The data presented here demonstrate major adaptive changes in corticostriatal information processing following chronic L-DOPA administration in the hemi-parkinsonian rat model. Specifically, we report that the primary deficit in synaptic information processing observed following 6-OHDA lesion is the inability to induce corticostriatal LTD in indirect pathway neurons. In addition we demonstrate that chronic L-DOPA treatment results in dramatic alterations in both the induction and normalization of synaptic plasticity in both direct and indirect pathway MSNs.
Based on intracellular staining and responses to dopamine agonists the characterization of type I and type II neurons and their identification as neurons corresponding to the `direct' and `indirect' pathways, respectively, has been extensively documented23
. In the present study, this characterization has been confirmed using retrograde tracing (from the GP) combined with juxtacellular labeling as well as by antidromic activation from the SNr. It should be noted that antidromic activation of striatal neurons has been considered unreliable14
, presumably due to current shunting by K+
. Indeed, in the present study, 35% of type I neurons failed to show an antidromic response. This could be the reason why a recent set of publications report the opposite characterization of MSN's based exclusively on antidromic activation from the SNr31
HFS of the motor cortex has been demonstrated consistently to induce LTD of cortically-evoked action potentials in striatal MSNs in vitro9
as well as in vivo8, 32
. In the current study, changes in plasticity, either potentiation or depression, were measured as changes in spike probability. HFS resulted in the induction of LTD in both striatonigral and striatopallidal neurons of control rats. Following 6-OHDA lesion, LTD could still be evoked in striatonigral neurons; in contrast, there was no significant effect of cortical HFS in striatopallidal neurons. These data are consistent with previous studies examining the role of dopamine D1 and D2 receptors in corticostriatal plasticity. Thus, corticostriatal LTD can be attenuated by sulpiride, and is absent in brain slices from both 6-OHDA lesioned rats7
and mice lacking D2 receptors33
. Thus, the absence of LTD in striatopallidal neurons observed in the current study is consistent with previous data reporting the dependence of LTD on D2 receptor activation34
. In contrast to the effect on striatopallidal neurons, there was no effect of unilateral DA depletion on the ability of cortical HFS to induce LTD in striatonigral neurons. This result is consistent with previous studies showing that corticostriatal LTD persists in mice lacking D1 receptors27
, although D1 receptors antagonists will block corticostriatal LTD35
. Taken together, our data suggest that a decrease in DA levels within the striatum would result in the loss of a component essential for the development of LTD predominantly in striatopallidal neurons, and a loss of control over motor inhibition.
Although corticostriatal plasticity following chronic treatment with L-DOPA has been investigated previously, such studies were limited in their interpretation due to several important factors: 1) these studies were performed in vitro in which afferent processes have been severed6
;2) changes in LTP were biased by either depolarization of the neuronal membrane in vivo36
or omission of magnesium ions in vitro6, 7
,; and 3) neurons of the direct and indirect pathway were not distinguished, confounding the interpretation of the functional outcome of the observed changes . Thus, we examined the effect of chronic L-DOPA treatment on corticostriatal plasticity in both striatonigral and striatopallidal neurons. Consistent with our observation that unilateral DA depletion only altered activity-dependent plasticity in striatopallidal neurons, the alterations in HFS-induced corticostriatal plasticity observed following chronic L-DOPA administration were restricted to the indirect projection neurons. Indeed, there was no disruption in cortically-evoked LTD in direct projecting neurons following DA denervation or after chronic L-DOPA treatment, suggesting that the induction of corticostriatal plasticity in striatopallidal neurons is not sensitive to tonic changes in dopaminergic transmission. In contrast, our most striking result is that chronic L-DOPA treatment resulted in a transition from cortically-evoked LTD to the complementary but opposite process of LTP in striatopallidal neurons. This is consistent with previous studies showing that HFS of cortical fibers from D2 receptor mutant mice robustly induces an NMDA independent LTP27
. Such a significant change in corticostriatal information processing is likely to have a dramatic effect on motor output under conditions of high cortical activity, and interfere with the ability of the indirect pathway to effectively modulate direct pathway motor output.
Previous data suggested that aberrant de-potentiation of LTP may play a role in LIDs. Thus, low frequency stimulation of cortical afferents can reverse LTP evoked by HFS6
. Similarly, in the present study LFS was able to attenuate LTD evoked by cortical HFS in striatonigral neurons recorded from intact rats. In contrast in hemiparkinsonian rats, LFS further depressed cortically driven responses suggesting a potential dopamine-dependent mechanism contributing to de-depression.
Interestingly, whereas no differences in HFS-evoked responses were observed between dyskinetic and non-dyskinetic rats, significantly different results were seen following LFS. Thus, chronic L-DOPA appeared to repair the deficit in LTD reversal observed in striatonigral neurons of lesioned rats, but only in the non-dyskinetic rats. In contrast, the deficit in LTD-reversal was retained in striatonigral neurons of dyskinetic rats. These data are in agreement, at least in part, with previous experiments reporting that rats displaying LIDs fail to reverse HFS-induced LTP in unidentified striatal neurons recorded in vitro6
. Our data suggest a loss of regulation over LTD in dyskinetic rats causing the striatonigral neurons to retain abnormally large depression of responses. Such an imbalance may be further exacerbated by the indirect neurons, which were found to display LTP (rather than LTD) following chronic L-DOPA treatment; an effect that could be reversed by LFS only in dyskinetic rats but not in non-dyskinetic rats. Consequently, in dyskinetic rats the regulation of synaptic plasticity in direct and indirect pathways are out of balance; LTD in striatonigral neurons is abnormally persistent and fails to be down-modulated, whereas in striatopallidal neurons LTP is abnormally sensitive to reversal. As such, there would be a strong attenuation in the ability of the indirect pathway to regulate the direct pathway during low activity periods.
One potential caveat in the interpretation of the current results is that chronic L-DOPA treatment exhibited substantial effects in both dyskinetic and non-dyskinetic rats. However, it must be noted that all rats in the current study were recorded in the drug-free state while the expression of LIDs is most prominent during peak cerebrospinal fluid levels of L-DOPA37
. Nonetheless, it has been suggested that the potential clinical actions of chronic L-DOPA administration arise from the induction of a priming effect that only manifests as LID during high levels of the drug38
. Thus, we propose that the aberrant corticostriatal plasticity in indirect pathway neurons may be responsible, at least in part, for the so called “priming” of the system. In addition, a deficit in the ability to reverse established plastic changes in direct neurons is observed only in L-DOPA-treated rats that display dyskinesia in response to an acute L-DOPA injection. This inability to reverse established plasticity is suggested to result in a pathological storage of nonessential motor information. Thus the aberrant induction of striatal plasticity in striatopallidal neurons combined with the disparate response to LFS in striatonigral and striatopallidal neurons during OFF states could facilitate LIDs expression during ON states.