The electrophysiological properties of distinct subpopulations of striatal medium-sized spiny neurons (MSSNs) were compared using enhanced green fluorescent protein as a reporter gene for identification of neurons expressing dopamine D1 and D2 receptor subtypes in mice. Whole-cell patch-clamp recordings in slices revealed that passive membrane properties were similar in D1 and D2 cells. All MSSNs displayed hyperpolarized resting membrane potentials but the threshold for firing action potentials was lower in D2 than in D1 neurons. In voltage clamp, the frequency of spontaneous excitatory postsynaptic currents was higher in D2 than in D1 cells and large-amplitude inward currents (> 100 pA) were observed only in D2 cells. After tetrodotoxin this difference was reduced, suggesting that sodium conductances contribute to the increased frequencies in D2 cells. After pharmacological blockade of GABA(A) receptors, a subset of D2 cells also displayed large spontaneous membrane depolarizations and complex responses to stimulation of the corticostriatal pathway. To further characterize ionotropic glutamate receptor function, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) was applied onto dissociated MSSNs. Application of AMPA alone or in the presence of cyclothiazide (an AMPA receptor desensitization blocker) evoked larger currents in D1 than in D2 cells. Together, these data demonstrate significant differences in electrophysiological properties of subpopulations of MSSNs defined by selective expression of D1 and D2 receptors. D2 cells display increased excitability and reflect ongoing cortical activity more faithfully than D1 cells, an effect that is independent of postsynaptic AMPA receptors and probably results from stronger synaptic coupling. This could help to explain the increased vulnerability of D2 MSSNs in neurodegenerative disorders.