Muscarinic Enhancement of Persistent Sodium Current Synchronizes Striatal Medium Spiny Neurons

2009 ◽  
Vol 102 (2) ◽  
pp. 682-690 ◽  
Author(s):  
Luis Carrillo-Reid ◽  
Fatuel Tecuapetla ◽  
Nicolas Vautrelle ◽  
Adán Hernández ◽  
Ramiro Vergara ◽  
...  
Keyword(s):  
Sodium Current ◽  
Network Dynamics ◽  
Receptor Activation ◽  
Procedural Memory ◽  
Negative Slope ◽  
Medium Spiny Neurons ◽  
Persistent Sodium Current ◽  
Intrinsic Properties ◽  
Bistable Behavior ◽  
Spiny Neurons

Network dynamics denoted by synchronous firing of neuronal pools rely on synaptic interactions and intrinsic properties. In striatal medium spiny neurons, N-methyl-d-aspartate (NMDA) receptor activation endows neurons with nonlinear capabilities by inducing a negative-slope conductance region (NSCR) in the current–voltage relationship. Nonlinearities underlie associative learning, procedural memory, and the sequential organization of behavior in basal ganglia nuclei. The cholinergic system modulates the function of medium spiny projection neurons through the activation of muscarinic receptors, increasing the NMDA-induced NSCR. This enhancement is reflected as a change in the NMDA-induced network dynamics, making it more synchronous. Nevertheless, little is known about the contribution of intrinsic properties that promote this activity. To investigate the mechanisms underlying the cholinergic modulation of bistable behavior in the striatum, we used whole cell and calcium-imaging techniques. A persistent sodium current modulated by muscarinic receptor activation participated in the enhancement of the NSCR and the increased network synchrony. These experiments provide evidence that persistent sodium current generates bistable behavior in striatal neurons and contributes to the regulation of synchronous network activity. The neuromodulation of bistable properties could represent a cellular and network mechanism for cholinergic actions in the striatum.

scholarly journals Inhibitory ultrapotent chemogenetics activate dopamine D1 receptor-expressing medium spiny neurons

2020 ◽  
Author(s):  
Stephanie C. Gantz ◽  
Maria M. Ortiz ◽  
Andrew J. Belilos ◽  
Khaled Moussawi
Keyword(s):  
Brain Slices ◽  
Reversal Potential ◽  
Cell Types ◽  
Receptor Activation ◽  
Dopamine D1 Receptor ◽  
D1 Receptor ◽  
Medium Spiny Neurons ◽  
Inhibitory Function ◽  
Spiny Neurons

SUMMARYUltrapotent chemogenetics, including the chloride-permeable inhibitory PSAM4-GlyR receptor, were recently proposed as a powerful strategy to selectively control neuronal activity in awake, behaving animals. We aimed to validate the inhibitory function of PSAM4-GlyR in dopamine D1 receptor-expressing medium spiny neurons (D1-MSNs) in the ventral striatum. Activation of PSAM4-GlyR with the uPSEM792 ligand enhanced rather than suppressed the activity of D1-MSNs in vivo as indicated by increased c-fos expression in D1-MSNs. Whole-cell recordings in mouse brain slices showed that activation of PSAM4-GlyR did not inhibit firing of action potentials in D1-MSNs. Activation of PSAM4-GlyR depolarized D1-MSNs, attenuated GABAergic inhibition, and shifted the reversal potential of PSAM4-GlyR current to more depolarized potentials, perpetuating the depolarizing effect of receptor activation. The data show that ‘inhibitory’ PSAM4-GlyR chemogenetics may actually activate certain cell types, and highlight the pitfalls of utilizing chloride conductances to inhibit neurons.

scholarly journals A Negative Slope Conductance of the Persistent Sodium Current Prolongs Subthreshold Depolarizations

2017 ◽  
Vol 113 (10) ◽  
pp. 2207-2217 ◽  
Author(s):  
Cesar C. Ceballos ◽  
Antonio C. Roque ◽  
Ricardo M. Leão
Keyword(s):  
Sodium Current ◽  
Negative Slope ◽  
Persistent Sodium Current

scholarly journals Persistent Sodium and Calcium Currents Cause Plateau Potentials in Motoneurons of Chronic Spinal Rats

2003 ◽  
Vol 90 (2) ◽  
pp. 857-869 ◽  
Author(s):  
Yunru Li ◽  
David J. Bennett
Keyword(s):  
Spinal Cord ◽  
Sodium Current ◽  
Negative Slope ◽  
Primary Role ◽  
Persistent Sodium Current ◽  
Plateau Potentials ◽  
Spike Threshold ◽  
Low Threshold ◽  
Chronic Spinal Rats ◽  
Initial Peak

