Exploring Short-Term Synaptic Plasticity and Its Implications in Autism

Short-term synaptic plasticity, a temporary change in synaptic strength lasting from seconds to minutes, is a crucial mechanism for neural communication and information processing. Two key types of short-term plasticity are paired pulse facilitation (PPF) and paired pulse depression (PPD). Understanding these mechanisms can provide insight into the molecular & genetic underpinnings of autism.

Paired Pulse Facilitation (PPF) occurs when two signals (pulses) arrive in quick succession at a synapse, with the second pulse producing a stronger response than the first. This is due to residual calcium (Ca2+) remaining in the presynaptic terminal after the first pulse, which enhances neurotransmitter release upon the arrival of the second pulse. This phenomenon is particularly significant at synapses with low initial release probability, ensuring that enough neurotransmitters are available for subsequent release.

Paired Pulse Depression (PPD), on the other hand, is characterized by a diminished response to the second pulse. This occurs at synapses with high initial release probability, where the first pulse depletes the readily releasable pool of neurotransmitters, leaving insufficient resources for the second pulse. The timing between the pulses is critical; if the interval is too long, Ca2+ dissipates, and vesicles are replenished, mitigating these effects.

In the context of autism, alterations in short-term plasticity have been linked to the disorder's characteristic neural and behavioral features. Research has shown that mutations in synaptic genes such as SYN1 and SYN2, which regulate synaptic vesicle dynamics, can disrupt short-term plasticity. These mutations result in increased PPF at excitatory synapses and enhanced synaptic depression at inhibitory synapses, leading to an excitatory/inhibitory (E/I) imbalance that contributes to network hyperexcitability and altered neuronal communication (Frontiers, 2015)​ (Frontiers)​.

Furthermore, neuroligin-3 mutations, associated with autism, have been found to differentially alter synaptic function in the hippocampus and cortex. These mutations can increase inhibitory synaptic transmission and disrupt endocannabinoid signaling, further impacting short-term plasticity and neural circuitry (Molecular Psychiatry, 2015)​ (Nature)​. These findings underscore the significant role of short-term plasticity in maintaining neural circuit function and how its disruption can contribute to pathogenesis.

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Understanding Short-Term Brain Changes and Autism

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Our brains constantly change how neurons (nerve cells) communicate to help us learn and remember things. Some of these changes happen very quickly and are known as short-term synaptic plasticity. This is when the connection strength between two neurons changes for a few seconds to a few minutes. Two important types of these changes are paired pulse facilitation (PPF) and paired pulse depression (PPD).

Paired Pulse Facilitation (PPF) happens when two signals arrive close together at a neuron connection, and the second signal is stronger than the first. This is because the first signal leaves behind some calcium, which helps release more chemical messengers for the second signal, making it stronger.

Paired Pulse Depression (PPD) is the opposite. When two signals come close together, the second signal is weaker. This happens because the first signal uses up most of the available chemical messengers, leaving fewer for the second signal.

These short-term changes are important for how our brains process information. In autism, scientists have found that these changes can be different. For example, certain gene mutations linked to autism can affect how well these short-term changes work. Some of these genes, like SYN1 and SYN2, help control the availability of chemical messengers at neuron connections. Mutations in these genes can lead to an imbalance in brain activity, making some signals too strong and others too weak (Frontiers, 2015)​ (Frontiers)​.

Other studies have shown that mutations in another gene, neuroligin-3, which is also linked to autism, can change how neurons communicate in different parts of the brain. These mutations can increase the strength of certain signals and disrupt the balance of brain activity (Molecular Psychiatry, 2015)​ (Nature)​. This imbalance can contribute to some of the behaviors seen in autism.

Understanding these short-term brain changes helps scientists learn more about how autism affects the brain and can lead to new ways to help people with autism.

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LTP and LTD and their Role in Autism

The Neuroscience of Autism 
Long Term Potentiation (LTP),  Long Term Depression (LTD) and their role in Autism.

LTP and LTD are critical forms of long term synaptic plasticity that underlie learning and memory. These processes are governed by Hebbian plasticity, a principle summarized as "cells that fire together, wire together." This means that the synaptic strength between two neurons increases when they are frequently active together (LTP), and decreases when they are less synchronized (LTD).

Spike-Timing Dependent Plasticity (STDP), a form of Hebbian plasticity, emphasizes the precise timing of neuronal spikes:

• LTP: Induced when a presynaptic neuron fires just before a postsynaptic neuron, typically within 20 milliseconds. This leads to a significant influx of calcium (Ca2+) through NMDA receptors and voltage-gated calcium channels (VGCCs), strengthening the synapse.
• LTD: Occurs when the postsynaptic neuron fires before the presynaptic neuron, usually within 20-100 milliseconds. This results in a weaker Ca2+ signal, leading to synaptic weakening.

