Early-life lead exposure recapitulates the selective loss of parvalbumin-positive GABAergic interneurons and subcortical dopamine system hyperactivity present in schizophrenia

Environmental factors have been associated with psychiatric disorders and recent epidemiological studies suggest an association between prenatal lead (Pb²⁺) exposure and schizophrenia (SZ). Pb²⁺ is a potent antagonist of the N-methyl-D-aspartate receptor (NMDAR) and converging evidence indicates that NMDAR hypofunction has a key role in the pathophysiology of SZ. The glutamatergic hypothesis of SZ posits that NMDAR hypofunction results in the loss of parvalbumin (PV)-positive GABAergic interneurons (PVGI) in the brain. Loss of PVGI inhibitory control to pyramidal cells alters the excitatory drive to midbrain dopamine neurons increasing subcortical dopaminergic activity. We hypothesized that if Pb²⁺ exposure in early life is an environmental risk factor for SZ, it should recapitulate the loss of PVGI and reproduce subcortical dopaminergic hyperactivity. We report that on postnatal day 50 (PN50), adolescence rats chronically exposed to Pb²⁺ from gestation through adolescence exhibit loss of PVGI in SZ-relevant brain regions. PV and glutamic acid decarboxylase 67 kDa (GAD67) protein were significantly decreased in Pb²⁺ exposed rats with no apparent change in calretinin or calbindin protein levels suggesting a selective effect on the PV phenotype of GABAergic interneurons. We also show that Pb²⁺ animals exhibit a heightened locomotor response to cocaine and express significantly higher levels of dopamine metabolites and D2-dopamine receptors relative to controls indicative of subcortical dopaminergic hyperactivity. Our results show that developmental Pb²⁺ exposure reproduces specific neuropathology and functional dopamine system changes present in SZ. We propose that exposure to environmental toxins that produce NMDAR hypofunction during critical periods of brain development may contribute significantly to the etiology of mental disorders.     

Extrinsic and local glutamatergic inputs of the rat hippocampal CA1 area differentially innervate pyramidal cells and interneurons

The two main glutamatergic pathways to the CA1 area, the Schaffer collateral/commissural input and the entorhinal fibers, as well as the local axons of CA1 pyramidal cells innervate both pyramidal cells and interneurons. To determine whether these inputs differ in their weights of activating GABAergic circuits, we have studied the relative proportion of pyramidal cells and interneurons among their postsynaptic targets in serial electron microscopic sections. Local axons of CA1 pyramidal cells, intracellularly labeled in vitro or in vivo, innervated a relatively high proportion of interneuronal postsynaptic targets (65.9 and 53.8%, in vitro and in vivo, respectively) in stratum (str.) oriens and alveus. In contrast, axons of in vitro labeled CA3 pyramidal cells in str. oriens and str. radiatum of the CA1 area made synaptic junctions predominantly with pyramidal cell spines (92.9%). The postsynaptic targets of anterogradely labeled medial entorhinal cortical boutons in CA1 str. lacunosum-moleculare were primarily pyramidal neuron dendritic spines and shafts (90.8%). The alvear group of the entorhinal afferents, traversing str. oriens, str. pyramidale, and str. radiatum showed a higher preference for innervating GABAergic cells (21.3%), particularly in str. oriens/alveus. These data demonstrate that different glutamatergic pathways innervate CA1 GABAergic cells to different extents. The results suggest that the numerically smaller CA1 local axonal inputs together with the alvear part of the entorhinal input preferentially act on GABAergic interneurons in contrast to the CA3, or the entorhinal input in str. lacunosum-moleculare. The results highlight differences in the postsynaptic target selection of the feed-forward versus recurrent glutamatergic inputs to the CA1 and CA3 areas.     

