Origin of STn Overactivity in PD

The STn plays a key role in the basal ganglia circuitry, and its hyperactivity may be a major factor in parkinsonian symptomatology (Marsden and Obeso, 1994). According to the classical PD model, it is the hypoactivity of the GPe that leads to increased STn activity, which in turn (in addition to the diminished influence of the direct striatal GABAergic input) induces the pathological overactivity of GPi (Figure 20.6). However, although stimulation of the STn induces a strong activation of GPe neurons, STn lesions result in a decreased activity of GPe neurons.

There is also physiological evidence suggesting that the STn is a driving force for not only the GPi, but also the GPe and even the SNc cells. In experiments in the normal rat, STn stimulation with the same parameters as in PD patients induced a transient but powerful inhibition (Benabid et al., 2002). As a consequence, a strong decrease in activity was recorded in the penducular pontine nucleus (PPN) (the equivalent of GPi in humans) and the SNc (Smith and Kieval, 2000). This increase in SNc activity, which should as a result produce more DA (Falkenburger et al., 2001), could be a possible mechanism of improvement of the PD symptoms. An increase of GP (equivalent to GPe in humans) is also recorded in rats after STn stimulation (Benazzouz et al., 1995). This could be due to a backfiring along the GPe-STn, and then the hyperexcited GPe, by its strong GABA projection, could in turn inhibit STn and GPi. However, experiments done recently in Benabid's laboratory (Benabid et al., 2002) have demonstrated that the destruction of GPe does not alter the effect of STn stimulation on GPi. Where then does this neural silencing arise from?

Apart from changing the tonic level of neural activity, other mechanisms such as resynchronization of the abnormal coupled neural circuits and cellular mechanisms (Bergman and Deuschl, 2002; Benabid et al., 2002; Bikson et al., 2001) may be involved in the stimulation effects. Coupled synchronized activity within otherwise (in normal conditions) segregated loops (Ni et al., 2001) may be induced under abnormal circumstances (DA depletion state in PD) as a result of either cellular local mechanisms in the STn-GPe axis (Vila et al., 1996) or dynamic circuitry alterations (cortico-striato-pallido-thalamic axis). This is indeed suggested by the double innervation pattern in the GPe (GABAergic inhibitory projections from the striatum together with dense glutamatergic excitatory input from STn). This in turn means that the resulting activity of GPe neurons is a counterbalancing of the activity of these two convergent pathways (Vila et al., 1996). A second interesting point is that axonal branches of a subthalamic fiber expand over groups of widely distributed pallidal neurons, whereas one striatal axon targets more restricted subsets of GPe cells (Herrero et al., 1996a). It is generally accepted that both projections converge on individual pallidal neurons. Thus, it seems apparent that the activity of the GPe neurons is balanced by the continuous interaction between two antagonistic inputs. This interaction is likely to be the cause of the decreased firing rate coupled with bursting activity recorded in pallidal neurons in monkeys with loss of dopaminergic neurons. Hence, parkinsonian signs may be a reflection of at least two different functional systems within the GP-STn axis (Plenz and Kital, 1999) that would, under abnormal circumstances (DA-depleted state), function as a unique coupled oscillating system.

Whether abnormal coupling occurs within the striato-pallidal axis or elsewhere, i.e., in cortical or thalamic sites (Calabresi et al., 1992, 1996), may depend upon the context and task (expectancy of reward, salience of the cue, goal-directed action) (Graybiel, 1998; Schultz, 1997). Of some importance is recent evidence suggesting that treatment with N-methyl-D-aspartate (NMDA) antagonists markedly affect both motor and cognitive functions in different animal species, including humans (Ault-man and Moghaddam, 2001; Fredriksson et al., 2001). Those findings reveal the importance of DA-glutamate (GLU) interactions and synergetic effects underlying the generation of both motor and cognitive symptoms in PD (Blanchet et al., 1999). There may be unique ways that D-GLU interactions take place in the parkinsonian state (Carlsson and Svensson, 1990; Chase and Oh, 2000; Chase et al., 2000) in producing such abnormal coupling phenomena.

In the normal, non-DA-depleted striatum, for the most part glutamatergic transmission is driven via activation of L-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors located on medium spiny neurons (Turski et al., 1991), as NMDA receptors are inactive at resting membrane potential. In Parkinson's disease, degeneration of the dopaminergic nigro-striatal pathway results in loss of dopamine D2 receptor-mediated modulation of striatal interneurons and decreased dopaminergic tone of medium spiny neurons (Greengard, 2001). Thus, stimulatory effects exerted by cortico-striatal and thalamo-striatal afferents are uninhibited, resulting in a shift in the membrane potential of striatal efferents to more depolarized potentials, which removes the magnesium block of NMDA receptors (Brotchie, 2000; Klockgether and Turski, 1993; Lange et al., 1997; Nash and Brotchie, 2002; Nash et al., 2000).

A cartoon illustration of a revised model that takes into account some of the aforementioned considerations is shown in Figure 20.7. We formulate two relatively simple hypotheses for the site(s)/pathway(s) involved in distorted storage and retrieval temporal memory processes seen in PD (Gillies and Arbuthnott, 2000). The first one posits that the distinct (direct-indirect) pathways do not really exist; dynamic functional reorganization of the system occurs under the parkinsonian state at a cellular rather than a circuitry level. Secondly, abnormal synchronized activity of the STn-GPe axis is suggested to be the major abnormality of DA depletion due to the persistent state of the negative cortico-striatal reinforcement signal. Segregation between loops is then abolished, and coupling phenomena occur, especially under conditions of nonreinforcement.

These ideas are to be taken as hypotheses to work on and are aimed mainly at highlighting the need for a careful reevaluation of current concepts of basal ganglia interactions. Studying cognitive deficits, along with motor disabilities in basal

FIGURE 20.7 Timing in the basal ganglia: a revised model. This cartoon is a schematic illustration of a revised map where STn is shown as the driving force not only for both pallidal segments (GPe and GPi) but also for the SNc cells. Parkinsonian signs are accordingly conceived as a reflection of different functional systems that under abnormal circumstances (DA-depleted states) function as a unique coupled oscillating system. Coupled synchronized activity within otherwise (in normal conditions) segregated loops within the GP-STn axis may be induced as a result of a new balance between cellular local mechanisms and dynamic circuitry alterations (indicated as accounts 1 and 2, respectively). White arrows indicate what part of the circuitry would in each case mediate coupling on retrieval or slowed encode.

FIGURE 20.7 Timing in the basal ganglia: a revised model. This cartoon is a schematic illustration of a revised map where STn is shown as the driving force not only for both pallidal segments (GPe and GPi) but also for the SNc cells. Parkinsonian signs are accordingly conceived as a reflection of different functional systems that under abnormal circumstances (DA-depleted states) function as a unique coupled oscillating system. Coupled synchronized activity within otherwise (in normal conditions) segregated loops within the GP-STn axis may be induced as a result of a new balance between cellular local mechanisms and dynamic circuitry alterations (indicated as accounts 1 and 2, respectively). White arrows indicate what part of the circuitry would in each case mediate coupling on retrieval or slowed encode.

ganglia diseases, is of major importance at our current stage of knowledge and calls for careful development of animal models as well as integration of empirical animal and human data.

The DBS technique was useful in suggesting the neural pathway through the STn mediate temporal memory retrieval. But the way this occurs in finer detail remains elusive. Future research revolving around the attempt to identify the respective neural mechanisms underlying the time-specific distortions of learning and retrieval may bring new insights for the underlying neurobiological mechanisms associated with cognitive sequelae of mental disorders (i.e., PD, schizophrenia).

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