Dopamine Triggers the Maturation of Striatal Spiny Projection Neuron Excitability during a Critical Period

Abstract

Neural circuits are formed and refined during childhood, including via critical changes in neuronal excitability. Here, we investigated the ontogeny of striatal intrinsic excitability. We found that dopamine neurotransmission increases from the first to the third postnatal week in mice and precedes the reduction in spiny projection neuron (SPN) intrinsic excitability during the fourth postnatal week. In mice developmentally deficient for striatal dopamine, direct pathway D1-SPNs failed to undergo maturation of excitability past P18 and maintained hyperexcitability into adulthood. We found that the absence of D1-SPN maturation was due to altered phosphatidylinositol 4,5-biphosphate dynamics and a consequent lack of normal ontogenetic increases in Kir2 currents. Dopamine replacement corrected these deficits in SPN excitability when provided from birth or during a specific period of juvenile development (P18-P28), but not during adulthood. These results identify a sensitive period of dopamine-dependent striatal maturation, with implications for the pathophysiology and treatment of neurodevelopmental disorders.

Dynamic postnatal development of the cellular and circuit properties of striatal D1 and D2 spiny projection neurons

“…Moreover, we show that many of the properties of mature D1 and D2 SPNs are already apparent by the first and second postnatal weeks, which is thought to be a period prior to much exploratory motor behaviour (Dehorter et al 2011) or exposure to structured input from the sensory periphery (Tobach et al 1971;Krug et al 2001;Akerman et al 2002;Ko et al 2013;Mowery et al 2015Mowery et al , 2016Mowery et al , 2017. This is consistent with the idea that neuronal specification can occur early in development (Lobo et al 2006(Lobo et al , 2008Arlotta et al 2008;Ehrman et al 2013;Lu et al 2014;Zhang et al 2016;Merchan-Sala et al 2017;Kelly et al 2018;Tinterri et al 2018;Xu et al 2018) with further postnatal development guided by, for example, neural activity (Zhang & Poo, 2001;Kozorovitskiy et al 2012;Peixoto et al 2016) and neuromodulation (Kozorovitskiy et al 2015;Lieberman et al 2018). Future work will be able to clarify the precise interaction of these factors during striatal development as well as their differential involvement in neurodevelopmental disorders (Graybiel & Rauch, 2000;Del Campo et al 2011;Langen et al 2011;McNaught & Mink, 2011;Shepherd, 2013;Albin, 2018).…”

“…Both SPNs are able to generate small ‘immature’ action potentials in the first postnatal days and both undergo a progressive decrease in their input resistance and a hyperpolarization of their resting membrane potential (Lieberman et al . ), concurrent with an ability to generate large ‘mature’ action potentials at higher firing frequencies (Peixoto et al . ).…”

“…We found a progressive development of both the intrinsic electrophysiological and the morphological properties of the D1 and D2 SPNs. Both SPNs are able to generate small 'immature' action potentials in the first postnatal days and both undergo a progressive decrease in their input resistance and a hyperpolarization of their resting membrane potential (Lieberman et al 2018), concurrent with an ability to generate large 'mature' action potentials at higher firing frequencies (Peixoto et al 2016). However, some differences were observed.…”

“…Initially, the size and duration of the action potentials were more mature for the D1 SPNs, possibly as a result of their J Physiol 597.21 suggested earlier birthdate (Marchand & Lajoie, 1986;van der Kooy & Fishell, 1987;Kelly et al 2018). Secondly, many of the differences in the electrical properties of SPNs, such as the comparatively more depolarized resting membrane potential, higher input resistance and higher firing frequencies of D2 SPNs, are already apparent in the second postnatal week and are maintained into adulthood (Gertler et al 2008;Peixoto et al 2016;Lieberman et al 2018). Morphologically we found that SPNs exhibit a radial dendritic morphology from birth, which undergoes a substantial elaboration concomitant with an increase in dendritic spine density occurring in parallel for the D1 and D2 SPNs.…”

Early life stress alters transcriptomic patterning across reward circuitry in male and female mice

“…Inhibition of noradrenergic cells from P10-21, but not P2-9 or P56-67, increased anxiety-and depression-like behavior in adult mice 36 . Dopamine signaling in the striatum matures rapidly from P10 through adolescence and is required from P18-28, but not from birth or in adulthood, for normal physiological development and related behaviors 37,38 . Rodent amygdala begins to support fear-learning at P10, plasticity and long-term potentiation develop in rodent hippocampus in the second postnatal week, and connectivity between human amygdala and h i p p o c a m p u s a p p e a r s t o d e v e l o p l a t e r i n children 19,39,40 .…”