Presynaptic modulation by somatostatin in the rat 1 neostriatum is altered in a model of Parkinsonism 2 3

26 Somatostatin (SST) is a peptide synthesized and released by a class of neostriatal 27 local GABAergic interneurons which, to some extent, are in charge of the 28 feedforward inhibitory circuit. Spiny projection neurons (SPNs) make synapses 29 with each other via their local axon collaterals shaping the feedback inhibitory 30 circuit. Both inhibitory circuits, feedforward and feedback, are related through SST 31 which being released by interneurons, presynaptically inhibits connections among 32 SPNs. Here we studied SST presynaptic modulation of synapses among SPNs in 33 the 6-OHDA rodent model of Parkinsonism. We performed antidromic field 34 stimulation from the external globus pallidus (GPe) and whole cell voltage clamp 35 recordings of antidromically evoked inhibitory postsynaptic currents (IPSCs) among 36 SPNs. SST presynaptically reduced IPSCs by about 34% in all control synapses 37 tested. But after striatal dopamine (DA) deprivation three changes became evident: 38 First, it was harder to evoke feedback inhibition. Second, presynaptic inhibition of 39 some SPNs connections was larger than in controls: 57% reduction in about 53% 40 of evoked IPSCs. Presynaptic inhibition was recorded from direct pathway neurons 41 (dSPNs). Third, SST also induced presynaptic facilitation in some SPNs 42 connections with 82% enhancement in about 43% of evoked IPSCs. Presynaptic 43 facilitation was recorded from indirect pathway neurons (iSPNs). Both inhibition 44 and facilitation were accompanied by corresponding changes in the paired pulse 45 ratio. It is demonstrated that after DA deprivation SST modulation is altered in 46 surviving feedback inhibitory synapses. It may underlie a homeostatic mechanism 47 trying to compensate for the excitability imbalance between direct and indirect 48 basal ganglia pathways found during Parkinsonism. 49