Cortical Regulation of Striatal Medium Spiny Neuron Dendritic Remodeling in Parkinsonism: Modulation of Glutamate Release Reverses Dopamine Depletion–Induced Dendritic Spine Loss

Abstract

Striatal medium spiny neurons (MSNs) receive glutamatergic afferents from the cerebral cortex and dopaminergic inputs from the substantia nigra (SN). Striatal dopamine loss decreases the number of MSN dendritic spines. This loss of spines has been suggested to reflect the removal of tonic dopamine inhibitory control over corticostriatal glutamatergic drive, with increased glutamate release culminating in MSN spine loss. We tested this hypothesis in two ways. We first determined in vivo if decortication reverses or prevents dopamine depletion--induced spine loss by placing motor cortex lesions 4 weeks after, or at the time of, 6-hydroxydopamine lesions of the SN. Animals were sacrificed 4 weeks after cortical lesions. Motor cortex lesions significantly reversed the loss of MSN spines elicited by dopamine denervation; a similar effect was observed in the prevention experiment. We then determined if modulating glutamate release in organotypic cocultures prevented spine loss. Treatment of the cultures with the mGluR2/3 agonist LY379268 to suppress corticostriatal glutamate release completely blocked spine loss in dopamine-denervated cultures. These studies provide the first evidence to show that MSN spine loss associated with parkinsonism can be reversed and point to suppression of corticostriatal glutamate release as a means of slowing progression in Parkinson's disease.

Baseline effects of transcranial direct current stimulation on glutamatergic neurotransmission and large-scale network connectivity

“…This finding is consistent with the previously observed intrinsic connectivity between the putamen and parietal cortex (Martino et al, 2008; Cao et al, 2009). To this end, given that the putamen consists primarily of spiny neurons which receive direct input from glutamatergic signaling, tDCS may also influence the inhibitory medium spiny neurons in this brain structure (Garcia et al, 2010; Girault, 2012). However, the putamen and the cortex have no monosynaptic anatomical connections, and so further research is needed to identify the mediating structures and signaling pathways by which tDCS operates.…”

Striatal shape in Parkinson's disease

“…Several lines of evidence suggest that glutamatergic synaptic and intraspine calcium channel dysregulation may play key roles in PD-related striatal spine pathology (Villalba and Smith, 2010; Burguière et al, 2013; Tian et al, 2010). Previous studies have shown that reducing glutamate release may prevent and/or reverse dopamine depletion-induced dendritic spine loss on medium spiny neurons (Neely et al, 2007; Garcia et al, 2010). In addition, the administration of an L-type calcium channel blocker in an animal model was shown to attenuate these spine losses (Soderstrom et al, 2010; Schuster et al, 2009; Bezard, 2010).…”

Progress toward advanced understanding of metabotropic glutamate receptors: structure, signaling and therapeutic indications

“…Corticostriatal synapses have been shown to be overactive in dopamine-depleted animals (Picconi, Centonze et al 2004, Centonze, Gubellini et al 2005), contributing to the loss of spines in striatal medium spiny neurons in PD (Garcia, Neely et al 2010). In addition, the deregulated plasticity (such as long-term depression and depotentiation) at corticostriatal synapses may underlie the mechanism of L-DOPA-induced dyskinesias (Picconi, Centonze et al 2003, Picconi, Bagetta et al 2011).…”