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.