Convergence and segregation of septal and median raphe inputs onto different subsets of hippocampal inhibitory interneurons

The convergence and segregation of medial septal and median raphe afferents in the innervation of different subpopulations of GABAergic interneurons was investigated in the rat hippocampal formation. Following local injections of 5,7-dihydroxytryptamine into the median raphe nucleus destroying all serotonergic neurons, iontophoretic injections of Phaseolus vulgaris leucoagglutinin (PHAL) into the medial septum resulted in anterograde labelling of axons in the hippocampus. The labelled varicose fibres made multiple contacts with calbindin D28K-, parvalbumin-, and cholecystokinin-immunoreactive interneurons. These results disproved the possibility that PHAL-labelled afferents innervating hippocampal interneurons following septal PHAL injections would have been raphe axons passing through the injection site. In the second set of experiments a double anterograde tracing technique (PHAL from the septum and biotinylated-PHAL from the median raphe) and a triple or double immunostaining procedure was used to determine the types of interneurons (calbindin D28K-, parvalbumin-, or cholecystokinin-immunoreactive) innervated by one, or the other, or both pathways. The results showed that parvalbumin-containing neurons were innervated by septal afferents but avoided by raphe axons, whereas calbindin D28K-containing cells, and to a smaller extent cholecystokinin-containing cells served as targets for both pathways. In some cases the same individual calbindin D28K- or cholecystokinin-containing neurons received multiple contacts from afferents of both septal and raphe origin. Thus, our results indicate that different subcortical nuclei modulate largely different inhibitory circuits in the hippocampal formation. However, considering the occasional convergence of the two subcortical nuclei not only onto the same type, but even onto the same individual calbindin D28K-containing interneurons, we propose that a particular inhibitory function, most probably feed-forward inhibition in the distal dendritic region, is under the control of both pathways.     

Postnatal development of calretinin- and parvalbumin-positive interneurons in the rat neostriatum: an immunohistochemical study

On the basis of cytochemical and morphologic differences, two classes of gamma-aminobutyric acidergic (GABAergic) interneurons expressing calcium-binding proteins have been identified in the striatum of adult animals: neurons expressing either parvalbumin (PV) or calretinin (CR). The function of these calcium-binding proteins is not clear, however, they are associated with distinct classes of inhibitory interneurons within the adult neostriatum. By using immunocytochemical techniques, we analyzed the postnatal maturation and the spatiotemporal distribution of PV- and CR-positive neurons in the rat neostriatum compared with a third class of interneurons characterized by the expression of the acetylcholine-synthesizing enzyme, choline acetyltransferase (ChAT). PV-positive cells appeared initially on postnatal day 9 in the lateral region of the striatum. During postnatal weeks 2 and 3, the numbers of PV-positive neurons increased, and this cell population spread progressively in a lateromedial direction. In contrast, CR-expressing neurons were present at birth. During the first few days after birth, the number of CR-immunoreactive cells increased, reaching a peak on postnatal day 5 before declining during the following 2 weeks. A mediolateral gradient was evident temporarily. ChAT-containing neurons were detectable at birth in the lateral striatum. During postnatal weeks 1 and 2, the neurons matured along a lateral-to-medial gradient. The results indicate that the maturation of striatal interneurons is regulated differentially during postnatal development, resulting in a distinct spatiotemporal genesis of phenotypes. The sequential expression of CR and PV suggests a stage-dependent development of subsets of inhibitory interneurons and, hence, the stage-dependent maturation of functionally distinct inhibitory circuits within the neostriatum.     

