ABSTRACT
BACKGROUND: Motor hyperactivity due to hyper-dopaminergic neurotransmission in the basal ganglia is well characterized; much less is known about the role of the neocortex in controlling motor behavior. METHODS: Locomotor behavior and motor, associative, and spatial learning were examined in mice with conditional null mutations of fibroblast growth factor receptor 1 (Fgfr1) restricted to telencephalic neural precursors (Fgfr1(f/f;hGfapCre)). Locomotor responses to a dopamine agonist (Amphetamine 2 mg/kg and Methylphenidate 10 mg/kg) and antagonists (SCH233390 .025 mg/kg and Haloperidol .2 mg/kg) were assessed. Stereological and morphological characterization of various monoaminergic, excitatory, and inhibitory neuronal subtypes was performed. RESULTS: Fgfr1(f/f;hGfapCre) mice have spontaneous locomotor hyperactivity characterized by longer bouts of locomotion and fewer resting points that is significantly reduced by the D1 and D2 receptor antagonists. No differences in dopamine transporter, tyrosine hydroxylase, or serotonin immunostaining were observed in Fgfr1(f/f;hGfapCre) mice. There was no change in cortical pyramidal neurons, but parvalbumin+, somatostatin+, and calbindin+ inhibitory interneurons were reduced in number in the cerebral cortex. The decrease in parvalbumin+ interneurons in cortex correlated with the extent of hyperactivity. CONCLUSIONS: Dysfunction in specific inhibitory cortical circuits might account for deficits in behavioral control, providing insights into the neurobiology of psychiatric disorders.
Subject(s)
Cerebral Cortex/pathology , Fibroblast Growth Factor 1/genetics , Hyperkinesis/genetics , Hyperkinesis/pathology , Neural Inhibition/genetics , Neurons/pathology , Amphetamine/therapeutic use , Animals , Behavior, Animal/drug effects , Biogenic Monoamines/metabolism , Cell Count/methods , Central Nervous System Stimulants/therapeutic use , Disease Models, Animal , Dopamine Agents/administration & dosage , Exploratory Behavior/drug effects , Fibroblast Growth Factor 1/deficiency , Glutamate Decarboxylase/metabolism , Hyperkinesis/drug therapy , Locomotion/drug effects , Locomotion/genetics , Male , Methylphenidate/therapeutic use , Mice , Mice, Knockout , Motor Activity/drug effects , Motor Activity/genetics , Nerve Tissue Proteins/metabolism , Signal Transduction/drug effects , Signal Transduction/geneticsABSTRACT
Sleep is a natural process that preserves energy, facilitates development, and restores the nervous system in higher animals. Sleep loss resulting from physiological and pathological conditions exerts tremendous pressure on neuronal circuitry responsible for sleep-wake regulation. It is not yet clear how acute and chronic sleep loss modify neuronal activities and lead to adaptive changes in animals. Here, we show that acute and chronic prolonged wakefulness in mice induced by modafinil treatment produced long-term potentiation (LTP) of glutamatergic synapses on hypocretin/orexin neurons in the lateral hypothalamus, a well-established arousal/wake-promoting center. A similar potentiation of synaptic strength at glutamatergic synapses on hypocretin/orexin neurons was also seen when mice were sleep deprived for 4 hours by gentle handling. Blockade of dopamine D1 receptors attenuated prolonged wakefulness and synaptic plasticity in these neurons, suggesting that modafinil functions through activation of the dopamine system. Also, activation of the cAMP pathway was not able to further induce LTP at glutamatergic synapses in brain slices from mice treated with modafinil. These results indicate that synaptic plasticity due to prolonged wakefulness occurs in circuits responsible for arousal and may contribute to changes in the brain and body of animals experiencing sleep loss.
Subject(s)
Intracellular Signaling Peptides and Proteins , Neuronal Plasticity , Neurons/metabolism , Neuropeptides , Sleep Deprivation/metabolism , Synapses/metabolism , Wakefulness , Animals , Benzhydryl Compounds/adverse effects , Benzhydryl Compounds/pharmacology , Central Nervous System Stimulants/adverse effects , Central Nervous System Stimulants/pharmacology , Cyclic AMP/metabolism , Dopamine/metabolism , Female , Hypothalamus/metabolism , Hypothalamus/pathology , Intracellular Signaling Peptides and Proteins/metabolism , Long-Term Potentiation , Male , Mice , Modafinil , Neuronal Plasticity/drug effects , Neurons/pathology , Neuropeptides/metabolism , Orexins , Receptors, Dopamine D1/metabolism , Sleep Deprivation/chemically induced , Sleep Deprivation/pathology , Synapses/pathology , Wakefulness/drug effectsABSTRACT
The adducin family of proteins interacts with the actin cytoskeleton and the plasma membrane in a calcium- and cAMP-dependent manner. Thus, adducins may be involved in changes in cytoskeletal organization resulting from synaptic stimulation. beta-Adducin knock-out mice were examined in physiological and behavioral paradigms related to synaptic plasticity to elucidate the role the adducin family plays in processes underlying learning and memory. In situ hybridization for alpha- and beta-adducin demonstrates that these mRNAs are found throughout the brain, with high levels of expression in the hippocampus. Schaffer collateral-CA1 tetanic long-term potentiation decayed rapidly in acute hippocampal slices from beta-adducin knock-out mice, although baseline spine morphology and postsynaptic density were normal. Interestingly, the input-output relationship was significantly increased in hippocampal slices from beta-adducin knock-out mice. Furthermore, beta-adducin knock-out mice were impaired in performance of fear conditioning and the water maze paradigm. The current results indicate that beta-adducin may play an important role in the cellular mechanisms underlying activity-dependent synaptic plasticity associated with learning and memory.
