Schematic neuronal circuits involving basal ganglia, cortex and the respective neurotransmitters (glutamate, GABA, DA) during the late stages of HD, characterized by bradykinesia. Apart from effects in indirect pathway, there is a decrease in the release of GABA into GPi (direct pathway), promoting the inhibitory output to the thalamus and decreased cortex stimulation. 

Context in source publication

Context 1

... can cause apraxia [57-58]. Moreover, the neurodegeneration induces changes in the number of N -methyl- D -aspartate (NMDA) receptors, suggesting that some components of glutamatergic transmission can be involved in the onset of HD [59]. Furthermore, some studies describe a regular and well-characterized cell death in the hypothalamus, more specifically in the lateral tuberal nucleus [60-61], due to a loss of somatostatin-positive neurons, and orexin-secreting neurons in lateral hypothalamus and prefrontal cortex [62-63]. Despite degeneration in several brain regions, one of the main pathological events in HD is the gradual atrophy of the striatum [1, for review]. The striatum is formed by caudate nucleus, putamen and striatum ventral, in which nucleus accumbens is included [24]. The medium-sized spiny neurons (MSN), which are equivalent to 95% of the striatal population [64], are the main neuronal target of striatal degeneration in HD and they produce γ -aminobutyric acid (GABA) as their inhibitory output neurotransmitter. This neuronal loss leads to a decrease in the levels of GABA, as well as in the enzymes responsible for its synthesis such as glutamate decarboxylase (GAD) [65]. Indeed, during HD there is a relative sparing of interneurons (larged-sized cholinergic neurons, medium-sized calretinin neurons and medium-sized NADPH positive interneurons, which also express nitric oxide synthase and somatostatin) and neuronal afferents (dopaminergic, serotoninergic and glutamatergic neurons) [29, for review]. The striatum receives massive glutamatergic and dopaminergic innervations. The excitatory glutamatergic input derives mainly from all regions of the cerebral cortex, as well as specific thalamic nuclei. The dopaminergic input comes from the SNpc. The mode of interaction between dopamine (DA) and glutamate has been an area of controversy, but it is generally believed that dopaminergic inputs modify the excitatory responses induced by glutamate [66, for review]. As shown in Figure 1, under normal conditions, DA from SNpc acts on dopamine receptors-subtype 1 (D1R) at GABAergic neurons in caudate/ putamen expressing substance P (SP), which release GABA and increase the inhibitory input at neurons at GPi/SNr (direct pathway). These are also GABAergic neurons that project to theinduced by glutamate [66, for review]. As shown in Figure 1, under normal conditions, DA from SNpc acts on dopamine receptors-subtype 1 (D1R) at GABAergic neurons in caudate/putamen expressing substance P (SP), which release GABA and increase the inhibitory input at neurons at GPi/SNr (direct pathway). These are also GABAergic neurons that project to the thalamus. On the other hand, DA also interacts with dopamine receptor-subtype 2 (D2R) on striatal GABAergic neurons that express enkephalin (Enk) (indirect pathway). These neurons project to the GPe controlling the release of GABA in the subthalamic nucleus, which release glutamate (excitatory projections) to the GPi/SNr. Thus, the direct and the indirect pathways promote a positive and a negative feedback into cortex, which in turn reflects in the control of movement through an excitatory and inhibitory projection from the basal ganglia. However, in HD the balance between the direct and indirect pathways is affected. In the initial stages of the disease, the indirect pathway is affected, leading to decreased release of GABA from caudate/putamen into GPe. This can be a result of an increase in the D2R (inhibitory receptor), an increase in the release of DA from SNpc in the area containing these receptors and/or dysfunction of corticostriatal pathway (described in section 3.1). Once activated, D2R inhibit adenylate cyclase and promote neuronal inhibition [1; 66, for review]. Consequently there is a decrease in the inhibition of GPe neurons that also express GABA. Thus, these will release more GABA to subthalamic nuclei and GPi. Taking into account that neurons from subthalamic nucleus to GPi/SNr are glutamatergic and that these will release less glutamate and be less active, the GABAergic neurons at GPi/SNr will be inhibited, releasing less GABA. Ultimately, this leads to a decrease in the inhibition of thalamus and an increase in the excitatory stimulation in cortex, resulting in an exacerbation of movements (Figure 2). MSNs that originate the indirect pathway appear to be more sensitive to the mutation than cells of the direct pathway [66, for review]. On the other hand, the loss of GABAergic neurons can also induce changes in the direct pathway. Neurons of the direct pathway contain substance P and preferentially express D1R (which, once activated, stimulate adenylate cyclase) [1; 66, for review]. Accordingly, a decrease in the release of GABA into GPi/SNr results in an