Role of Striatal Direct Pathway 2-Arachidonoylglycerol Signaling in Sociability and Repetitive Behavior

Abstract

These data suggest a role for 2-AG deficiency in social deficits and repetitive behavior, and they demonstrate a key role for 2-AG in regulating striatal direct-pathway MSNs.

Cyclic AMP‐dependent protein kinase and D1 dopamine receptors regulate diacylglycerol lipase‐α and synaptic 2‐arachidonoyl glycerol signaling

“…For example, one form of eCB‐LTD in iMSNs is regulated by D2Rs via a mechanism that requires cAMP/PKA signaling and RGS4 (Lerner & Kreitzer, ) and was blocked by a DGLα inhibitor, but DGLα knockout mice were not available to confirm this interpretation. However, DGLα knockout mice were recently used to show that DGLα is required for the on‐demand synthesis and mobilization of 2‐AG to induce DSE, a well‐defined form of short term striatal synaptic plasticity, in both dMSNs and iMSNs (Shonesy et al, , ). In general, dMSNs and iMSNs express either D1Rs or D2Rs, which can simulate or inhibit adenylyl cyclase, respectively (Beaulieu & Gainetdinov, ).…”

“…Our electrophysiological studies show that DSE in dMSNs is enhanced by a D1R agonist via a mechanism requiring PKA activity (Figure ), strongly supporting the physiological relevance of our biochemical data showing that PKA enhances DGLα activity by phosphorylating Ser798 (Figures ). Interestingly, even though DGLα expression is required for DSE in both dMSNs and iMSNs (Shonesy et al, ), the specific deletion of DGLα from dMSNs significantly reduces baseline total striatal levels of 2‐AG, whereas the deletion of DGLα from iMSNs had no significant impact on baseline 2‐AG levels (Shonesy et al, ). A potential explanation of these findings is that while activity‐dependent synaptic 2‐AG mobilization and DSE can be similarly induced in both cells types, tonic DGLα activity is higher in dMSNs than in iMSNs under basal, unstimulated conditions.…”

“…Acute brain slice preparation and whole cell patch clamp recordings were performed essentially as previously described (Shonesy et al, , , ). D1‐tdTomato or D2‐eGFP mice were anesthetized with isoflurane and transcardially perfused with cold, oxygenated (95% v/v O 2 , 5% v/v CO 2 ) N ‐methyl‐ d ‐glucamine (NMDG)‐containing artificial cerebrospinal fluid (ACSF), comprised of (in mM): 92 NMDG, 2.5 KCl, 1.25 NaH 2 PO 4 , 30 NaHCO 3 , 25 glucose, 5 ascorbate, 20 HEPES, 3 Na‐pyruvate, 0.5 CaCl 2 .4H 2 O, 10 MgSO 4 .7H 2 O. NMDG‐ACSF was titrated to pH 7.3–7.4 with HCl.…”

“…Medium spiny neurons (MSNs) in the dorsal striatum integrate excitatory synaptic inputs from the cortex and thalamus to modulate action selection and motor coordination (reviewed in: Mathur & Lovinger, ; Zhai, Tanimura, Graves, Shen, & Surmeier, )). MSNs in the direct and indirect output pathways (dMSNs and iMSNs, respectively) express either D1‐ or D2‐dopamine receptors (D1Rs or D2Rs), respectively (Shonesy et al, , ; Wu et al, ; Xu et al, ), and are critically modulated by dopamine innervation from the substantia nigra (reviewed in: Burguiere, Monteiro, Mallet, Feng, & Graybiel, ; Gerfen & Surmeier, ; Gunaydin & Kreitzer, ; Zhai et al, )). Moreover, glutamatergic inputs to both dMSNs and iMSNs can be modulated by cannabinoid receptor‐dependent short‐ and long‐term depression (Lerner & Kreitzer, ; Shonesy et al, , ; Song, Anderson, Sutton, Dao, & Martemyanov, ).…”

“…MSNs in the direct and indirect output pathways (dMSNs and iMSNs, respectively) express either D1‐ or D2‐dopamine receptors (D1Rs or D2Rs), respectively (Shonesy et al, , ; Wu et al, ; Xu et al, ), and are critically modulated by dopamine innervation from the substantia nigra (reviewed in: Burguiere, Monteiro, Mallet, Feng, & Graybiel, ; Gerfen & Surmeier, ; Gunaydin & Kreitzer, ; Zhai et al, )). Moreover, glutamatergic inputs to both dMSNs and iMSNs can be modulated by cannabinoid receptor‐dependent short‐ and long‐term depression (Lerner & Kreitzer, ; Shonesy et al, , ; Song, Anderson, Sutton, Dao, & Martemyanov, ). Thus, the intersecting striatal actions of D1Rs and D2Rs, canonically acting to increase or decrease cAMP signaling in striatal medium spiny neurons projecting via the direct/indirect output pathways, respectively, with eCBs are critical for the dynamic regulation of striatal output to the basal ganglia, exerting complex behavioral effects.…”