After chronic spinal cord injury motoneurons exhibit large plateau potentials (sustained depolarizations triggered by brief inputs) that play a primary role in the development of muscle spasms and spasticity (Bennett et al. 2001a , b ). The present study examined the voltage-gated persistent inward currents (PICs) underlying these plateaus. Adult rats were spinalized at the S2 sacral spinal level and after 2 mo, when spasticity developed, intracellular recordings were made from motoneurons below the injury. For recording, the whole sacrocaudal spinal cord was removed and maintained in vitro in normal artificial cerebral spinal fluid (nACSF), without application of neuromodulators. During a slow triangular voltage-clamp command (ramp) a PIC was activated with a threshold of –54.2 ± 4.8 mV (similar to plateau threshold), with a peak current of 2.88 ± 0.95 nA and produced a pronounced negative-slope region in the V–I relation. This PIC was in part mediated by Cav1.3 L-type calcium channels because it was low threshold and significantly reduced by 10 to 20 μM nimodipine or 400 μM Cd2+. The PIC that remained during a calcium channel blockade (in Cd2+) was completely and rapidly blocked by tetrodotoxin (TTX; 0.5 to 2 μM), and thus was a TTX-sensitive persistent sodium current. This persistent sodium current was activated rapidly about 7 mV below the spike threshold (spike threshold –46.1 ± 4.5 mV), contributed approximately 1/2 of the initial peak of the total PIC, inactivated partly to contribute only approximately 1/3 of the sustained PIC (at 5 to 10 s), and deactivated rapidly with hyperpolarization (<50 ms). When TTX was added to the bath first, the nimodipine-sensitive persistent calcium current (L-type) was seen in isolation; it was slowly activated (>250 ms), had a low but variable threshold (either slightly above or below the spike threshold), contributed the other approximately 1/2 of the initial peak of the total PIC (before TTX), did not usually inactivate with time (contributed approximately two-thirds of the sustained PIC), and deactivated slowly with hyperpolarization to rest (in >300 ms). In summary, low-threshold persistent calcium (Cav1.3) and sodium currents spontaneously develop in motoneurons of chronic spinal rats and these enable large, rapidly activated plateaus that ultimately lead to spasticity.

scholarly journals Global and local excitation and inhibition shape the dynamics of the cortico-striatal-thalamo-cortical pathway

2017 ◽  
Author(s):  
Anca R Radulescu ◽  
Joanna Herron ◽  
Caitlin Kennedy ◽  
Annalisa Scimemi
Keyword(s):  
Network Dynamics ◽  
Relative Strength ◽  
Medium Spiny Neurons ◽  
Linear Modeling ◽  
Obsessive Compulsive ◽  
D2 Dopamine Receptors ◽  
Compulsive Disorder ◽  
Spiny Neurons ◽  
Strength Of Excitation ◽  
Global And Local

The cortico-striatal-thalamo-cortical (CSTC) pathway is a brain circuit that controls movement execution, habit formation and reward. Hyperactivity in the CSTC pathway is involved in obsessive compulsive disorder, a neuropsychiatric disorder characterized by the execution of repetitive involuntary movements. The striatum shapes the activity of the CSTC pathway through the coordinated activation of two classes of medium spiny neurons (MSNs) expressing D1 or D2 dopamine receptors. The exact mechanisms by which balanced excitation/inhibition of these cells controls the network dynamics of the CSTC pathway remain unclear. Here we use non-linear modeling of neuronal activity and bifurcation theory to investigate how global and local changes in excitation/inhibition of MSNs regulate the activity of the CSTC pathway. Our findings indicate that a global and proportionate increase in excitation/inhibition pushes the system to states of generalized hyper-activity throughout the entire CSTC pathway. Certain disproportionate changes in global excitation/inhibition trigger network oscillations. Local changes in the excitation/inhibition of MSNs generate specific oscillatory behaviors in MSNs and in the CSTC pathway. These findings indicate that subtle changes in the relative strength of excitation/inhibition of MSNs can powerfully control the network dynamics of the CSTC pathway in ways that are not easily predicted by its synaptic connections.

D1 Dopamine Receptor Activation Reduces GABAA Receptor Currents in Neostriatal Neurons Through a PKA/DARPP-32/PP1 Signaling Cascade

2000 ◽  
Vol 83 (5) ◽  
pp. 2996-3004 ◽  
Author(s):  
Jorge Flores-Hernandez ◽  
Salvador Hernandez ◽  
Gretchen L. Snyder ◽  
Zhen Yan ◽  
Allen A. Fienberg ◽  
...  
Keyword(s):  
Dopamine Receptor ◽  
Voltage Clamp ◽  
Protein Phosphatase ◽  
Receptor Activation ◽  
Protein Phosphatase 1 ◽  
Signaling Cascade ◽  
Medium Spiny Neurons ◽  
Receptor Stimulation ◽  
Spiny Neurons ◽  
Skf 81297

Dopamine is a critical determinant of neostriatal function, but its impact on intrastriatal GABAergic signaling is poorly understood. The role of D1 dopamine receptors in the regulation of postsynaptic GABAA receptors was characterized using whole cell voltage-clamp recordings in acutely isolated, rat neostriatal medium spiny neurons. Exogenous application of GABA evoked a rapidly desensitizing current that was blocked by bicuculline. Application of the D1 dopamine receptor agonist SKF 81297 reduced GABA-evoked currents in most medium spiny neurons. The D1 dopamine receptor antagonist SCH 23390 blocked the effect of SKF 81297. Membrane-permeant cAMP analogues mimicked the effect of D1 dopamine receptor stimulation, whereas an inhibitor of protein kinase A (PKA; Rp-8-chloroadenosine 3′,5′ cyclic monophosphothioate) attenuated the response to D1 dopamine receptor stimulation or cAMP analogues. Inhibitors of protein phosphatase 1/2A potentiated the modulation by cAMP analogues. Single-cell RT-PCR profiling revealed consistent expression of mRNA for the β1 subunit of the GABAAreceptor—a known substrate of PKA—in medium spiny neurons. Immunoprecipitation assays of radiolabeled proteins revealed that D1 dopamine receptor stimulation increased phosphorylation of GABAA receptor β1/β3 subunits. The D1dopamine receptor-induced phosphorylation of β1/β3 subunits was attenuated significantly in neostriata from DARPP-32 mutants. Voltage-clamp recordings corroborated these results, revealing that the efficacy of the D1 dopamine receptor modulation of GABAA currents was reduced in DARPP-32-deficient medium spiny neurons. These results argue that D1 dopamine receptor stimulation in neostriatal medium spiny neurons reduces postsynaptic GABAA receptor currents by activating a PKA/DARPP-32/protein phosphatase 1 signaling cascade targeting GABAA receptor β1 subunits.

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