Endocannabinoids Mediate Synaptic Plasticity At

30 Activation of Type 1 cannabinoid receptors (CB1R) in many central nervous system 31 structures induces both short and long term changes in synaptic transmission. Within 32 mammalian striatum, endocannabinoids (eCB) are one of several mechanisms that 33 induce synaptic plasticity at glutamatergic terminals onto medium spiny neurons. 34 Striatal synaptic plasticity may contribute a critical component of adaptive motor 35 coordination and procedural learning. Songbirds are advantageous for studying the 36 neural mechanisms of motor learning because they possess a neural pathway necessary 37 for song learning and adult song plasticity that includes a striato-pallidal nucleus, area X 38 (homologous to a portion of mammalian basal ganglia). Recent findings suggest that 39 eCBs contribute to vocal development. For example, dense CB1R expression in song 40 control nuclei peaks around the closure of the sensori-motor integration phase of song 41 development. Also, systemic administration of a CB1R agonist during vocal development 42 impairs song learning. Here we test whether activation of CB1R alters excitatory 43 synaptic input on spiny neurons in area X of adult male zebra finches. Application of the 44 CB1R agonist WIN55212-2 decreased EPSC amplitude; that decrease was blocked by the 45 CB1R antagonist AM251. Guided by eCB experiments in mammalian striatum we tested 46 and verified that at least two mechanisms indirectly activate CB1Rs through eCBs in area 47 X. First, activation of group I metabotropic glutamate receptors with the agonist DHPG 48 induced a CB1R mediated reduction in EPSC amplitude. Second, we observed that a 10 49 second postsynaptic depolarization induced a calcium-mediated, eCB-dependent 50 decrease in synaptic strength that resisted rescue with late CB1R blockade. Together, 51 these results show that eCB modulation occurs at inputs to area X spiny neurons and 52 could influence motor learning and production. 53 54 CB1R dependent synaptic plasticity in songbird area X