Facilitated glutamatergic transmission in the striatum of D2 dopamine receptor-deficient mice

Dopamine (DA) receptors play an important role in the modulation of excitability and the responsiveness of neurons to activation of excitatory amino acid receptors in the striatum. In the present study, we utilized mice with genetic deletion of D-2 or D-4 DA receptors and their wild-type (WT) controls to examine if the absence of either receptor subtype affects striatal excitatory synaptic activity. Immunocytochemical analysis verified the absence of D-2 or D-4 protein expression in the striatum of receptor-deficient mutant animals. Sharp electrode current- and whole cell patch voltage-clamp recordings were obtained from slices of receptor-deficient and WT mice. Basic membrane properties were similar in D-2 and D-4 receptor-deficient mutants and their respective WT controls. In current- clamp recordings in WT animals, very little low-amplitude spontaneous synaptic activity was observed. The frequency of these spontaneous events was increased slightly in D-2 receptor-deficient mice. In addition, large-amplitude depolarizations were observed in a subset of neurons from only the D-2 receptor-deficient mutants. Bath application of the K+ channel blocker 4-aminopyridine (100 muM) and bicuculline methiodide (10 muM, to block synaptic activity due to activation of GABA(A) receptors) markedly increased spontaneous synaptic activity in receptor-deficient mutants and WTs. Under these conditions, D-2 receptor-deficient mice displayed significantly more excitatory synaptic activity than their WT controls, while there was no difference between D-4 receptor-deficient mice and their controls. In voltage-clamp recordings, there was an increase in frequency of spontaneous glutamate receptor-mediated inward currents without a change in mean amplitude in D-2 receptor-deficient mutants. In WT mice, activation of D-2 family receptors with quinpirole decreased spontaneous excitatory events and conversely sulpiride, a D-2 receptor antagonist, increased activity. In D-2 receptor-deficient mice, sulpiride had very little net effect. Morphologically, a subpopulation of medium-sized spiny neurons from D-2 receptor-deficient mice displayed decreased dendritic spines compared with cells from WT mice. These results provide evidence that D-2 receptors play an important role in the regulation of glutamate receptor-mediated activity in the corticostriatal or thalamostriatal pathway. These receptors may function as gatekeepers of glutamate release or of its subsequent effects and thus may protect striatal neurons from excessive excitation.