increase in the inhibition of thalamus and consequently in a decrease of cortex stimulation and decrease of movement. These circuits can explain the rigidity and bradykinesia observed in the late stages of HD (Figure 3). mHtt induces neuronal dysfunction, leading to the dysruption of neuronal circuits, namely the corticostriatal pathway. It is becoming increasingly clear that major morphological alterations in the striatum are probably primed initially by alterations in the intrinsic functional properties of MSNs. Some of these alterations, including increased sensitivity of NMDA receptors in subpopulations of striatal neurons (likely in combination with pathological signaling downstream of glutamate receptor activation), increased glutamate release from cortical afferents and/or reduced uptake of glutamate by glia, may lead to abnormalities of the corticostriatal pathway [38; 66, for review]. Indeed, the dysfunction of the corticostriatal pathway leads to complex alterations that consist of early increased excitability involving a combination of changes in inhibitory GABAergic cortical microcircuits and presynaptic deregulation of neurotransmitter release, thus exposing MSNs to glutamate in excess. Previously, Rosas et al. (2005) [67] provided evidence of early and selective cortical degeneration during the motor preclinical stages of HD, indicating that cortical dysfunction contributes to the human pathology. The selective vulnerability of the cortex very early in disease is not surprising given that Htt aggregates can be readily detected in the cortex of individuals at risk of HD, who died before exhibiting any symptoms [68]. The increased levels of glutamate in the synaptic cleft of cortico-striatal projections will lead to an enhanced response of the NMDA receptors to glutamate activation. This in turn will causes an increase in intracellular Ca 2+ concentrations with consequent excitotoxicity, including mitochondrial dysfunction, activation of the Ca 2+ -dependent neuronal isoform of nitric oxide (NO) synthase, generation of NO and ROS, activation of Ca 2+ dependent proteases, such as calpains, and apoptosis [e.g. 69]. Moreover, increased striatal GABA function can severely impair the integrative and output capabilities of MSNs and cause a lack of regulation of pallidal and nigral neurons [66, for review]. Clearance of extracellular excitatory neurotransmitters is largely performed by glutamate transporters [GLT-1 (glutamate transporter-1) and GLAST (glutamate aspartate transporter)] in astrocytes. mHtt was previously shown to cause reduced expression of GLT-1 in the brains of HD models, such as R6/1 and R6/2 mice, that express the exon 1 of the human Htt gene with 115 or 150 CAGs, respectively after symptom onset, as well as in cultured astrocytes expressing N-terminal fragment of mHtt, promoting excitotoxic neuronal death [70-71]. Indeed, an increase in glutamate concentration extracellularly was demonstrated in the cortex of HD patients [72] and in the neostriatum of post-mortem HD brains [73]. Alterations in glutamate release and cortico-striatal currents were also detected in YAC128 mice model (expressing human full-length (FL) mHtt with 128-glutamines) [74]. A byphasic age-dependent change in corticostriatal activity was demonstrated in these animals. In a pre-symptomatic stage, synaptic responses, postsynaptic currents, and glutamate release are increased, whereas at a symptomatic stage there is a reduction in synaptic responses and postsynaptic currents [74]. Okamoto and colleagues further reported different effects of mHtt on synaptic and extrasynaptic NMDA receptors. It was shown that activation of synaptic NMDA receptors induces mHtt inclusions, increasing neuronal resistance to mHtt-mediated cell death. On the other hand, stimulation of extrasynaptic NMDA receptors increases neuronal vulnerability to mHtt-induced cell death and disaggregate mHtt [75] [for review, 38; 76]. Accordingly, the importance of increased extrasynaptic NMDA receptor signaling and expression on HD mice phenotype onset was recently strengthened [77]. Thus, the presence of mHtt also can lead to a synaptic deregulation through changes in glutamate release and excitability of different NMDA receptors. Accordingly, the group of Lynn Raymond [78] has previously identified a significant role for the NR2B subunit of NMDA receptors in HD pathogenesis (striatal degeneration); importantly, NR2B subunits are mostly located extrasynaptically [79]. The decreased expression of (pre-synaptic) glutamate transporters, which are important in regulating the levels of glutamate in the synaptic cleft, underlies an effect of mHtt on gene transcription [72; 80]. Several data also demonstrate a direct link between mHtt, glutamate signaling and calcium deregulation in striatal neurons [for review, 38]. Calcium signaling, can be regulated by the expression of genes directly or indirectly related to its homeostasis; these include copine V, striatin, SCNb4 and alpha actinin 2, which show diminished expression levels in presymptomatic R6/1 mice [82]. These findings are consistent with previous studies reporting dysfunction in calcium signaling in ...