GABAergic inputs from direct and indirect striatal projection neurons onto cholinergic interneurons in the primate putamen

Striatal cholinergic interneurons (ChIs) are involved in reward‐dependent learning and the regulation of attention. The activity of these neurons is modulated by intrinsic and extrinsic γ‐aminobutyric acid (GABA)ergic and glutamatergic afferents, but the source and relative prevalence of these diverse regulatory inputs remain to be characterized. To address this issue, we performed a quantitative ultrastructural analysis of the GABAergic and glutamatergic innervation of ChIs in the postcommissural putamen of rhesus monkeys. Postembedding immunogold localization of GABA combined with peroxidase immunostaining for choline acetyltransferase showed that 60% of all synaptic inputs to ChIs originate from GABAergic terminals, whereas 21% are from putatively glutamatergic terminals that establish asymmetric synapses, and 19% from other (non‐GABAergic) sources of symmetric synapses. Double pre‐embedding immunoelectron microscopy using substance P and Met‐/Leu‐enkephalin antibodies to label GABAergic terminals from collaterals of “direct” and “indirect” striatal projection neurons, respectively, revealed that 47% of the indirect pathway terminals and 36% of the direct pathway terminals target ChIs. Together, substance P‐ and enkephalin‐positive terminals represent 24% of all synapses onto ChIs in the monkey putamen. These findings show that ChIs receive prominent GABAergic inputs from multiple origins, including a significant contingent from axon collaterals of direct and indirect pathway projection neurons. J. Comp. Neurol. 521:2502–2522, 2013. © 2013 Wiley Periodicals, Inc.     

Projections from basal forebrain to prefrontal cortex comprise cholinergic, GABAergic and glutamatergic inputs to pyramidal cells or interneurons

The present study was undertaken to characterize the pre- and postsynaptic constituents of the basal forebrain (BF) projection to the prefrontal cortex in the rat, and determine whether it includes glutamatergic in addition to established γ-aminobutyric acid (GABA)ergic and cholinergic elements. BF fibres were labelled by anterograde transport using biotin dextran amine (BDA) and dual-stained for the vesicular transporter proteins (VTPs) for glutamate (VGluT), GABA (VGAT) or acetylcholine (VAChT). Viewed by fluorescence microscopy and estimated by stereology, proportions of BDA-labelled varicosities were found to be stained for VGluT2 (and not VGluT1 or 3), VGAT or VAChT (representing, respectively, ∼15%, ∼52% and ∼19% within the infralimbic cortex). Each type was present in all, though commonly most densely in deep, cortical layers. Material was triple-stained for postsynaptic proteins to examine whether BDA+VTP+ varicosities might form excitatory or inhibitory synapses, respectively, labelled by postsynaptic density-95 kDA (PSD-95) or gephyrin (Geph). Viewed by confocal microscopy, a majority of BDA+/VGluT2+ varicosities were found to be apposed to PSD-95+ elements, and a majority of BDA+/VGAT+ varicosities to be apposed to Geph+ elements. Other series were triple-stained for cell marker proteins to assess whether the varicosities contacted interneurons or pyramidal cells. Viewed by confocal microscopy, BDA-labelled VGluT2+, VGAT+ and VAChT+ BF terminals were all found in contact with calbindin+ interneurons, whereas VGAT+ BF terminals were also seen in contact with parvalbumin+ interneurons and non-phosphorylated neurofilament+ pyramidal cells. Through distinct glutamatergic, GABAergic and cholinergic projections, the BF can thus influence cortical activity in a diverse manner.     

Independent inputs by VGLUT2- and VGLUT3-positive glutamatergic terminals onto rat sympathetic preganglionic neurons

To characterize glutamatergic axon terminals onto sympathetic preganglionic neurons (SPNs), we visualized immunohistochemically three vesicular glutamate transporters (VGLUTs) in the intermediolateral cell column (IML) of rat thoracic spinal cord. VGLUT2 and VGLUT3 immunoreactivities but not VGLUT1 immunoreactivity were distributed in the IML and found in terminals making asymmetric synapses and apposed to dendrites immunopositive for choline acetyltransferase, an SPN marker. VGLUT2 and VGLUT3 immunoreactivities were not co-localized with each other. A population of VGLUT2-immunoreactive but not VGLUT3-immunoreactive terminals were adrenergic or noradrenergic. Some of VGLUT3-immunoreactive but not VGLUT2-immunoreactive terminals contained serotonin. These results indicate at least two independent glutamatergic terminal populations, which include a distinct monoaminergic subpopulation, making excitatory inputs onto SPNs.     

