Developmental regulation of thalamus-driven pauses in striatal cholinergic interneurons.

In response to salient sensory cues, the tonically active striatal cholinergic interneuron (ChI) exhibits a characteristic synchronized "pause" thought to facilitate learning and the execution of motivated behavior. We report that thalamostriatal-driven ChI pauses are enhanced in ex vivo brain slices from infantile (P10) mice, with decreasing expression in preadolescent (P28) and adult (P100) mice concurrent with waning excitatory input to ChIs. Our data are consistent with previous reports that the adult ChI pause is dependent on dopamine signaling, but we find that the robust pausing at P10 is dopamine independent. Instead, elevated expression of the noninactivating delayed rectifier Kv7.2/3 current promotes pausing in infantile ChIs. Because this current decreases over development, a parallel increase in Ih further attenuates pause expression. These findings demonstrate that cell intrinsic and circuit mechanisms of ChI pause expression are developmentally determined and may underlie changes in learning properties as the nervous system matures.

Coordinated Postnatal Maturation of Striatal Cholinergic Interneurons and Dopamine Release Dynamics in Mice.

Dynamic changes in motor abilities and motivated behaviors occur during the juvenile and adolescent periods. The striatum is a subcortical nucleus critical to action selection, motor learning, and reward processing. Its tonically active cholinergic interneuron (ChI) is an integral regulator of the synaptic activity of other striatal neurons, as well as afferent axonal projections of midbrain dopamine (DA) neurons; however, little is known about its development. Here, we report that ChI spontaneous activity increases during postnatal development of male and female mice, concomitant with a decreased afterhyperpolarization (AHP). We characterized the postnatal development of four currents that contribute to the spontaneous firing rate of ChIs, including ISK, IA, Ih, and INaP We demonstrated that the developmental increase in INaP drives increased ChI firing rates during the postnatal period and can be reversed by the INaP inhibitor, ranolazine. We next addressed whether immature cholinergic signaling may lead to functional differences in DA release during the juvenile period. In the adult striatum, nicotinic acetylcholine receptors (nAChRs) prevent linear summation of DA release in response to trains of high-frequency stimuli. We show that, in contrast, during the second postnatal week, DA release linearly sums with trains of high-frequency stimuli. Consistently, nAChR antagonists exert little effect on dopamine release at postnatal day (P)10, but enhance the summation of evoked DA release in mice older than postnatal day P28. Together, these results reveal that postnatal maturation of ChI activity is due primarily to enhanced INaP and identify an interaction between developing cholinergic signaling and DA neurotransmission in the juvenile striatum.SIGNIFICANCE STATEMENT Motor skills and motivated behavior develop rapidly in juvenile rodents. Recent work has highlighted processes that contribute to the postnatal maturation of striatal principal neurons during development. The functional development of the striatal cholinergic interneuron (ChI), however, has been unexplored. In this study, we tracked the ontogeny of ChI activity and cellular morphology, as well as the developmental trajectory of specific conductances that contribute to the activity of these cells. We further report a link between cholinergic signaling and dopamine (DA) release, revealing a change in the frequency-dependence of DA release during the early postnatal period that is mediated by cholinergic signaling. This study provides evidence that striatal microcircuits are dynamic during the postnatal period and that they undergo coordinated maturation.

mTOR Suppresses Macroautophagy During Striatal Postnatal Development and Is Hyperactive in Mouse Models of Autism Spectrum Disorders.

Macroautophagy (hereafter referred to as autophagy) plays a critical role in neuronal function related to development and degeneration. Here, we investigated whether autophagy is developmentally regulated in the striatum, a brain region implicated in neurodevelopmental disease. We demonstrate that autophagic flux is suppressed during striatal postnatal development, reaching adult levels around postnatal day 28 (P28). We also find that mTOR signaling, a key regulator of autophagy, increases during the same developmental period. We further show that mTOR signaling is responsible for suppressing autophagy, via regulation of Beclin-1 and VPS34 activity. Finally, we discover that autophagy is downregulated during late striatal postnatal development (P28) in mice with in utero exposure to valproic acid (VPA), an established mouse model of autism spectrum disorder (ASD). VPA-exposed mice also display deficits in striatal neurotransmission and social behavior. Correction of hyperactive mTOR signaling in VPA-exposed mice restores social behavior. These results demonstrate that neurons coopt metabolic signaling cascades to developmentally regulate autophagy and provide additional evidence that mTOR-dependent signaling pathways represent pathogenic signaling cascades in ASD mouse models that are active during specific postnatal windows.

Autophagic bias in the striatum.

Macroautophagy/autophagy is implicated in the maintenance of normal neuronal activity through the regulation of synaptic function and plasticity. However, differences in autophagic degradation within different classes of neurons have not been examined. We have recently demonstrated that autophagy plays very different roles in the two closely related principal neurons of the striatum - the spiny projection neurons of the direct (dSPN) and indirect (iSPN) pathways. Behavioral and electrophysiological experiments revealed that the absence of autophagy in either of these SPN pathways produces unique effects on motor learning, dendritic length, and intrinsic excitability. Specifically, autophagy is required for the normal development of synaptic inputs onto dSPNs, while being required for intrinsic excitability in iSPNs. In iSPNs, this occurs through the regulation of the activity of the KCNJ/Kir2 ion channel, and provides a first demonstration of autophagic control of neuronal intrinsic excitability. ABBREVIATIONS: ASD: autism spectrum disorders; dSPNs: direct pathway spiny projection neurons; iSPNs: indirect pathway spiny projection neurons; Kir2: inwardly rectifying potassium channel 2.

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

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.