Abstract
Age-related alterations in the expression of genes and corticostriatal synaptic plasticity were studied in the dorsal striatum of mice of four age groups from young (2-3 months old) to old (18–24 months of age) animals. A significant decrease in transcripts encoding neuronal nitric oxide (NO) synthase and receptors involved in its activation (NR1 subunit of the glutamate NMDA receptor and D1 dopamine receptor) was found in the striatum of old mice using gene array and real-time RT-PCR analysis. The old striatum showed also a significantly higher number of GFAP-expressing astrocytes and an increased expression of astroglial, inflammatory, and oxidative stress markers. Field potential recordings from striatal slices revealed age-related alterations in the magnitude and dynamics of electrically induced long-term depression (LTD) and significant enhancement of electrically induced long-term potentiation in the middle-aged striatum (6-7 and 12-13 months of age). Corticostriatal NO-dependent LTD induced by pharmacological activation of group I metabotropic glutamate receptors underwent significant reduction with aging and could be restored by inhibition of cGMP hydrolysis indicating that its age-related deficit is caused by an altered NO-cGMP signaling cascade. It is suggested that age-related alterations in corticostriatal synaptic plasticity may result from functional alterations in receptor-activated signaling cascades associated with increasing neuroinflammation and a prooxidant state.
Highlights
Normal aging is associated with declining sensorimotor control and cognitive functions which may result from changes in the cortex-basal ganglia circuits involved in planning, initiation, and control of voluntary movements
Numerous neurochemical and pharmacological studies have reported alterations in all major striatal neurotransmitter systems with aging [9,10,11,12,13], only a few analysed alterations in corticostriatal synaptic plasticity in animal models of normal aging showing an age-related decrease in short-term plasticity [14] and some deficit in two different forms of long-term plasticity associated with activation of N-methyl-D-aspartate- (NMDA-) type glutamate receptors (NMDAR) [14, 15]
We found that striatal tissue from old (≥18 months) mice is characterized by decreased expression of major genes involved in nitric oxide (NO) production, namely, genes encoding for the essential NR1 subunit of the NMDAR, D1R, and neuronal NO synthase (NOS)
Summary
Normal aging is associated with declining sensorimotor control and cognitive functions which may result from changes in the cortex-basal ganglia circuits involved in planning, initiation, and control of voluntary movements. As a primary input structure of the basal ganglia the striatum receives cortical information through topographically organized glutamatergic projections to its principal medium size spiny neurons which integrate and transfer it to the output structures under control of dopaminergic input from the substantia nigra and striatal cholinergic and nitrergic interneurons. This interaction of dopamine, acetylcholine, and nitric oxide neurotransmitter systems determines whether corticostriatal transmission is amplified (LTP) or dampened (LTD) following repetitive activation [8]. Numerous neurochemical and pharmacological studies have reported alterations in all major striatal neurotransmitter systems with aging [9,10,11,12,13], only a few analysed alterations in corticostriatal synaptic plasticity in animal models of normal aging showing an age-related decrease in short-term plasticity [14] and some deficit in two different forms of long-term plasticity associated with activation of N-methyl-D-aspartate- (NMDA-) type glutamate receptors (NMDAR) [14, 15]
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