A Feud that Wasn't: Acetylcholine Evokes Dopamine Release in the Striatum

In this issue of Neuron, Threlfell et al. (2012) report that synchronous activation of cholinergic interneurons evokes striatal dopamine release by activating presynaptic nicotinic acetylcholine receptors. These findings call for a fundamental reevaluation of the long-standing view that dopamine and acetylcholine “feud” over control of striatal circuitry

PKA Phosphorylation of NCLX Reverses Mitochondrial Calcium Overload and Depolarization, Promoting Survival of PINK1-Deficient Dopaminergic Neurons

Mitochondrial Ca2+ overload is a critical, preceding event in neuronal damage encountered during neurodegenerative and ischemic insults. We found that loss of PTEN-induced putative kinase 1 (PINK1) function, implicated in Parkinson disease, inhibits the mitochondrial Na+/Ca2+ exchanger (NCLX), leading to impaired mitochondrial Ca2+ extrusion. NCLX activity was, however, fully rescued by activation of the protein kinase A (PKA) pathway. We further show that PKA rescues NCLX activity by phosphorylating serine 258, a putative regulatory NCLX site. Remarkably, a constitutively active phosphomimetic mutant of NCLX (NCLXS258D) prevents mitochondrial Ca2+ overload and mitochondrial depolarization in PINK1 knockout neurons, thereby enhancing neuronal survival. Our results identify an mitochondrial Ca2+ transport regulatory pathway that protects against mitochondrial Ca2+ overload. Because mitochondrial Ca2+ dyshomeostasis is a prominent feature of multiple disorders, the link between NCLX and PKA may offer a therapeutic target

Mutant huntingtin enhances activation of dendritic Kv4 K+ channels in striatal spiny projection neurons

Huntington\u27s disease (HD) is initially characterized by an inability to suppress unwanted movements, a deficit attributable to impaired synaptic activation of striatal indirect pathway spiny projection neurons (iSPNs). To better understand the mechanisms underlying this deficit, striatal neurons in ex vivo brain slices from mouse genetic models of HD were studied using electrophysiological, optical and biochemical approaches. Distal dendrites of iSPNs from symptomatic HD mice were hypoexcitable, a change that was attributable to increased association of dendritic Kv4 potassium channels with auxiliary KChIP subunits. This association was negatively modulated by TrkB receptor signaling. Dendritic excitability of HD iSPNs was rescued by knocking-down expression of Kv4 channels, by disrupting KChIP binding, by restoring TrkB receptor signaling or by lowering mutant-Htt (mHtt) levels with a zinc finger protein. Collectively, these studies demonstrate that mHtt induces reversible alterations in the dendritic excitability of iSPNs that could contribute to the motor symptoms of HD

Interneuronal Nitric Oxide Signaling Mediates Post-synaptic Long-Term Depression of Striatal Glutamatergic Synapses

SummaryExperience-driven plasticity of glutamatergic synapses on striatal spiny projection neurons (SPNs) is thought to be essential to goal-directed behavior and habit formation. One major form of striatal plasticity, long-term depression (LTD), has long appeared to be expressed only pre-synaptically. Contrary to this view, nitric oxide (NO) generated by striatal interneurons was found to induce a post-synaptically expressed form of LTD at SPN glutamatergic synapses. This form of LTD was dependent on signaling through guanylyl cyclase and protein kinase G, both of which are abundantly expressed by SPNs. NO-LTD was unaffected by local synaptic activity or antagonism of endocannabinoid (eCb) and dopamine receptors, all of which modulate canonical, pre-synaptic LTD. Moreover, NO signaling disrupted induction of this canonical LTD by inhibiting dendritic Ca2+ channels regulating eCb synthesis. These results establish an interneuron-dependent, heterosynaptic form of post-synaptic LTD that could act to promote stability of the striatal network during learning

Delayed Spine Pruning of Direct Pathway Spiny Projection Neurons in a Mouse Model of Parkinson’s Disease

In animal models of Parkinson’s disease (PD), principal striatal spiny projection neurons (SPNs) lose axospinous synapses. However, there has been a disagreement about whether this loss is restricted to a specific type of SPN or not, as some studies have reported pruning in both direct pathway SPNs and indirect pathway SPNs, while others have found this pruning to be restricted to indirect pathway SPNs. One possible explanation for the discrepancy is the period between the induction of the parkinsonian state and the assessment of spine loss. To test this hypothesis, transgenic mice were subjected to unilateral 6-hydroxydopamine (6-OHDA) lesions of nigrostriatal dopaminergic neurons and then direct pathway SPNs examined in ex vivo brain slices using two photon laser scanning microscopy either one or 2 months afterwards. These studies revealed that 1 month after the lesion, there was no loss of spines in direct pathway SPNs. However, 2 months after the lesion, spine loss was significant in direct pathway SPNs. In addition to reconciling the existing literature on the impact of the parkinsonian state on axospinous synapse elimination in SPNs, our results suggest that the delayed spine loss in direct pathway SPNs is not driven by homeostatic mechanisms [as posited for indirect pathway (iSPNs)], but rather by network pathophysiology

Targeting the pedunculopontine nucleus in Parkinson’s disease: Time to go back to the drawing board

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/147041/1/mds27540.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/147041/2/mds27540_am.pd

Nitric oxide regulates synaptic transmission between spiny projection neurons

Recurrent axon collaterals are a major means of communication between spiny projection neurons (SPNs) in the striatum and profoundly affect the function of the basal ganglia. However, little is known about the molecular and cellular mechanisms that underlie this communication. We show that intrastriatal nitric oxide (NO) signaling elevates the expression of the vesicular GABA transporter (VGAT) within recurrent collaterals of SPNs. Down-regulation of striatal NO signaling resulted in an attenuation of GABAergic signaling in SPN local collaterals, down-regulation of VGAT expression in local processes of SPNs, and impaired motor behavior. PKG1 and cAMP response element-binding protein are involved in the signal transduction that transcriptionally regulates VGAT by NO. These data suggest that transcriptional control of the vesicular GABA transporter by NO regulates GABA transmission and action selection.United States Army Medical Research Acquisition Activity (Grant W81XWH-09-1-0108