Pathological gamma oscillations, impaired dopamine release, synapse loss and reduced dynamic range of unitary glutamatergic synaptic transmission in the striatum of hypokinetic Q175 Huntington mice
Introduction
Huntington’s disease (HD) is a severe monogenetic disorder with a pathological gain of function. Disease progression is associated with a broad range of alterations in motor, cognitive and emotional performances eventually leading to dementia and premature death within an average of 20 years after the appearance of first symptoms (see (Walker, 2007, Ross et al., 2014) for a review of clinical studies). A characteristic feature of HD at earlier stages is the appearance of uncontrolled muscle contractions (chorea), whereas Parkinson-like symptoms, including hypokinesia, increased muscle tone and occasional tremor, are key symptoms of advanced HD. In 8–10% of cases (the Westphal variety of HD) the afflicted patients present without chorea and exhibit hypokinesia from the very beginning. The degree of motor impairment (hypokinesia, rigor and bradykinesia) but not chorea correlates with the neuropathological scores of disease severity (Rosenblatt et al., 2003).
Although the focus of the present report will be placed on the cellular basis of hypokinesia, it is deemed necessary to first provide a set of functional indicators of motor impairment to further characterize the selected mouse model of HD, the Z-Q175-KI mouse (Menalled et al., 2012). In comparison with the better known R6/2 HD mice, Q175 mice display motor disturbances at an older age and also survive longer, although the number of CAG repeats is extremely high (on average 184). At the selected age of 1 year Q175 heterozygotes and homozygotes (HOMs) exhibit motor deficits for at least 4 months (Menalled et al., 2012, Heikkinen et al., 2012, Loh et al., 2013).
As for the cellular basis of the transition from chorea/hyperactivity to dystonia/hypokinesia we shall regard three principal possibilities: (i) sequential degeneration of neuronal subsets in the striatum, (ii) dopamine depletion and (iii) deficiency of corticostriatal synaptic transmission. Neuropathological studies of human HD brains suggested that the DRD2/enkephalin-expressing striatal projection neurons (SPNs) of the indirect pathway (iSPNs) undergo neurodegeneration before the DRD1/substance P-expressing SPNs of the direct pathway (dSPNs) decrease in number (Reiner et al., 1988, Sapp et al., 1995, Glass et al., 2000, Deng et al., 2004). According to the hypothesis of (Albin et al., 1989), the motor symptoms would then initially reflect the imbalance between the direct/indirect pathways with their facilitatory/suppressive role in motor activity and, later on, manifest the complete breakdown of signal transmission through the basal ganglia.
However, hypokinesia and rigidity might occur in the absence of substantial neuron loss in the striatum, as is the case in patients with the idiopathic parkinson syndrome (IPS) where motor impairments are mainly caused by the degeneration of dopaminergic neurons in the brain stem. Is then hypokinesia in HD caused by insufficiency of dopamine signaling (see (Cepeda et al., 2014) for a comprehensive review of clinical and animal studies)? Indeed, functional tests in HD preparations in vitro demonstrated reduced DA release (Petersen et al., 2002, Johnson et al., 2006, Callahan and Abercrombie, 2011, Dallerac et al., 2015) and impaired D1-dependent modulation of glutamatergic synaptic transmission (Joshi et al., 2009). It should be mentioned that some of these findings were stage-dependent, consistent with the notion that chorea might be associated with hyperactive dopamine signaling (Jahanshahi et al., 2010, Dallerac et al., 2015). Unfortunately, still little is known on the state of dopaminergic innervation and the capacity for striatal dopamine release of intact HD mice exhibiting hypokinesia. To fill this gap of knowledge was the second aim of the present study.
Finally, it had been suggested that corticostriatal uncoupling could be a cause of motor impairment in advanced HD (Cepeda et al., 2007, Joshi et al., 2009, Hong et al., 2012). However, the exact mechanism of lost corticostriatal control is still far from being understood. Since, for technical reasons, HD-related differences in the release characteristics of corticostriatal synapses are difficult to prove it has remained unclear whether reduced corticostriatal coupling is expressed at the level of individual corticostriatal connections or mainly due to degeneration of cortical pyramidal neurons. A first answer to this question could be obtained by recording unitary EPSCs (uEPSCs) of presumed corticostriatal origin. Such connections can be identified on the basis of their characteristic short-term plasticity, as it was shown that corticostriatal but not thalamostriatal EPSCs exhibit paired-pulse facilitation (PPF) under standard conditions (Ding et al., 2008). The results of these experiments could then be confronted with the results of synapse counts using the vesicular glutamate transporter 1 (VGLUT1) as a marker of synaptic terminals of cortical origin (Deng et al., 2013).
On the whole, our material from 1-year-old Q175 mice renders support to the hypothesis that HD hypokinesia is associated with a reduction of dopaminergic and glutamatergic innervation in the striatum and occurs prior to the substantial loss of DARPP-32-labeled striatal projection cells.