The relevance of irrelevance to schizophrenia

Jeffrey Gray's neuropsychological theory of the positive symptoms of schizophrenia has been highly influential by enabling a strong link between animal and human research. Central to the development and testing of this theory has been the phenomenon and paradigm of latent inhibition (LI-the retardation of learning that one stimulus predicts the occurrence of another due to pre-exposure of the first stimulus). We review findings relating to its alteration in patients with schizophrenia (acute and chronic), people high on dimensions of schizotypy and the effects of amphetamine and anti-psychotic medication in humans. We suggest that many human-LI paradigms still suffer from theoretical and practical limitations, but that recent developments are beginning to address these. Finally we explore the idea that the paradigm of Learned Irrelevance (LIRR-the retardation of learning that one stimulus predicts the occurrence of another due to pre-exposure of both stimuli but in an unrelated manner) might be used to complement studies on LI in exploring the cognitive distortions suffered by patients with schizophrenia.     

The spatial distribution of glutamatergic inputs to dendrites of retinal ganglion cells

The spatial pattern of excitatory glutamatergic input was visualized in a large series of ganglion cells of the rabbit retina, by using particle-mediated gene transfer of an expression plasmid for postsynaptic density 95-green fluorescent protein (PSD95-GFP). PSD95-GFP was confirmed as a marker of excitatory input by co-localization with synaptic ribbons (RIBEYE and kinesin II) and glutamate receptor subunits. Despite wide variation in the size, morphology, and functional complexity of the cells, the distribution of excitatory synaptic inputs followed a single set of rules: 1) the linear density of synaptic inputs (PSD95 sites/linear mum) varied surprisingly little and showed little specialization within the arbor; 2) the total density of excitatory inputs across individual arbors peaked in a ring-shaped region surrounding the soma, which is in accord with high-resolution maps of receptive field sensitivity in the rabbit; and 3) the areal density scaled inversely with the total area of the dendritic arbor, so that narrow dendritic arbors receive more synapses per unit area than large ones. To achieve sensitivity comparable to that of large cells, those that report upon a small region of visual space may need to receive a denser synaptic input from within that space.     

A glutamatergic deficiency model of schizophrenia

Although the presence of hyperdopaminergia has been demonstrated in the brains of people with schizophrenia, at least in some circumstances, other neurotransmitters are important in this disorder, and a glutamatergic deficiency model of schizophrenia is proposed. It is suggested that the amount of sensory input allowed to reach the cerebral cortex is restricted by an inhibitory effect of the striatal complexes on the thalamus, thereby protecting it from being overwhelmed. Several strands of evidence are presented to support the concept that a weakened glutamatergic tone increases the risk of sensory overload and of exaggerated responses in the monoaminergic systems that could result in psychosis.     

Parvalbumin‐producing striatal interneurons receive excitatory inputs onto proximal dendrites from the motor thalamus in male mice

In rodents, the dorsolateral striatum regulates voluntary movement by integrating excitatory inputs from the motor‐related cerebral cortex and thalamus to produce contingent inhibitory output to other basal ganglia nuclei. Striatal parvalbumin (PV)‐producing interneurons receiving this excitatory input then inhibit medium spiny neurons (MSNs) and modify their outputs. To understand basal ganglia function in motor control, it is important to reveal the precise synaptic organization of motor‐related cortical and thalamic inputs to striatal PV interneurons. To examine which domains of the PV neurons receive these excitatory inputs, we used male bacterial artificial chromosome transgenic mice expressing somatodendritic membrane–targeted green fluorescent protein in PV neurons. An anterograde tracing study with the adeno‐associated virus vector combined with immunodetection of pre‐ and postsynaptic markers visualized the distribution of the excitatory appositions on PV dendrites. Statistical analysis revealed that the density of thalamostriatal appositions along the dendrites was significantly higher on the proximal than distal dendrites. In contrast, there was no positional preference in the density of appositions from axons of the dorsofrontal cortex. Population observations of thalamostriatal and corticostriatal appositions by immunohistochemistry for pathway‐specific vesicular glutamate transporters confirmed that thalamic inputs preferentially, and cortical ones less preferentially, made apposition on proximal dendrites of PV neurons. This axodendritic organization suggests that PV neurons produce fast and reliable inhibition of MSNs in response to thalamic inputs and process excitatory inputs from motor cortices locally and plastically, possibly together with other GABAergic and dopaminergic dendritic inputs, to modulate MSN inhibition.     

