Garnik Akopian

Effects of Treadmill Exercise on Dopaminergic Transmission in the 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Lesioned Mouse Model of Basal Ganglia Injury

Studies have suggested that there are beneficial effects of exercise in patients with Parkinsons disease, but the underlying molecular mechanisms responsible for these effects are poorly understood. Studies in rodent models provide a means to examine the effects of exercise on dopaminergic neurotransmission. Using intensive treadmill exercise, we determined changes in striatal dopamine in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned mouse. C57BL/6J mice were divided into four groups: (1) saline, (2) saline plus exercise, (3) MPTP, and (4) MPTP plus exercise. Exercise was started 5 d after MPTP lesioning and continued for 28 d. Treadmill running improved motor velocity in both exercise groups. All exercised animals also showed increased latency to fall (improved balance) using the accelerating rotarod compared with nonexercised mice. Using HPLC, we found no difference in striatal dopamine tissue levels between MPTP plus exercise compared with MPTP mice. There was an increase detected in saline plus exercise mice. Analyses using fast-scan cyclic voltammetry showed increased stimulus-evoked release and a decrease in decay of dopamine in the dorsal striatum of MPTP plus exercise mice only. Immunohistochemical staining analysis of striatal tyrosine hydroxylase and dopamine transporter proteins showed decreased expression in MPTP plus exercise mice compared with MPTP mice. There were no differences in mRNA transcript expression in midbrain dopaminergic neurons between these two groups. However, there was diminished transcript expression in saline plus exercise compared with saline mice. Our findings suggest that the benefits of treadmill exercise on motor performance may be accompanied by changes in dopaminergic neurotransmission that are different in the injured (MPTP-lesioned) compared with the noninjured (saline) nigrostriatal system.

Enhancing neuroplasticity in the basal ganglia: the role of exercise in Parkinson's disease.

Epidemiological and clinical trials have suggested that exercise is beneficial for patients with Parkinsons disease (PD). However, the underlying mechanisms and potential for disease modification are currently unknown. This review presents current findings from our laboratories in patients with PD and animal models. The data indicate that alterations in both dopaminergic and glutamatergic neurotransmission, induced by activity‐dependent (exercise) processes, may mitigate the cortically driven hyper‐excitability in the basal ganglia normally observed in the parkinsonian state. These insights have potential to identify novel therapeutic treatments capable of reversing or delaying disease progression in PD.

Treadmill exercise reverses dendritic spine loss in direct and indirect striatal medium spiny neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease.

Exercise has been shown to be beneficial for Parkinsons disease (PD). A major interest in our lab has been to investigate how exercise modulates basal ganglia function and modifies disease progression. Dopamine (DA) depletion leads to loss of dendritic spines within the caudate nucleus and putamen (striatum) in PD and its animal models and contributes to motor impairments. Striatal medium spiny neurons (MSNs) can be delineated into two populations, the dopamine D1 receptor (DA-D1R)-containing MSNs of the direct pathway and dopamine D2 receptor (DA-D2R)-containing MSNs of the indirect pathway. There is evidence to suggest that the DA-D2R-indirect pathway MSNs may be preferentially affected after DA-depletion with a predominate loss of dendritic spine density when compared to MSNs of the DA-D1R-direct pathway in rodents; however, others have reported that both pathways may be affected in primates. The purpose of this study was to investigate the effects of intensive exercise on dendritic spine density and arborization in MSNs of these two pathways in the MPTP mouse model of PD. We found that MPTP led to a decrease in dendritic spine density in both DA-D1R- and DA-D2R-containing MSNs and 30 days of intensive treadmill exercise led to increased dendritic spine density and arborization in MSNs of both pathways. In addition, exercise increased the expression of synaptic proteins PSD-95 and synaptophysin. Taken together these findings support the potential effect of exercise in modifying synaptic connectivity within the DA-depleted striatum and in modifying disease progression in individuals with PD.

