Abstract

The corticostriatal pathway provides most of the excitatory glutamatergic input into the striatum and it plays an important role in the development of the phenotype of Huntington's disease (HD). This review summarizes results obtained from genetic HD mouse models concerning various alterations in this pathway. Evidence indicates that dysfunctions of striatal circuits and cortical neurons that make up the corticostriatal pathway occur during the development of the HD phenotype, well before there is significant neuronal cell loss. Morphological changes in the striatum are probably primed initially by alterations in the intrinsic functional properties of striatal medium-sized spiny neurons. Some of these alterations, including increased sensitivity of N-methyl-d-aspartate receptors in subpopulations of neurons, might be constitutively present but ultimately require abnormalities in the corticostriatal inputs for the phenotype to be expressed. Dysfunctions of the corticostriatal pathway are complex and there are multiple changes as demonstrated by significant age-related transient and more chronic interactions with the disease state. There also is growing evidence for changes in cortical microcircuits that interact to induce dysfunctions of the corticostriatal pathway. The conclusions of this review emphasize, first, the general role of neuronal circuits in the expression of the HD phenotype and, second, that both cortical and striatal circuits must be included in attempts to establish a framework for more rational therapeutic strategies in HD. Finally, as changes in cortical and striatal circuitry are complex and in some cases biphasic, therapeutic interventions should be regionally specific and take into account the temporal progression of the phenotype.

Keywords: Cortex; Striatum; Electrophysiology; Mouse models; Glutamate; Pathway

Abbreviations: HD, Huntington's disease; CAG, (cytosine adenine guanine) DNA triplet sequence coding for glutamine; YAC, yeast artificial chromosome; Tg, transgenic; MSSN, medium-sized spiny neuron; NMDA, N-methyl-d-aspartate; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; D1, dopamine D1 receptor subtype; D2, dopamine D2 receptor subtype; A₁, adenosine 1 receptor subtype; A_2A, adenosine 2A receptor subtype; mGluR_2/3, group II metabotropic glutamate receptor subtypes; mGluR₅, group I metabotropic glutamate receptor; CB₁, cannabinoid 1 receptor subtype; GABA, γ-aminobutyric acid; GABA_A and GABA_B, ionotropic and metabotropic GABA receptor subtypes; Kir2.1 and 2.3, inwardly rectifying potassium channels; Kv2.1, voltage-activated potassium channel underlying delayed rectification; HVA, high voltage-activated; EPSP, excitatory postsynaptic potential; NR1 and NR2A/B, N-methyl-d-aspartate receptor subunits; GluR6, glutamate receptor subunit constitutive of kainate receptors; 3-NP, 3-nitropropionic acid; BDNF, brain derived neurotrophic factor; TrkB, tyrosine kinase receptor subtype that binds neurotrophins, in particular BDNF; EGFP, enhanced green fluorescent protein; RT-PCR, reverse transcriptase polymerase chain reaction; ADAC, adenosine amine congener, a selective A₁ adenosine receptor agonist; CGS21680, a selective A_2A adenosine receptor agonist; L-DOPA, levodopa, metabolic precursor of dopamine; PSD95, postsynaptic density 95; CREB, cAMP response element binding protein; LTD, long-term depression; LTP, long-term potentiation

Article Outline

1. Introduction

2. Genetic mouse models of HD

3. The corticostriatal pathway and its target neurons in the striatum

3.1. Cell types in the striatum and their vulnerability in HD

3.2. The gatekeepers of glutamate release in the corticostriatal pathway

4. Electrophysiology and morphology of the striatum and cortex in mouse models of HD

4.1. Morphology in striatum and cortex

4.2. Electrophysiology in cortex

4.3. Passive and active cellular membrane properties in striatum

4.4. Glutamate receptors

4.5. Synaptic responses

4.5.1. Evoked synaptic responses

4.5.2. Spontaneous excitatory postsynaptic currents

4.6. GABA function in HD

5. Synaptic plasticity in HD

6. Selective neuronal vulnerability in HD

6.1. Why are the MSSNs more vulnerable?

6.2. Selective vulnerability of enkephalin-containing cells

7. Rescuing synaptic dysfunction

7.1. Drugs that reduce cortical excitability and glutamate release

7.2. Manipulating BDNF

8. Conclusions

Acknowledgements

References