Loss of glutamate signaling from the thalamus to dorsal striatum impairs motor function and slows the execution of learned behaviors

Parkinson's disease (PD) is primarily associated with the degeneration of midbrain dopamine neurons, but it is now appreciated that pathological processes like Lewy-body inclusions and cell loss affect several other brain regions, including the central lateral (CL) and centromedian/parafascicular (CM/PF) thalamic regions. These thalamic glutamatergic neurons provide a non-cortical excitatory input to the dorsal striatum, a major projection field of dopamine neurons. To determine how thalamostriatal signaling may contribute to cognitive and motor abnormalities found in PD, we used a viral vector approach to generate mice with loss of thalamostriatal glutamate signaling specifically restricted to the dorsal striatum (CAV2(cre)-Slc17a6(lox/lox) mice). We measured motor function and behaviors corresponding to cognitive domains (visuospatial function, attention, executive function, and working memory) affected in PD. CAV2(cre)-Slc17a6(lox/lox) mice were impaired in motor coordination tasks such as the rotarod and beam-walk tests compared with controls (CAV2(cre)-Slc17a6(+/+) mice). They did not demonstrate much cognitive impairment in the Morris water maze or a water U-maze, but had slower processing reaction times in those tests and in a two-way active avoidance task. These mice could model an aspect of bradyphrenia, the slowness of thought that is often seen in patients with PD and other neurological disorders.