grooming. Interestingly, these behavioural phenotypes resembled core symptoms observed in autism spectrum disorder (ASD) which is known to involve aberrant striatal activity. As such, we wished to understand the role of Nk3r within a mouse model of ASD. We found that the Cntnap2 knockout (KO) mouse model had increased striatal Nk3r expression throughout the first ten postnatal days compared to control mice. In addition, Cntnap2 KO mice showed deficits in the activity of CINs and changes in social behaviours comparable to Osanetant-treated mice. Chronic activation of Nk3r using the specific agonist Senktide during P0-P10 restored the intrinsic properties of striatal adult CINs and prevented core behaviours of ASD in this model. This study reveals a crucial role of Nk3r in the maturation of striatal CINs and related behaviours. It highlights the need to investigate further the role of Nk3r in the pathogenesis of ASD and the potential as a new therapeutic target for this condition. Show more