The immunological basis of glutamatergic disturbance in schizophrenia: towards an integrated view

This overview presents a hypothesis to bridge the gap between psychoneuroimmunological findings and recent results from pharmacological, neurochemical and genetic studies in schizophrenia. In schizophrenia, a glutamatergic hypofunction is discussed to be crucially involved in dopaminergic dysfunction. This view is supported by findings of the neuregulin- and dysbindin genes, which have functional impact on the glutamatergic system. Glutamatergic hypofunction is mediated by NMDA (N-methyl-D-aspartate) receptor antagonism. The only endogenous NMDA receptor antagonist identified up to now is kynurenic acid (KYN-A). KYN-A also blocks the nicotinergic acetycholine receptor, i.e. increased KYN-A levels can explain psychotic symptoms and cognitive deterioration. KYN-A levels are described to be higher in the CSF and in critical CNS regions of schizophrenics. Another line of evidence suggests that of the immune system in schizophrenic patients is characterized by an imbalance between the type-1 and the type-2 immune responses with a partial inhibition of the type-1 response, while the type-2 response is relatively over-activated. This immune constellation is associated with the inhibition of the enzyme indoleamine 2,3-dioxygenase (IDO), because type-2 cytokines are potent inhibitors of IDO. Due to the inhibition of IDO, tryptophan is predominantly metabolized by tryptophan 2,3-dioxygenase (TDO), which is located in astrocytes, but not in microglia cells. As indicated by increased levels of S100B, astrocytes are activated in schizophrenia. On the other hand, the kynurenine metabolism in astrocytes is restricted to the dead-end arm of KYN-A production. Accordingly, an increased TDO activity and an accumulation of KYN-A in the CNS of schizophrenics have been described. Thus, the immune-mediated glutamatergic-dopaminergic dysregulation may lead to the clinical symptoms of schizophrenia. Therapeutic consequences, e.g. the use of antiinflammatory cyclooxygenase-2 inhibitors, which also are able to directly decrease KYN-A, are discussed.     

The role of oscillations and synchrony in cortical networks and their putative relevance for the pathophysiology of schizophrenia

Neural oscillations and their synchronization may represent a versatile signal to realize flexible communication within and between cortical areas. By now, there is extensive evidence to suggest that cognitive functions depending on coordination of distributed neural responses, such as perceptual grouping, attention-dependent stimulus selection, subsystem integration, working memory, and consciousness, are associated with synchronized oscillatory activity in the theta-, alpha-, beta-, and gamma-band, suggesting a functional mechanism of neural oscillations in cortical networks. In addition to their role in normal brain functioning, there is increasing evidence that altered oscillatory activity may be associated with certain neuropsychiatric disorders, such as schizophrenia, that involve dysfunctional cognition and behavior. In the following article, we aim to summarize the evidence on the role of neural oscillations during normal brain functioning and their relationship to cognitive processes. In the second part, we review research that has examined oscillatory activity during cognitive and behavioral tasks in schizophrenia. These studies suggest that schizophrenia involves abnormal oscillations and synchrony that are related to cognitive dysfunctions and some of the symptoms of the disorder. Perspectives for future research will be discussed in relationship to methodological issues, the utility of neural oscillations as a biomarker, and the neurodevelopmental hypothesis of schizophrenia.     

