CPT1C is required for synaptic plasticity and oscillatory activity that supports motor, associative and non-associative learning.

Carnitine palmitoyltransferase 1c (CPT1C) is a neuron-specific protein widely distributed throughout the CNS and highly expressed in discrete brain areas including the hypothalamus, hippocampus, amygdala and different motor regions. Its deficiency has recently been shown to disrupt dendritic spine maturation and AMPA receptor synthesis and trafficking in the hippocampus, but its contribution to synaptic plasticity and cognitive learning and memory processes remains mostly unknown. Here, we aimed to explore the molecular, synaptic, neural network and behavioural role of CPT1C in cognition-related functions by using CPT1C knockout (KO) mice. CPT1C-deficient mice showed extensive learning and memory deficits. The CPT1C KO animals exhibited impaired motor and instrumental learning that seemed to be related, in part, to locomotor deficits and muscle weakness but not to mood alterations. In addition, CPT1C KO mice showed detrimental hippocampus-dependent spatial and habituation memory, most probably attributable to inefficient dendritic spine maturation, impairments in long-term plasticity at the CA3-CA1 synapse and aberrant cortical oscillatory activity. In conclusion, our results reveal that CPT1C is not only crucial for motor function, coordination and energy homeostasis, but also has a crucial role in the maintenance of learning and memory cognitive functions. KEY POINTS: CPT1C, a neuron-specific interactor protein involved in AMPA receptor synthesis and trafficking, was found to be highly expressed in the hippocampus, amygdala and various motor regions. CPT1C-deficient animals exhibited energy deficits and impaired locomotion, but no mood changes were found. CPT1C deficiency disrupts hippocampal dendritic spine maturation and long-term synaptic plasticity and reduces cortical γ oscillations. CPT1C was found to be crucial for motor, associative and non-associative learning and memory.

Anatomical and pharmacological relationship between acetylcholine and nitric oxide in the prepositus hypoglossi nucleus of the cat: functional implications for eye-movement control.

The prepositus hypoglossi (PH) nucleus has been proposed as a pivotal structure for horizontal eye-position generation in the oculomotor system. Recent studies have revealed that acetylcholine (ACh) in the PH nucleus could mediate the persistent activity necessary for this process, although the origin of this ACh remains unknown. It is also known that nitric oxide (NO) in the PH nucleus plays an important role in the control of velocity balance, being involved in a negative feedback control of tonic signals arriving at the PH nucleus. As it could be expected that neurons taking part in eye-position generation must control their tonic background inputs, the existence of a relationship between nitrergic and cholinergic neurons is hypothesized. In the present study we analyzed the distribution, size, and morphology of choline acetyltransferase-positive neurons, and their relationship with neuronal nitric oxide synthase in the PH nucleus of the cat. As presumed, some 96% of cholinergic neurons were also nitrergic in the PH nucleus, suggesting that NO is regulating the level of ACh released by cholinergic PH neurons. Furthermore, we studied the alterations induced by muscarinic-receptor agonists and antagonists on spontaneous and vestibularly induced eye movements in the alert cat and compared them with those induced in previous studies by modification of NO levels in the same animal preparation. The results suggest that ACh is necessary for the generation of saccadic and vestibular eye-position signals, whereas the NO is stabilizing the eye-position generator by controlling background activity reaching cholinergic neurons in the PH nucleus.

A cholinergic mechanism for eye fixation.

A basic question regarding the integrative properties of the central nervous system is how transient motor commands or brief sensory stimuli are able to evoke persistent neural changes, mainly in the form of a sustained tonic rate of action potentials. Examples of this persistent neural activity have been reported in prefrontal (Fuster, 1997) and entorhinal (Egorov et al., 2002) cortices, as part of the neural mechanisms involved in short-term working memory (Goldman-Rakic, 1995). Interestingly enough, the general organization of motor systems assumes the presence of bursts of short-lasting motor commands encoding movement characteristics such as velocity, duration, and amplitude, followed by a maintained tonic firing encoding the position at which the moving appendage should be maintained (Robinson, 1981; Moschovakis, 1997). Thus, persistent neural activity seems to be necessary for both behavioral (positions of fixation) and cognitive (working memory) processes.

A cholinergic mechanism underlies persistent neural activity necessary for eye fixation.

It is generally accepted that the prepositus hypoglossi (PH) nucleus is the site where horizontal eye-velocity signals are integrated into eye-position ones. However, how does this neural structure produce the sustained activity necessary for eye fixation? The generation of the neural activity responsible for eye-position signals has been studied here using both in vivo and in vitro preparations. Rat sagittal brainstem slices including the PH nucleus and the paramedian pontine reticular formation (PPRF) rostral to the abducens nucleus were used for recording intracellularly the synaptic activation of PH neurons from the PPRF. Single electrical pulses applied to the PPRF showed a monosynaptic projection on PH neurons. This synapse was found to be glutamatergic in nature, acting on alpha-amino-3-hydroxy-5-methylisoxazole propionate (AMPA)/kainate receptors. Train stimulation (100 ms, 50-200 Hz) of the PPRF evoked a depolarization of PH neurons, exceeding (by hundreds of ms) the duration of the stimulus. Both duration and amplitude of this long-lasting depolarization were linearly related to train frequency. The train-evoked sustained depolarization was demonstrated to be the result of the additional activation of cholinergic fibers projecting onto PH neurons, because it was prevented by slice superfusion with atropine sulfate and pirenzepine (two cholinergic antagonists), and mimicked by carbachol and McN-A-343 (two cholinergic agonists). These results were confirmed in alert behaving cats. Microinjections of atropine and pirenzepine evoked an ipsilateral gaze-holding deficit consisting of an exponential-like, centripetal eye movement following saccades directed toward the injected site. These findings suggest that the sustained activity present in PH neurons carrying eye-position signals is the result of the combined action of PPRF neurons and the facilitative role of cholinergic terminals, both impinging on PH neurons. The present results are discussed in relation to other proposals regarding integrative properties of PH neurons and/or related neural circuits.

