Effects of Dopaminergic Modulation on the Integrative Properties of the Ventral Striatal Medium Spiny Neuron

Abstract

Moyer JT, Wolf JA, Finkel LH. Effects of dopaminergic modulation on the integrative properties of the ventral striatal medium spiny neuron. J Neurophysiol 98: 3731-3748, 2007. First published October 3, 2007 doi:10.1152/jn.00335.2007. Dopaminergic modulation produces a variety of functional changes in the principal cell of the striatum, the medium spiny neuron (MSN). Using a 189-compartment computational model of a ventral striatal MSN, we simulated whole cell D1-and D2-receptor-mediated modulation of both intrinsic (sodium, calcium, and potassium) and synaptic currents (AMPA and NMDA). Dopamine (DA) modulations in the model were based on a review of published experiments in both ventral and dorsal striatum. To objectively assess the net effects of DA modulation, we combined reported individual channel modulations into either D1-or D2-receptor modulation conditions and studied them separately. Contrary to previous suggestions, we found that D1 modulation had no effect on MSN nonlinearity and could not induce bistability. In agreement with previous suggestions, we found that dopaminergic modulation leads to changes in input filtering and neuronal excitability. Importantly, the changes in neuronal excitability agree with the classical model of basal ganglia function. We also found that DA modulation can alter the integration time window of the MSN. Interestingly, the effects of DA modulation of synaptic properties opposed the effects of DA modulation of intrinsic properties, with the synaptic modulations generally dominating the net effect. We interpret this lack of synergy to suggest that the regulation of whole cell integrative properties is not the primary functional purpose of DA. We suggest that D1 modulation might instead primarily regulate calcium influx to dendritic spines through NMDA and L-type calcium channels, by both direct and indirect mechanisms. I N T R O D U C T I O NDysfunction in the dopamine (DA) modulatory system is involved in a number of clinical disorders, including Parkinson's disease, drug addiction, and schizophrenia. One of the major sites of dopaminergic innervation in the brain is the striatum, consisting of the dorsal striatum (which includes the caudate and putamen) and the ventral striatum (which includes the nucleus accumbens core and shell). The principal cell of the striatum is the medium spiny projection neuron (MSN), which constitutes between 85 and 95% of the total cell population, depending on the species and relative location in the striatum (O'Donnell and Grace 1993;Tepper et al. 2004).The effects of DA on the MSN have been extensively studied and depend on the class of receptor expressed by the cell. Most MSNs coexpress two or more species of receptors, although D1 and D2 receptors (D1R and D2R, respectively) are the most prevalent. D2, D3, and D4 receptors are pharmacologically similar, as are D1 and D5 receptors (Vallone et al. 2000). Research to date suggests that striatal MSNs express primarily either D1Rs or D2Rs (Gerfen et al. 1990;Le Moine and Bloch 1996;Maurice e...

Timing-Dependent Regulation of Evoked Spiking in Nucleus Accumbens Neurons by Integration of Limbic and Prefrontal Cortical Inputs

“…The lack of efficacy of DA receptor blockade in particular is notable (cf. Moyer et al 2007;Nicola et al 2004a) and could be explained by the focus of the current study on evoked spiking rather than subthreshold (Brady and O'Donnell 2004) or population-evoked potentials (Goto and Grace 2005). To reconcile these different accounts of DA actions in NAcc neurons, it may be necessary to measure evoked activity at multiple scales simultaneously and to test drug effects within single neurons (rather than between neurons as in the current study).…”

Dopamine-modulated dynamic cell assemblies generated by the GABAergic striatal microcircuit

“…We introduced a framework for reformulating and extending this model to replicate the output of a detailed dopamine-modulated multi-compartment model (Moyer et al, 2007) -see (Humphries et al, submitted) for details. The MSN population is split in two by the expression of the dominant dopamine receptor type (D1 or D2).…”

“…where we only decrease k by a factor of (1 − αφ 2 ), which is sufficient to model the increased sensitivity to injection current following D2 activation (Moyer et al, 2007). We model synaptic input to all the MSNs as…”

“…where τ z is the appropriate synaptic time constant, and S (t) is the number of pre-synaptic spikes arriving at all the neuron's receptors of type z at time t. Finally, we have the term B(v) that models the voltage-dependent magnesium plug in the NMDA receptors (Moyer et al, 2007)…”

Opposite Effects of Stimulant and Antipsychotic Drugs on Striatal Fast-Spiking Interneurons

“…In simplified models, dopamine is often considered to excite striatonigral projection cells through D1 receptors and inhibit striatopallidal cells through D2 receptors; however, the effects of dopamine signaling on neuronal ion channels are actually highly complex (for example, Moyer et al, 2007). Studies that directly examine the effects of stimulants on striatal neuron firing rates have found heterogeneous results (for example, Gardiner et al, 1988), which depend on many factors including the behavioral state of the animal (reviewed in Rebec 2006).…”