The influence of the glutamatergic system on cognition in schizophrenia: A systematic review

Previous literature showing the role of the glutamatergic system on cognition in schizophrenia has been inconclusive. 44 relevant pharmacological, candidate gene and neuroimaging studies were identified through systematic search following PRISMA guidelines. To be included, studies must have observed at least one objective measure of cognitive performance in patients with schizophrenia and either manipulated or measured the glutamatergic system. Of the cognitive domains observed, memory, working memory and executive functions appear to be most influenced by the glutamatergic pathway. In addition, evidence from the literature suggests that presynaptic components synthesis and uptake of glutamate is involved in memory, while postsynaptic signalling appears to be involved in working memory. In addition, it appears that the glutamatergic pathway is particularly involved in cognitive flexibility and learning potential in regards to executive functioning. The glutamatergic system appears to contribute to the cognitive deficits in schizophrenia, whereby different parts of the pathway are associated with different cognitive domains. This review demonstrates the necessity for cognition to be examined by domain as opposed to globally.     

The role of estrogen in schizophrenia: implications for schizophrenia practice guidelines for women.

OBJECTIVE: The objective of this paper is to integrate what is known about estrogen effects on symptoms and treatment response into a global understanding of schizophrenia. The aim is to expand Canadian schizophrenia guidelines to include the specific needs of women. METHOD: We searched the Medline database; keywords included estrogen, estrogen replacement therapy, schizophrenia, psychosis, treatment, tardive dyskinesia (TD), and women. We examined reference lists from relevant articles to ensure that our review was complete. We review the evidence for the effects of estrogen in schizophrenia and we make recommendations for the next revision of official practice guidelines. RESULTS: The epidemiologic evidence suggests that, relative to men, women show an initial delay in onset age of schizophrenia, with a second onset peak after age 44 years. This points to a protective effect of estrogen, confirming animal research that has documented both neurotrophic and neuromodulatory effects. Clinical research results indicate that symptoms in women frequently vary with the menstrual cycle, worsening during low estrogen phases. Pregnancy is often, though not always, a less symptomatic time for women, but relapses are frequent postpartum. Some work suggests that in the younger age groups women require lower antipsychotic dosages than men but that following menopause they require higher dosages. Estrogen has been used effectively as an adjunctive treatment in women with schizophrenia. Estrogen may also play a preventive role in TD. CONCLUSIONS: Symptom evaluation and diagnosis in women needs to take hormonal status into account. Consideration should be given to cycle-modulated neuroleptic dosing and to careful titration during pregnancy, postpartum, and at menopause. We recommend that discretionary use of newer neuroleptic medication and adjuvant estrogen therapy be considered.     

Laterality in animals: relevance to schizophrenia

Anomalies in the laterality of numerous neurocognitive dimensions associated with schizophrenia have been documented, but their role in the etiology and early development of the disorder remain unclear. In the study of normative neurobehavioral organization, animal models have shed much light on the mechanisms underlying and the factors affecting adult patterns of both functional and structural asymmetry. Nonhuman species have more recently been used to investigate the environmental, genetic, and neuroendocrine factors associated with developmental language disorders in humans. We propose that the animal models used to study the basis of lateralization in normative development and language disorders such as dyslexia could be modified to investigate lateralized phenomena in schizophrenia.     

