Biology Reference
In-Depth Information
Medium spiny neurons are inhibitory GABAergic cells of the striatum with numerous
small spines. These medium size neurons mainly received glutamatergic inputs from the
neocortex and the thalamus. Moreover, immunoelectron microscopy studies have shown that
dopamine D1 and D2 receptors are localized in dendritic spines of the striatum [Bergson et
al., 1995; Yung et al., 1995]. Dopamine is a transmitter that modulates fast excitatory
glutamatergic transmission. In acutely dissociated neostriatal medium spiny neurons,
constitutively active PP1c, anchored in the vicinity of AMPA receptors by spinophilin, keeps
the channel in the dephosphorylated (“low activity”) state. At glutamatergic corticostriatal
synapses, dopamine can have modulatory effects on synaptic plasticity [Calabresi et al.,
2007]. In response to D1 receptor stimulation, PKA phosphorylates a PP1c binding protein
DARPP-32 (dopamine- and cyclic AMP-regulated phosphoprotein, MW 32 kDa),
and
phosphoDARPP-32 potently inhibits PP1c [Greengard et al., 1999].
Activation of the D1
receptor/PKA/DARPP-32 cascade converts AMPA channels to the phosphorylated (“high
activity”) state [Yan et al., 1999]. Likewise, spinophilin Ser-94 phosphorylation alone by
PKA reduces the ability of the scaffolding protein to associates with F-actin in mouse
neurons. In striatonigral medium spiny neurons, D1 receptors stimulation activates
spinophilin Ser-94 phosphorylation via PKA/DARPP32 dependent inhibition of PP1c. A
2A
adenosine receptor stimulation has the same effect in striatopallidal medium spiny neurons. It
was proposed that in medium spiny neurons, dopamine and adenosine could modulate
spinophilin Ser-94 phosphorylation resulting in a dissociation of the spinophilin/PP1c
complex from F-actin within the spines. Modulation of the localization of the
spinophilin/PP1c complex could contribute to regulate excitatory neurotransmission mediated
by AMPA (and NMDA) receptors [Uematsu et al., 2005]. Phosphorylation by CaMKII also
reduced the affinity of spinophilin for F-actin and brought an additional level of regulation of
AMPA channel [Grossman et al., 2004].
Both spinophilin and neurabin 1 are required for
dopamine-mediated plasticity in striatum but with distinct roles [Allen et al., 2006]. D1-
mediated regulation of AMPA receptor was deficient in striatal neurons from both spinophilin
and neurabin 1 KO mices. LTP was deficient in neurabin 1 KO mice but not in spinophilin
KO mice. LTP was rescued at the corticospinal synapses following D1 receptor activation. In
contrast to these observations, LTD was deficient in spinophilin KO mice but not in neurabin
1 KO mice, and this form of synaptic plasticity was rescued following D2 receptor activation.
D1 receptor stimulation results in PKA-mediated phosphorylation of GluR1 subunit at Ser-
845 [Snyder et al., 2000] and NR1 subunit at Ser-897 [Snyder et al., 1998]. In both KO mices
an increase in GluR1 Ser-845 phosphorylation was observed following D1 receptor
stimulation while in contrast NR1 Ser-897 phosphorylation was unchanged. The authors
suggested an indirect effect in which spinophilin and neurabin 1 are involved in dopamine-
mediated control over AMPA receptor trafficking to the synaptic membrane [Allen et al.,
2006].
It is interesting to note that α-adrenergic signalling regulated NMDA receptor function in
the central nervous system [Liu et al., 2006]. Most α
1
- and α
2
-AR subtypes are highly
expressed in various regions of the central nervous system. α
1
-AR activation reduced NMDA
receptor-mediated currents in prefrontal cortex pyramidal neurons. The α
1
-AR effect
depended on the phospholipase C-IP
3
-Ca
2+
pathway and is down-regulated by RGS2 and
RGS4. The regulating effects of RGS2 and RGS4 were lost in spinophilin KO mice
suggesting that the effect of α
1
-AR signalling on NMDA receptor-current is attenuated by
