J Neurol Res

Journal of Neurology Research, ISSN 1923-2845 print, 1923-2853 online, Open Access

Article copyright, the authors; Journal compilation copyright, J Neurol Res and Elmer Press Inc

Journal website https://jnr.elmerpub.com

Review

Volume 16, Number 2, June 2026, pages 55-66

The Orexin System in Pediatric Learning Difficulties: Neurobiological Foundations for Educational, Psychoeducational and Behavioral Therapies

↓ **Table 1.** Differences Between Neurotransmitters and Neuropeptides
Characteristic	Neurotransmitters	Neuropeptides (like orexin)
GABA: gamma-aminobutyric acid; NPY: neuropeptide Y.
Size	Small molecules	Large molecules (peptides/proteins)
Examples	Dopamine, serotonin, acetylcholine, GABA, glutamate	Orexin, oxytocin, vasopressin, substance P, NPY
Synthesis	Synthesized in nerve terminals	Synthesized in cell body, transported to terminals
Storage	Small synaptic vesicles	Large dense-core vesicles
Release	Released at synapses	Can be released from multiple sites along neuron
Action	Fast, milliseconds	Slower, seconds to minutes, longer lasting
Reuptake	Taken back up by reuptake systems	Degraded by peptidases
Receptors	Various (ionotropic, metabotropic)	G-protein coupled receptors (GPCRs)
Effect	Rapid, direct signal	Modulatory, adjusts neuronal sensitivity

↓ Table 1. Differences Between Neurotransmitters and Neuropeptides

Characteristic

Neurotransmitters

Neuropeptides (like orexin)

GABA: gamma-aminobutyric acid; NPY: neuropeptide Y.

Size

Small molecules

Large molecules (peptides/proteins)

Examples

Dopamine, serotonin, acetylcholine, GABA, glutamate

Orexin, oxytocin, vasopressin, substance P, NPY

Synthesis

Synthesized in nerve terminals

Synthesized in cell body, transported to terminals

Storage

Small synaptic vesicles

Large dense-core vesicles

Release

Released at synapses

Can be released from multiple sites along neuron

Action

Fast, milliseconds

Slower, seconds to minutes, longer lasting

Reuptake

Taken back up by reuptake systems

Degraded by peptidases

Receptors

Various (ionotropic, metabotropic)

G-protein coupled receptors (GPCRs)

Effect

Rapid, direct signal

Modulatory, adjusts neuronal sensitivity

↓ **Table 2.** Activation of Key Intracellular Pathway for Long-Term Potentiation (LTP) via Binding of Orexin and Its Receptors
Pathway	Full name	Key role in LTP	Major effects
AMPA: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid.
Ca²⁺/CaMKII	Calcium/calmodulin-dependent protein kinase II	Initiates early-phase LTP through rapid phosphorylation events	Phosphorylates AMPA receptors, increases synaptic conductance and receptor insertion
PKC	Protein kinase C	Supports both induction and maintenance of LTP	Modulates receptor trafficking and cytoskeletal remodeling
cAMP/PKA	Cyclic adenosine monophosphate/protein kinase A	Converts short-term potentiation into long-term LTP	Activates cAMP response element biding (CREB) for gene transcription and synaptic protein expression
ERK/MAPK	Extracellular signal–regulated kinase/mitogen-activated protein kinase	Converts synaptic activity into nuclear gene expression	Activates CREB, promotes long-term structural synaptic changes
PI3K/Akt	Phosphoinositide 3-kinase/protein kinase B	Promotes neuronal survival and dendritic protein synthesis	Activates mTOR, stabilizes long-term LTP maintenance
mTOR	Mammalian target of rapamycin	Regulates dendritic protein translation needed for late-phase LTP	Supports local protein synthesis and long-term memory consolidation
BDNF-TrkB	Brain-derived neurotrophic factor/tropomyosin receptor kinase B	Enhances synaptic plasticity and strengthens LTP	Increases CREB activation, dendritic growth, and spine density

↓ Table 2. Activation of Key Intracellular Pathway for Long-Term Potentiation (LTP) via Binding of Orexin and Its Receptors

Pathway

Full name

Key role in LTP

Major effects

AMPA: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid.

Ca²⁺/CaMKII

Calcium/calmodulin-dependent protein kinase II

Initiates early-phase LTP through rapid phosphorylation events

Phosphorylates AMPA receptors, increases synaptic conductance and receptor insertion

PKC

Protein kinase C

Supports both induction and maintenance of LTP

Modulates receptor trafficking and cytoskeletal remodeling

cAMP/PKA

Cyclic adenosine monophosphate/protein kinase A

Converts short-term potentiation into long-term LTP

Activates cAMP response element biding (CREB) for gene transcription and synaptic protein expression

ERK/MAPK

Extracellular signal–regulated kinase/mitogen-activated protein kinase

Converts synaptic activity into nuclear gene expression

Activates CREB, promotes long-term structural synaptic changes

PI3K/Akt

Phosphoinositide 3-kinase/protein kinase B

Promotes neuronal survival and dendritic protein synthesis

Activates mTOR, stabilizes long-term LTP maintenance

mTOR

Mammalian target of rapamycin

Regulates dendritic protein translation needed for late-phase LTP

Supports local protein synthesis and long-term memory consolidation

BDNF-TrkB

Brain-derived neurotrophic factor/tropomyosin receptor kinase B

Enhances synaptic plasticity and strengthens LTP

Increases CREB activation, dendritic growth, and spine density