Altered AMPA receptor expression with treadmill exercise in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine‐lesioned mouse model of basal ganglia injury

Dopamine depletion leads to impaired motor performance and increased glutamatergic‐mediated hyperexcitability of medium spiny neurons in the basal ganglia. Intensive treadmill exercise improves motor performance in both saline treatment and the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) mouse model of Parkinsons disease. In the present study, we investigated the effect of high‐intensity treadmill exercise on changes in alpha‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor (AMPAR) subunit expression, because these receptor channels confer the majority of fast excitatory neurotransmission in the brain, and their subunit composition provides a key mechanism for regulating synaptic strength and synaptic neuroplasticity and is important in modulating glutamatergic neurotransmission. Within the dorsolateral striatum of MPTP mice, treadmill exercise increased GluR2 subunit expression, with no significant effect on GluR1. Furthermore, neurophysiological studies demonstrated a reduction in the size of excitatory postsynaptic currents (EPSCs) in striatal medium spiny neurons (as determined by the input‐output relationship), reduced amplitude of spontaneous EPSCs, and a loss of polyamine‐sensitive inward rectification, all supportive of an increase in heteromeric AMPAR channels containing the GluR2 subunit. Phosphorylation of GluR2 at serine 880 in both saline‐treated and MPTP mice suggests that exercise may also influence AMPAR trafficking and thus synaptic strength within the striatum. Finally, treadmill exercise also altered flip isoforms of GluR2 and GluR1 mRNA transcripts. These findings suggest a role for AMPARs in mediating the beneficial effects of exercise and support the idea that adaptive changes in GluR2 subunit expression may be important in modulating experience‐dependent neuroplasticity of the injured basal ganglia.

Regional differences in the expression of corticostriatal synaptic plasticity.

Field recordings of responses to activation of corticostriatal afferents were made in coronally sectioned rat brain slices. Each recording site was categorized according to its medial to lateral and rostral to caudal position to investigate anatomical differences in synaptic plasticity. Individual responses were highly variable exhibiting extremes of tetanus induced depression and potentiation. Consequently, averaging masked the capacity of these synapses to express long-term forms of plasticity. Block of GABA(A) inhibition and elimination of dopaminergic input with 6-hydroxydopamine lesions both acted to increase the expression of potentiation, but again considerable variability was observed. Separation of recordings into medial and lateral groups revealed clear anatomical trends which contributed to the variability observed in the total sample. Paired-pulse, post-tetanic and long-term potentiation was greater in medial than in lateral groups in normal artificial cerebral spinal fluid. Similar tendencies were seen after block of GABA(A) receptors with bicuculline. 6-Hydroxydopamine lesions in combination with bicuculline treatment reduced medial to lateral differences. Factoring in medial to lateral trends revealed block of GABA(A) receptor mediated inhibition had its greatest effect on medial corticostriatal responses and 6-hydroxydopamine lesions had their greatest effect on lateral responses. From these data we suggest anatomical variation in striatal circuitry may underlie regional differences in synaptic plasticity evoked by corticostriatal activation.

Functional state of corticostriatal synapses determines their expression of short- and long-term plasticity

Relationships between presynaptic function and short‐ and long‐term plasticity were investigated at adult corticostriatal synapses. Wide variability was observed in the expression of short‐ and long‐term synaptic plasticity. Intracellular records from 47 cells produced 17 examples of LTD (<90% of control), 10 examples of no long‐term change (between 90–110% of control), and 20 examples of LTP (>110% of control). Similar variation existed in paired‐pulse and posttetanic plasticities. The variability expressed in all three forms of plasticity appears to be related, based on correlations found between the paired‐pulse ratio (PPR) and tetanus‐induced short‐ (3 min posttetanus) and long‐term plasticities (16–20 min posttetanus). These data suggest that tetanus‐induced changes in synaptic strength are related to the intrinsic, preconditioned behavior of synapses. Every cell showing paired‐pulse depression also expressed LTD in response to high‐frequency activation of its afferents. Those synapses showing paired‐pulse potentiation tended to express LTP, although exceptions did exist. Similar relationships were found in a parallel analysis of population spikes. PPR also changed in association with the expression of posttetanic and long‐term depression. Greater paired‐pulse potentiation was observed in medial intracellular recordings, but no medial to lateral differences were seen in posttetanic plasticities. Field recordings also showed a medial bias toward paired‐pulse and posttetanic potentiation, but not in long‐term plasticity. Block of postsynaptic L‐type Ca2+ channels with nifedipine eliminated LTD expression, but overall no differences were found between nifedipine and control cells. Synapse 38:271–280, 2000.

Chronic brain oxidation in a glutathione peroxidase knockout mouse model results in increased resistance to induced epileptic seizures.

