No abstract

The neurotrophin brain-derived neurotrophic factor (BDNF) plays an important role in the activity-dependent regulation of synaptic structure and function, particularly of the glutamatergic synapses. BDNF may be released in the mature form, which activates preferentially TrkB receptors, or as proBDNF, which is coupled to the stimulation of the p75 NTR . In the mature form BDNF induces rapid effects on glutamate release, and may induce short-and long-term effects on the postsynaptic response to the neurotransmitter. BDNF may affect glutamate receptor activity by inducing the phosphorylation of the receptor subunits, which may also affect the interaction with intracellular proteins and, consequently, their recycling and localization to defined postsynaptic sites. Stimulation of the local protein synthesis and transcription activity account for the delayed effects of BDNF on glutamatergic synaptic strength. Several evidences show impaired synaptic plasticity of glutamatergic synapses in diseases where compromised BDNF function has been observed, such as Huntington's disease, depression, anxiety, and the BDNF polymorphism Val66Met, suggesting that upregulating BDNF-activated pathways may be therapeutically relevant. This review focuses on recent advances in the understanding of the regulation of the glutamatergic synapse by BDNF, and its implications in synaptic plasticity.

No abstract

Ghrelin is a peptide mainly produced by the stomach and released into circulation, affecting energy balance and growth hormone release. These effects are guided largely by the expression of the ghrelin receptor growth hormone secretagogue type 1a (GHS-R1a) in the hypothalamus and pituitary. However, GHS-R1a is expressed in other brain regions, including the hippocampus, where its activation enhances memory retention. Herein we explore the molecular mechanism underlying the action of ghrelin on hippocampal-dependent memory. Our data show that GHS-R1a is localized in the vicinity of hippocampal excitatory synapses, and that its activation increases delivery of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic-type receptors (AMPARs) to synapses, producing functional modifications at excitatory synapses. Moreover, GHS-R1a activation enhances two different paradigms of long-term potentiation in the hippocampus, activates the phosphatidylinositol 3-kinase, and increases GluA1 AMPAR subunit and stargazin phosphorylation. We propose that GHS-R1a activation in the hippocampus enhances excitatory synaptic transmission and synaptic plasticity by regulating AMPAR trafficking. Our study provides insights into mechanisms that may mediate the cognitionenhancing effect of ghrelin, and suggests a possible link between the regulation of energy metabolism and learning.T he appetite-stimulating peptide ghrelin is a 28-aa peptide predominantly produced by X/A-like cells in the oxyntic glands of the stomach as well as in the intestine (1), and secreted into the blood stream. This peptide promotes pituitary growth hormone secretion, through activation of the growth hormone secretagogue type 1a receptor (GHS-R1a) or ghrelin receptor (2). Additionally, ghrelin is involved in the regulation of energy balance by increasing food intake and reducing fat utilization (3). Plasma ghrelin levels rise before meals and decrease thereafter (4), a pattern which is consistent with the implication of ghrelin in preprandial hunger and meal initiation. Ghrelin is secreted into the circulation and crosses the blood-brain barrier (5, 6), but there is also evidence for ghrelin synthesis locally in the brain (2,7,8). The GHS-R1a receptor mRNA was initially found in the hypothalamus and in the pituitary gland (9), and later detected in the hippocampus (10). GHS-R1a is a G protein-coupled seventransmembrane domain receptor (3), which can signal through guanine nucleotide-binding protein (G protein) subunit alpha 11 (Gq class) to activate phosphatidylinositol-specific phospholipase C, generating 1,4,5-triphosphate (IP 3 ) responsible for Ca 2+ intracellular release from endoplasmic reticulum, and diacylglicerol, which in turn activates protein kinase C (PKC) (11). Ghrelin receptor activation is also coupled to the phosphatidylinositol 3 (PI3)-kinase signaling cascade in different cellular systems through a pertussis toxin-sensitive G protein (G i/o α) (11), and to protein kinase A (PKA) in isolated hypothalamic neurons, modulating N-type Ca 2+ channels (12).T...

Abstract Neuropsychiatric disorders share susceptibility genes, suggesting a common origin. One such gene is CNTNAP2 encoding contactin-associated protein 2 (CASPR2), which harbours mutations associated to autism, schizophrenia, and intellectual disability. Antibodies targeting CASPR2 have also been recently described in patients with several neurological disorders, such as neuromyotonia, Morvan’s syndrome, and limbic encephalitis. Despite the clear implication of CNTNAP2 and CASPR2 in neuropsychiatric disorders, the pathogenic mechanisms associated with alterations in CASPR2 function are unknown. Here, we show that Caspr2 is expressed in excitatory synapses in the cortex, and that silencing its expression in vitro or in vivo decreases the synaptic expression of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors and the amplitude of AMPA receptor-mediated currents. Furthermore, Caspr2 loss of function blocks synaptic scaling in vitro and experience-dependent homoeostatic synaptic plasticity in the visual cortex. Patient CASPR2 antibodies decrease the dendritic levels of Caspr2 and synaptic AMPA receptor trafficking, and perturb excitatory transmission in the visual cortex. These results suggest that mutations in CNTNAP2 may contribute to alterations in AMPA receptor function and homoeostatic plasticity, and indicate that antibodies from anti-CASPR2 encephalitis patients affect cortical excitatory transmission.