Muscarinic m1 and m2 receptor proteins in local circuit and projection neurons of the primate striatum: Anatomical evidence for cholinergic modulation of glutamatergic prefronto-striatal pathways

The cellular and subcellular localization of muscarinic receptor proteins m i and m2 was examined in the neostriatum of macaque monkeys by using light and electron microscopic immunocytochemical techniques. Double-labeling imm unocytochemistry revealed mi receptors in calbindin-D28k-positive medium sp iny projection neurons. Muscarinic mi labeling was dramatically more intens e in the striatal matrix compartment in juvenile monkeys but more intense i n striosomes in the adult caudate, suggesting that mi expression undergoes a developmental age-dependent change. Ultrastructurally, mi receptors were predominantly localized in asymmetric synapse-forming spines, indicating th at these spines receive extrastriatal excitatory afferents. The association of m1-positive spines with lesion-induced degenerating prefronto-striatal axon terminals demonstrated that these afferents originate in part from the prefrontal cortex. The synaptic localization of m1 in these spines indicat es a role of mi in the modulation of excitatory neurotransmission. To a les ser extent, mi was present in symmetric synapses, where it may also modulat e inhibitory neurotransmission originating from local striatal neurons or t he substantia nigra. Conversely, m2/choline acetyltransferase (ChAT) double labeling revealed that m2-positive neurons corresponded to large aspiny ch olinergic interneurons and ultrastructurally, that the majority of m2 label ed axons formed symmetric synapses. The remarkable segregation of the mi an d m2 receptor proteins to projection and local circuit neurons suggests a f unctional segregation of mi and m2 mediated cholinergic actions in the stri atum: mi receptors modulate extrinsic glutamatergic and monoaminergic affer ents and intrinsic GABAergic afferents onto projection neurons, whereas m2 receptors regulate acetylcholine release from axons of cholinergic interneu rons. J. Comp. Neurol. 434:445-460, 2001. (C) 2001 Wiley-Liss, Inc.