Systemic administration of kainic acid (KA) to rodents results in limbic seizures and subsequent neurodegeneration similar to that observed in certain types of human epilepsy, and it is a commonly used animal model for this disease. Oxidative stress has been suggested to play a role in the neuronal injury associated with KA administration. Based on this observation, chronic treatment with antioxidants has been proposed as a possible protective therapy against neuronal damage associated with epileptic seizures. Here we demonstrate by histochemical, electrophysiological, and biochemical means that knockout mice with decreased activity of the protective antioxidant enzyme glutathione peroxidase, which display elevated basal brain oxidative stress levels, are resistant to KA-induced seizure activity and neurodegeneration. This appears to be a result of decreased NMDA receptor function due to oxidation of its NR1 subunit. This suggests that the chronic use of antioxidants as antiepileptic agents to modulate NMDA-dependent seizure-induced neurodegeneration may be detrimental rather than protective and calls into question their use as a therapeutic agent in the treatment of epilepsy.

Age-Dependent Modulation of Synaptic Plasticity and Insulin Mimetic Effect of Lipoic Acid on a Mouse Model of Alzheimer’s Disease

Alzheimer’s disease is a progressive neurodegenerative disease that entails impairments of memory, thinking and behavior and culminates into brain atrophy. Impaired glucose uptake (accumulating into energy deficits) and synaptic plasticity have been shown to be affected in the early stages of Alzheimer’s disease. This study examines the ability of lipoic acid to increase brain glucose uptake and lead to improvements in synaptic plasticity on a triple transgenic mouse model of Alzheimer’s disease (3xTg-AD) that shows progression of pathology as a function of age; two age groups: 6 months (young) and 12 months (old) were used in this study. 3xTg-AD mice fed 0.23% w/v lipoic acid in drinking water for 4 weeks showed an insulin mimetic effect that consisted of increased brain glucose uptake, activation of the insulin receptor substrate and of the PI3K/Akt signaling pathway. Lipoic acid supplementation led to important changes in synaptic function as shown by increased input/output (I/O) and long term potentiation (LTP) (measured by electrophysiology). Lipoic acid was more effective in stimulating an insulin-like effect and reversing the impaired synaptic plasticity in the old mice, wherein the impairment of insulin signaling and synaptic plasticity was more pronounced than those in young mice.

Regulation of hippocampal synaptic plasticity by estrogen and progesterone.

Accumulating evidence indicates that the ovarian steroid hormones estrogen and progesterone regulate a wide variety of nonreproductive functions in the central nervous system by interacting with several molecular and cellular processes. A growing literature reporting results obtained in rodent models suggests that 17beta-estradiol, the most potent of the biologically relevant estrogens, facilitates some forms of learning and memory, and in particular, those involving hippocampus-dependent tasks. Hippocampal long-term potentiation and long-term depression of synaptic transmission are types of synaptic plasticity that have been extensively studied, as they are considered as cellular models of memory formation in the brain. In this chapter, we review the literature that analyzes and compares the effects of estrogen and progesterone on synaptic transmission and synaptic plasticity in rodents. Understanding the nonreproductive functions of estrogen and progesterone in the hippocampus has far-reaching implications not only for our basic understanding of neuroendocrinology and neurobiology, but also for developing better treatment of age-related diseases such as Alzheimers disease.

Urban air pollutants reduce synaptic function of CA1 neurons via an NMDA/NȮ pathway in vitro

Airborne particulate matter (PM) from urban vehicular aerosols altered glutamate receptor functions and induced glial inflammatory responses in rodent models after chronic exposure. Potential neurotoxic mechanisms were analyzed in vitro. In hippocampal slices, 2 h exposure to aqueous nanosized PM (nPM) selectively altered post‐synaptic proteins in cornu ammonis area 1 (CA1) neurons: increased GluA1, GluN2A, and GluN2B, but not GluA2, GluN1, or mGlur5; increased post synaptic density 95 and spinophilin, but not synaptophysin, while dentate gyrus (DG) neurons were unresponsive. In hippocampal slices and neurons, MitoSOX red fluorescence was increased by nPM, implying free radical production. Specifically, NȮ production by slices was increased within 15 min of exposure to nPM with dose dependence, 1–10 μg/mL. Correspondingly, CA1 neurons exhibited increased nitrosylation of the GluN2A receptor and dephosphorylation of GluN2B (S1303) and of GluA1 (S831 & S845). Again, DG neurons were unresponsive to nPM. The induction of NȮ and nitrosylation were inhibited by AP5, an NMDA receptor antagonist, which also protects neurite outgrowth in vitro from inhibition by nPM. Membrane injury (EthidiumD‐1 uptake) showed parallel specificity. Finally, nPM decreased evoked excitatory post‐synaptic currents of CA1 neurons. These findings further document the selective impact of nPM on glutamatergic functions and identify novel responses of NMDA receptor‐stimulated NȮ production and nitrosylation reactions during nPM‐mediated neurotoxicity.