Family interventions in schizophrenia: Issues of relevance for Asian countries

A growing body of research evidence has confirmed the efficacy of family-interventions as adjuncts to antipsychotics for the treatment of schizophrenia. Much of the recent evidence for such interventions derives from Asian, principally Chinese, studies. These trials have shown that relatively simple forms of family-interventions have wide ranging benefits, and can be implemented successfully in routine clinical settings. With the accumulation of this evidence in their favour, family-interventions for schizophrenia in Asia are poised to take the next critical step, that of wider implementation and improved accessibility for potential users. However, several issues merit consideration. Family-interventions need to be based on a culturally-informed theory, which incorporates cultural variables of relevance in these countries. While the ideal format for conducting family-interventions is still to be determined, it is quite evident that for such interventions to be useful they need to be simple, inexpensive, needs-based, and tailored to suit the socio-cultural realities of mental health systems in Asian countries. The evidence also suggests that delivery by non-specialist personnel is the best way to ensure that such services reach those who stand to benefit most from these treatments. However, there are several existing challenges to the process of dissemination of family-interventions. The major challenges include the achievement of a critical mass of trained professionals capable of delivering these interventions, and finding innovative solutions to make family-interventions more acceptable to families. If these hurdles are overcome, we could look forward to a genuine collaboration with families, who have always been the mainstay of care for the mentally ill in Asia.     

The role of the glutamatergic system in alcohol addiction

New animal models have been developed which mimic several aspects of alcoholism. These models provide the basis to study the neurobiological mechanisms of "addicted behaviour". At least two different neurobiological pathways which are involved in the development and maintenance of addicted behaviour have been identified. The first pathway involves the opioidergic system and probably the mesolimbic dopaminergic system and may induce alcohol craving and relapse due to the mood enhancing, positive reinforcing effects of alcohol consumption. A second pathway involves several components of the glutamatergic system (in particular NMDA receptors) and may induce alcohol craving and relapse by negative motivational states including withdrawal and stress. In particular conditioned withdrawal and stress-induced relapse are mediated by a hypertrophic glutamatergic system. Thus it has recently been shown that the NMDA receptor modulator acamprosate inhibits conditioned abstinence behaviour in rats. Although more systematic work is needed to fully define these different neurobiological pathways involved in addicted behaviour, preclinical studies have identified low affinity non-competitive NMDA receptor antagonists as a novel potential generation of anti-relapse compounds and clinical studies have already been initiated in order to test these compounds in alcoholic patients.     

Selective remodeling of glutamatergic transmission to striatal cholinergic interneurons after dopamine depletion

The widely held view that the pathophysiology of Parkinson's disease arises from an under‐activation of the direct pathway striatal spiny neurons (dSPNs) has gained support from a recently described weakening of the glutamatergic projection from the parafascicular nucleus (PfN) to dSPNs in experimental parkinsonism. However, the impact of the remodeling of the thalamostriatal projection cannot be fully appreciated without considering its impact on cholinergic interneurons (ChIs) that themselves preferentially activate indirect pathway spiny neurons (iSPNs). To study this thalamostriatal projection, we virally transfected with Cre‐dependent channelrhodopsin‐2 (ChR2) the PfN of Vglut2‐Cre mice that were dopamine‐depleted with 6‐hydroxydopamine (6‐OHDA). In parallel, we studied the corticostriatal projection to ChIs in 6‐OHDA‐treated transgenic mice expressing ChR2 under the Thy1 promoter. We found the 6‐OHDA lesions failed to affect short‐term synaptic plasticity or the size of unitary responses evoked optogenetically in either of these projections. However, we found that NMDA‐to‐AMPA ratios at PfN synapses—that were significantly larger than NMDA‐to‐AMPA ratios at cortical synapses—were reduced by 6‐OHDA treatment, thereby impairing synaptic integration at PfN synapses onto ChIs. Finally, we found that application of an agonist of the D₅ dopamine receptors on ChIs potentiated NMDA currents without affecting AMPA currents or short‐term plasticity selectively at PfN synapses. We propose that dopamine depletion leads to an effective de‐potentiation of NMDA currents at PfN synapses onto ChIs which degrades synaptic integration. This selective remodeling of NMDA currents at PfN synapses may counter the selective weakening of PfN synapses onto dSPNs in parkinsonism.