Altered parvalbumin-positive neuron distribution in basal ganglia of individuals with Tourette syndrome

Abstract

Tourette syndrome (TS) is a childhood neuropsychiatric disorder characterized by motor and vocal tics. Imaging studies found alterations in caudate (Cd) and putamen volumes. To investigate possible alterations in cell populations, postmortem basal ganglia tissue from individuals with TS and normal controls was analyzed by using unbiased stereological techniques. A markedly higher total neuron number was found in the globus pallidus pars interna (GPi) of TS. In contrast, a lower neuron number and density was observed in the globus pallidus pars externa and in the Cd. An increased number and proportion of the GPi neurons were positive for the calcium-binding protein parvalbumin in tissue from TS subjects, whereas lower densities of parvalbumin-positive interneurons were observed in both the Cd and putamen of TS subjects. This change is consistent with a developmental defect in tangential migration of some GABAergic neurons. The imbalance in striatal and GPi inhibitory neuron distribution suggests that the functional dynamics of cortico-striato-thalamic circuitry are fundamentally altered in severe, persistent TS.T ourette syndrome (TS) is a childhood neuropsychiatric disorder characterized by persistent motor and vocal tics, which may or may not abate upon entering adulthood. Tics are sudden stereotyped motor sequences of varying intensity and complexity, often preceded by compulsions or sensory phenomena. Neither the etiology nor the pathophysiology of TS is well understood. Both genetic and environmental factors are thought to be important, but the exact role of each has not yet been identified (1). Epigenetic events that increase the risk of developing tic disorder or TS include perinatal hypoxic-ischemic events that damage the periventricular germinal matrix and adjacent deep regions of the brain (2). A considerable amount of data implicates the cortico-striato-thalamo-cortical circuit in TS pathophysiology, particularly basal ganglia (BG) abnormalities. The BG, a richly interconnected set of nuclei, is essential for the initiation and correct implementation of learned sequences of motor and cognitive segments that characterize purposive behavior. The two major inputs into the BG, from the cerebral cortex and the intralaminar nuclei of the thalamus, enter into the striatum, which consists of the caudate (Cd) and putamen (Pt). The firing of cortical inputs drives activity in both medium spiny neurons (MSNs) (3) and several types of interneurons, including parvalbumin (PV)-positive (PVϩ) GABAergic interneurons (4). Striatal PVϩ interneurons are connected by electrical junctions and form a web of inhibitory synapses throughout the striatum, coordinating the activities of MSNs, and likely increasing their threshold of firing in response to cortical inputs (5, 6). MSNs, which are the large majority of neurons in the striatum, project to the globus pallidus pars interna (GPi), either directly or indirectly via the subthalamic nucleus and the globus pallidus pars externa (GPe). These two pathways can be differentiate...

Opposite Effects of Stimulant and Antipsychotic Drugs on Striatal Fast-Spiking Interneurons

“…The exact role of FSIs in normal striatal information processing is unknown, although there is evidence that they are involved in the suppression of unwanted actions . Consistent with this idea, a reduction in the number of striatal PV + cells has been observed in humans with Tourette syndrome (Kalanithi et al, 2005), for which a major therapy remains D2 receptor antagonists.…”

“…For example, the uniform suppression of FSI firing by eticlopride indicates that the therapeutic benefits of D2 antagonists in Tourette syndrome are unlikely to derive from increasing FSI firing to compensate for their reduced number (Kalanithi et al, 2005). Rather, given that a deficit in striatal FSIs is found in a rodent model of paroxysmal dystonia (Gernert et al, 2000), and that dystonias and dyskinesias are produced by local GABA blockade in striatum (for example, Yoshida et al, 1991;Worbe et al, 2009), FSI suppression is a strong candidate mechanism for the adverse behavioral effects of antipsychotic treatment (which include dystonias, dyskinesias, and akathesia; Hyman et al, 1995).…”

Attention-Deficit/Hyperactivity Disorder–like Phenotype in a Mouse Model with Impaired Actin Dynamics

“…In ACC mice, the balance between excitation and inhibition (E/I balance) is shifted toward excitation. Maintenance of the E/I balance is crucial for the functionality of the brain (49), and E/I imbalance is postulated to underlie the pathogenesis of neuropsychiatric disorders, such as autism, schizophrenia or Tourette's syndrome (50)(51)(52). More recent studies have associated E/I imbalance with ADHD (31,(53)(54)(55).…”

Tourette syndrome research highlights from 2016

“…These mice showed hyperactivity and altered firing of some cells at the onset of the transition from quiescence to locomotion. How this may relate to lower numbers of parvalbumin-containing interneurons in TS 36 is unclear. An interesting contrast based on the parvalbumin data is provided by a model in which fast-spiking interneurons in the dorsal striatum were ablated 37 .…”