Section snippets
Ethical approval
The present experiments were performed in fully adult mice from a colony of Z-Q175-KI provided by the CHDI (“Cure Huntington’s disease Initiative”) foundation. Every precaution was taken to minimize stress and to reduce the number of animals used in each series of experiments. The work described here has been carried out in accordance with the EU Directive 2010/63/EU for animal experiments and complies with the requirements for manuscripts submitted to biomedical journals. The work was
Signs of hypokinesia in Q175 mice
When evaluating the motor activities in HD mice it is necessary to take into account the circadian rhythms of activity and sleep (Loh et al., 2013), as HD-related deviations might be more prominent at night. The graph of Fig. 1 presents the motor activity as the number of deflections registered by a sensitive Sartorius balance throughout an entire light–dark (LD) cycle in a sound-proof cage. During the night period HD mice displayed hyperactivity in the form of a delayed decline of the initial
Hypokinesia in Q175 mice
The starting point of this study was the observation that Q175 homozygotes exhibited signs of hypokinesia, especially when tested during day-light. The term hypokinesia refers to impairment of movement initiation due to difficulty selecting and/or activating respective motor programs in the basal ganglia. Based on the comparison of WT and Q175 HOMs we have interpreted the following observations as signs of hypokinesia: Reduced number of spontaneous movements on a balance after exposure to light
Conclusion
Our results suggest that restoring synaptic dopamine and glutamate release should normalize striatal activity at rest, abolish pathological gamma oscillations and alleviate the symptom of hypokinesia.
Acknowledgment
This work is supported by the Cure Huntington’s Disease Initiative foundation (A-7815), the German Research Council (Gr986/10-1, Exc 257/1), Charité Research Funds (2015-040) and intramural funds of the Leibniz Institute of Neurobiology. We highly appreciate the expert advice of Dr. Hannes Schmidt at the Max Delbrück Center for Molecular Medicine Berlin and Dr. Svetlana Warton, retired from the University of Sydney. Jörg Rösner at the Neurocure Microscope Core Facility provided skilled
References (74)
- et al.
The functional anatomy of basal ganglia disorders
Trends Neurosci
(1989) - et al.
Immunohistochemical localization of DARPP-32 in striatal projection neurons and striatal interneurons: implications for the localization of D1-like dopamine receptors on different types of striatal neurons
Brain Res
(1991) - et al.
Serotonin and dopamine striatal innervation in Parkinson’s disease and Huntington’s chorea
Parkinsonism Relat Disord
(2011) - et al.
The role of dopamine in Huntington’s disease
Prog Brain Res
(2014) - et al.
The corticostriatal pathway in Huntington’s disease
Prog Neurobiol
(2007) - et al.
Differential loss of striatal projection systems in Huntington’s disease: a quantitative immunohistochemical study
J Chem Neuroanat
(2004) - et al.
Loss of corticostriatal and thalamostriatal synaptic terminals precedes striatal projection neuron pathology in heterozygous Q140 Huntington’s disease mice
Neurobiol Dis
(2013) - et al.
Corticostriatal dysfunction and glutamate transporter 1 (GLT1) in Huntington’s disease: interactions between neurons and astrocytes
Basal Ganglia
(2012) - et al.
The pattern of neurodegeneration in Huntington’s disease: a comparative study of cannabinoid, dopamine, adenosine and GABA(A) receptor alterations in the human basal ganglia in Huntington’s disease
Neurosci
(2000) - et al.