Cooperative glutamatergic and cholinergic mechanisms generate short-term modifications of synaptic effectiveness in prepositus hypoglossi neurons.

To maintain horizontal eye position on a visual target after a saccade, extraocular motoneurons need a persistent (tonic) neural activity, called "eye-position signal," generated by prepositus hypoglossi (PH) neurons. We have shown previously in vitro and in vivo that this neural activity depends, among others mechanisms, on the interplay of glutamatergic transmission and cholinergic synaptically triggered depolarization. Here, we used rat sagittal brainstem slices, including PH nucleus and paramedian pontine reticular formation (PPRF). We made intracellular recordings of PH neurons and studied their synaptic activation from PPRF neurons. Train stimulation of the PPRF area evoked a cholinergic-sustained depolarization of PH neurons that outlasted the stimulus. EPSPs evoked in PH neurons by single pulses applied to the PPRF presented a short-term potentiation (STP) after train stimulation. APV (an NMDA-receptor blocker) or chelerythrine (a protein kinase-C inhibitor) had no effect on the sustained depolarization, but they did block the evoked STP, whereas pirenzepine (an M1 muscarinic antagonist) blocked both the sustained depolarization and the STP of PH neurons. Thus, electrical stimulation of the PPRF area activates both glutamatergic and cholinergic axons terminating in the PH nucleus, the latter producing a sustained depolarization probably involved in the genesis of the persistent neural activity required for eye fixation. M1-receptor activation seems to evoke a STP of PH neurons via NMDA receptors. Such STP could be needed for the stabilization of the neural network involved in the generation of position signals necessary for eye fixation after a saccade.

Role of cerebellar interpositus nucleus in the genesis and control of reflex and conditioned eyelid responses.

The role of cerebellar circuits in the acquisition of new motor abilities is still a matter of intensive debate. To establish the contribution of posterior interpositus nucleus (PIN) to the performance and/or acquisition of reflex and classically conditioned responses (CRs) of the eyelid, the effects of microstimulation and/or pharmacological inhibition by muscimol of the nucleus were investigated in conscious cats. Microstimulation of the PIN in naive animals evoked ramp-like eyelid responses with a wavy appearance, without producing any noticeable plastic functional change in the cerebellar and brainstem circuits involved. Muscimol microinjections decreased the amplitude of reflex eyeblinks evoked by air puffs, both when presented alone or when paired with a tone as conditioned stimulus (CS). In half-conditioned animals, muscimol injections also decreased the amplitude and damped the typical wavy profile of CRs, whereas microstimulation of the same sites increased both parameters. However, neither muscimol injections nor microstimulation modified the expected percentage of CRs, suggesting a major role of the PIN in the performance of eyelid responses rather than in the learning process. Moreover, the simultaneous presentation of CS and microstimulation in well trained animals evoked CRs similar in amplitude to the added value of those evoked by the two stimuli presented separately. In contrast, muscimol-injected animals developed CRs to paired CS and microstimulation presentations, larger than those evoked by the two stimuli when presented alone. It is concluded that the PIN contributes to the enhancement of both reflex and conditioned eyelid responses and to the damping of resonant properties of neuromuscular elements controlling eyelid kinematics.

A cholinergic synaptically triggered event participates in the generation of persistent activity necessary for eye fixation.

An exciting topic regarding integrative properties of the nervous system is how transient motor commands or brief sensory stimuli are able to evoke persistent neuronal changes, mainly as a sustained, tonic action potential firing. A persisting firing seems to be necessary for postural maintenance after a previous movement. We have studied in vitro and in vivo the generation of the persistent neuronal activity responsible for eye fixation after spontaneous eye movements. Rat sagittal brainstem slices were used for the intracellular recording of prepositus hypoglossi (PH) neurons and their synaptic activation from nearby paramedian pontine reticular formation (PPRF) neurons. Single electrical pulses applied to the PPRF showed a monosynaptic glutamatergic projection on PH neurons, acting on AMPA-kainate receptors. Train stimulation of the PPRF area evoked a sustained depolarization of PH neurons exceeding (by hundreds of milliseconds) stimulus duration. Both duration and amplitude of this sustained depolarization were linearly related to train frequency. The train-evoked sustained depolarization was the result of interaction between glutamatergic excitatory burst neurons and cholinergic mesopontine reticular fibers projecting onto PH neurons, because it was prevented by slice superfusion with cholinergic antagonists and mimicked by cholinergic agonists. As expected, microinjections of cholinergic antagonists in the PH nucleus of alert behaving cats evoked a gaze-holding deficit consisting of a re-centering drift of the eye after each saccade. These findings suggest that a slow, cholinergic, synaptically triggered event participates in the generation of persistent activity characteristic of PH neurons carrying eye position signals.

Análisis de las causas más frecuentes de incumplimiento terapéutico / No disponible

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Actuación del farmacéutico ante la falta de medicamentos en la farmacia comunitaria / No disponible

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