Research has revealed substantial alterations in LTP, LTD, and Hebbian plasticity in autism, providing insights into the neural mechanisms that contribute to autism’s cognitive and behavioral characteristics

1. Hippocampal Dysfunction:

   • Studies on animal models, such as the BTBR mouse model of autism, show impaired hippocampal LTP. This impairment correlates with the learning and memory deficits commonly observed in autism (Rubenstein & Merzenich, 2003; Bourgeron, 2015)​ (Frontiers)​​ (Nature)​.

2. Cerebellar Abnormalities:

   • Atypical LTD has been noted in the cerebellum, a region critical for motor control and coordination. This could underlie the motor deficits observed in autism (Fatemi et al., 2012)​ (Nature)​.

3. Genetic Factors:

   • Mutations in synaptic genes such as SHANK3, NRXN1, and NLGN3, which are vital for maintaining synaptic plasticity, have been linked to autism. These mutations can disrupt the balance of LTP and LTD, leading to synaptic dysfunctions associated with autism (Durand et al., 2007; Südhof, 2008)​ (Frontiers)​​ (Nature)​.

4. Neuromodulators:

   • Dopamine (DA) is a key neuromodulator that can modulate the direction and extent of synaptic changes. It acts through D1/D5 receptors to enhance LTP or through D2 receptors to promote LTD. This modulation is essential for adaptive learning and behavior in autism (Yagishita et al., 2014)​ (Frontiers)​.

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References:

• Rubenstein, J. L., & Merzenich, M. M. (2003). Model of autism: increased ratio of excitation/inhibition in key neural systems. Genes, Brain and Behavior, 2(5), 255-267.
• Bourgeron, T. (2015). From the genetic architecture to synaptic plasticity in autism spectrum disorder. Nature Reviews Neuroscience, 16(9), 551-563.
• Fatemi, S. H., Aldinger, K. A., Ashwood, P., Bauman, M. L., Blaha, C. D., Blatt, G. J., ... & Welsh, J. P. (2012). Consensus paper: Pathological role of the cerebellum in autism. The Cerebellum, 11(3), 777-807.
• Durand, C. M., Betancur, C., Boeckers, T. M., Bockmann, J., Chaste, P., Fauchereau, F., ... & Bourgeron, T. (2007). Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nature Genetics, 39(1), 25-27.
• Südhof, T. C. (2008). Neuroligins and neurexins link synaptic function to cognitive disease. Nature, 455(7215), 903-911.
• Yagishita, S., Hayashi-Takagi, A., Ellis-Davies, G. C., Urakubo, H., Ishii, S., & Kasai, H. (2014). A critical time window for dopamine actions on the structural plasticity of dendritic spines. Science, 345(6204), 1616-1620.

What is LTP and LTD and how do they relate to Autism?

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Our brain cells (neurons) connect with each other through synapses, which are like tiny bridges for communication. These connections can change in strength, helping us learn and remember. Two key ways these connections change are Long-Term Potentiation (LTP) and Long-Term Depression (LTD).

• LTP: This is when the connection between two neurons gets stronger. Think of it like a friendship that grows stronger the more you interact.
• LTD: This is when the connection weakens, similar to a friendship that fades when you stop interacting.

Hebbian Plasticity

Hebbian plasticity is a rule that explains how these changes happen: "cells that fire together, wire together." This means that if two neurons are active at the same time, their connection strengthens (LTP). If one neuron is active while the other is not, their connection weakens (LTD).

How LTP and LTD are Different in Autism

Research has shown that people with autism often have differences in how LTP and LTD work, which can affect learning and behavior:

1. Memory and Learning:

   • Studies on animals have shown that the hippocampus, a brain area crucial for memory, has trouble with LTP in autism. This might explain some learning difficulties seen in autism (Rubenstein & Merzenich, 2003; Bourgeron, 2015)​ (Frontiers)​​ (Nature)​.

2. Movement and Coordination:

   • The cerebellum, which helps control movement, shows problems with LTD in autism. This can lead to issues with coordination and motor skills (Fatemi et al., 2012)​ (Nature)​.

3. Genes and Synapses:

   • Certain genes that help keep synapses strong and flexible can be different in people with autism. For example, genes like SHANK3 and NRXN1 are important for synaptic strength. Changes in these genes can disrupt the balance of LTP and LTD, affecting how neurons communicate (Durand et al., 2007; Südhof, 2008)​ (Frontiers)​​ (Nature)​.

4. Role of Dopamine:

   • Dopamine is a chemical in the brain that helps regulate mood and movement. It also affects LTP and LTD. In autism, dopamine might not work the same way, influencing learning and behavior (Yagishita et al., 2014)​ (Frontiers)​.

Understanding these differences helps scientists find better ways to support autistics, aiming to improve learning, memory, and coordination.

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