Brain-derived neurotrophic factor modulates GABAergic synaptic transmission by enhancing presynaptic glutamic acid decarboxylase 65 levels, promoting asynchronous release and reducing the number of activated postsynaptic receptors
Neurosci
(2005)
Passive electrical membrane properties of rat neostriatal neurons in an in vitro slice preparation
Brain Res
RGS4 is required for dopaminergic control of striatal LTD and susceptibility to parkinsonian motor deficits
Neuron
Age-related axonal swellings precede other neuropathological hallmarks in a knock-in mouse model of Huntington’s disease
Neurobiol Aging
Genetic rescue of CB1 receptors on medium spiny neurons prevents loss of excitatory striatal synapses but not motor impairment in HD mice
Neurobiol Dis
Electrophysiological measures as potential biomarkers in Huntington’s disease: review and future directions
Brain Res Rev
Abnormal spinal cord pain processing in Huntington’s disease. The role of the diffuse noxious inhibitory control
Clin Neurophysiol
Evidence for dysfunction of the nigrostriatal pathway in the R6/1 line of transgenic Huntington’s disease mice
Neurobiol Dis
Impaired TrkB receptor signaling underlies corticostriatal dysfunction in Huntington’s disease
Neuron
Corticostriatal synaptic adaptations in Huntington’s disease
Curr Opin Neurobiol
Neurochemical characterization of the striatum and the nucleus accumbens in L-type Ca(v)1.3 channels knockout mice
Neurochem Int
Evidence for a preferential loss of enkephalin immunoreactivity in the external globus pallidus in low grade Huntington’s disease using high resolution image analysis
Neurosci
Learning a new behavioral strategy in the shuttle-box increases prefrontal dopamine
Neurosci
Dopaminergic modulation of striatal networks in health and Parkinson’s disease
Curr Opin Neurobiol
Feedforward and feedback inhibition in neostriatal GABAergic spiny neurons
Brain Res Rev
The self-tuning neuron: synaptic scaling of excitatory synapses
Cell
Huntington’s disease
Lancet
Dopamine and glutamate in Huntington’s disease: a balancing act
CNS Neurosci Ther
Striatal neurochemical changes in transgenic models of Huntington’s disease
J Neurosci Res
Distinct subclasses of medium spiny neurons differentially regulate striatal motor behaviors
Proc Natl Acad Sci U S A
Severe deficiencies in dopamine signaling in presymptomatic Huntington’s disease mice
Proc Natl Acad Sci U S A
Decreased striatal monoaminergic terminals in Huntington disease
Neurology
Oscillatory nature of human basal ganglia activity: relationship to the pathophysiology of Parkinson’s disease
Mov Disord
Dissociable effects of dopamine on neuronal firing rate and synchrony in the dorsal striatum
Front Integr Neurosci
In vivo dopamine efflux is decreased in striatum of both fragment (R6/2) and full-length (YAC128) transgenic mouse models of Huntington’s disease
Front Syst Neurosci
Rescuing the corticostriatal synaptic disconnection in the R6/2 mouse model of Huntington’s disease: exercise, adenosine receptors and ampakines
PLoS Curr
Transient and progressive electrophysiological alterations in the corticostriatal pathway in a mouse model of Huntington’s disease
J Neurosci
Altered brain neurotransmitter receptors in transgenic mice expressing a portion of an abnormal human huntington disease gene
Proc Natl Acad Sci U S A
Cited by (37)
Early impairment of thalamocortical circuit activity and coherence in a mouse model of Huntington's disease
2021, Neurobiology of DiseaseCitation Excerpt :In addition to potential dysfunction in thalamocortical projections, CPNs that project to the thalamus are preferentially lost (Hedreen et al., 1991), suggesting potential reciprocal disruption in cortico-thalamocortical circuitry. Corticostriatal circuits have been extensively studied in HD (Blumenstock and Dudanova, 2020; Miller et al., 2011; Naze et al., 2018; Ponzi et al., 2020; Rothe et al., 2015), however, the role of the thalamus and the thalamocortical projection in HD has been understudied, even though some of the earliest sensory, attention, and cognitive deficits are clearly associated with thalamocortical circuits. In human HD, there is evidence for significant cell loss within the thalamus (Heinsen et al., 1999; Heinsen et al., 1996), although it is not known if thalamic atrophy occurs in parallel or is secondary to cortical damage.
Protein changes in synaptosomes of Huntington's disease knock-in mice are dependent on age and brain region
2020, Neurobiology of DiseaseCitation Excerpt :For example, stimulus induced release of glutamate from synaptosomes of Q140/Q140 HD striatum is increased and glutamate release in brain slices from HD transgenic mice is reduced (Li et al., 2003; Valencia et al., 2013). Dopamine release is reduced in the striatum of HD R6/2 and Q175 HD mice (Johnson et al., 2006; Rothe et al., 2015). Endosome recycling of cargoes including Glut3, transferrin receptor and EAAC1 are impaired in HD neurons due to abnormal activity of the GTPase Rab11 which is also known to have a critical role recycling synaptic vesicles to the presynaptic membrane (Li et al., 2009; Li et al., 2010; McClory et al., 2014; Kokotos et al., 2018).
Astrocytes and presynaptic plasticity in the striatum: Evidence and unanswered questions
2018, Brain Research BulletinCitation Excerpt :The idea of release facilitation in individual corticostriatal synapses with deficient glutamate uptake would however be at variance with the prevailing viewpoint that “the field has moved from thinking that striatal pathology in HD was driven by excitotoxic mechanisms to the view that, if anything, it is a hypoexcitability disorder driven by impaired corticostriatal signaling” (Plotkin and Surmeier, 2015). Synapse counts in Q140 hets (Deng et al., 2013) and Q175 homs (Rothe et al., 2015) showed lower than in WT densities of vGluT1-IR terminals. Several labs reported a respective decrease in the spine density of HD mice in the striatum.
Unravelling and Exploiting Astrocyte Dysfunction in Huntington's Disease
2017, Trends in Neurosciences
- †
These authors equally contributed to the material of this paper.
- ‡
With deep sadness we dedicate this publication to the memory of Holger Stark who suddenly died on the 18th of February, 2015.