Facilitated glutamatergic transmission in the striatum of D-2 dopamine receptor-deficient mice

Dopamine (DA) receptors play an important role in the modulation of excitab ility and the responsiveness of neurons to activation of excitatory amino a cid 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) contro ls to examine if the absence of either receptor subtype affects striatal ex citatory synaptic activity. Immunocytochemical analysis verified the absenc e of D-2 or D-4 protein expression in the striatum of receptor-deficient mu tant animals. Sharp electrode current- and whole cell patch voltage-clamp r ecordings were obtained from slices of receptor-deficient and WT mice. Basi c membrane properties were similar in D-2 and D-4 receptor-deficient mutant s and their respective WT controls. In current- clamp recordings in WT anim als, very little low-amplitude spontaneous synaptic activity was observed. The frequency of these spontaneous events was increased slightly in D-2 rec eptor-deficient mice. In addition, large-amplitude depolarizations were obs erved 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 bi cuculline methiodide (10 muM, to block synaptic activity due to activation of GABA(A) receptors) markedly increased spontaneous synaptic activity in r eceptor-deficient mutants and WTs. Under these conditions, D-2 receptor-def icient mice displayed significantly more excitatory synaptic activity than their WT controls, while there was no difference between D-4 receptor-defic ient mice and their controls. In voltage-clamp recordings, there was an inc rease in frequency of spontaneous glutamate receptor-mediated inward curren ts without a change in mean amplitude in D-2 receptor-deficient mutants. In WT mice, activation of D-2 family receptors with quinpirole decreased spon taneous excitatory events and conversely sulpiride, a D-2 receptor antagoni st, increased activity. In D-2 receptor-deficient mice, sulpiride had very little net effect. Morphologically, a subpopulation of medium-sized spiny n eurons from D-2 receptor-deficient mice displayed decreased dendritic spine s compared with cells from WT mice. These results provide evidence that D-2 receptors play an important role in the regulation of glutamate receptor-m ediated activity in the corticostriatal or thalamostriatal pathway. These r eceptors may function as gatekeepers of glutamate release or of its subsequ ent effects and thus may protect striatal neurons from excessive excitation .