Table 1.

Mechanisms of synaptic plasticity and their involvement in ALS pathogenesis.

Anatomical Site	Patient or Animal Model	Type of Plastic Changes	Compensatory or Pathological?	References
Cerebral cortex	ALS patients	Reduced cortical connections	Pathological	[39]
	ALS patients	Increased neuronal excitability	Pathological	[40,41]
	ALS patients	Increased cortical connections or increased neuronal excitability	Compensatory	[42,43,44,45,46,47]
	SOD1 tg mouse	Reduced LTP	Pathological	[48]
	FUS tg mouse	Hyperexcitability; impaired synaptic plasticity	Pathological	[49,50,51]
	FUS tg Drosophila	Increased neuronal excitability	Pathological	[52]
	SOD1 tg mouse	Increased neuronal excitability	Compensatory	[53]
	TDP-43 tg mouse	Impaired synaptic plasticity, synaptic density and LTP	Pathological	[54,55,56,57]
	TDP-43 KO mouse	Impaired synaptic plasticity and LTP	Pathological	[58]
Hippocampus	ALS patients	Reduced and altered neurogenesis	Pathological	[59]
	C9orf72 KO mouse	Reduced neurogenesis	Pathological	[60]
	C9orf72 mutant patients and mice	Impaired synaptic function and plasticity	Pathological	[61,62]
	FUS tg mouse	Hyperexcitability	Pathological	[49,50,51]
	Ataxin2-mutant Drosophila	Alteration of long-term memory	Pathological	[63]
	TDP-43 tg mouse	Reduced LTP and synaptic density	Pathological	[56,57]
	TDP-43 KO mouse	Reduced LTP and synaptic density	Pathological	[64]
	TDP-43 KO rat	Increased LTP—enlarged dendritic spines	Compensatory	[65]
	SOD1 tg mouse	Excitotoxicity	Pathological	[66]
	SOD1 tg mouse	Increased synaptic plasticity and LTP	Compensatory	[66,67,68]
Spinal cord and brainstem	ALS patients	Reduced activity of inhibitory interneurons—increased MN activity	Compensatory	[69]
	ALS patients	Hyperexcitability and excitotoxicity	Pathological	[69]
	ALS patients	Reduced MN soma size and dendrites	Pathological	[70,71]
	SOD1 tg mouse	MN soma size plasticity—arborization of dendrites and proximal fibers	Compensatory	[31,33]
	SOD1 tg mouse	Hyperexcitability and excitotoxicity	Pathological	[72]
	SOD1 tg mouse	Increase of C-boutons in MNs	Compensatory	[73,74,75]
	SOD1 tg mouse	MN dendrite branching	Compensatory	[76]
	VEGF tg mouse	Impaired synaptic plasticity	Pathological	[77]
	SOD1 tg mouse	Brainstem neurogenesis	Compensatory	[78]
	Neurotoxic MN removal	Synaptic plasticity	Compensatory	[34,35,36,37,79,80,81]
	SOD1 tg rat	Phrenic long-term facilitation	Compensatory	[82,83]
NMJ	ALS patients	Neurotrophic support from muscle	Compensatory	[84]
	SOD1 tg mouse	Altered NMJ sprouting	Pathological	[85]
	Mnd mouse	Altered NMJ sprouting	Pathological	[85]
	Pmn mouse	Altered NMJ sprouting	Pathological	[85]
	SOD1 tg mouse	Detachment of synaptic terminals	Pathological	[86]
	SOD1 tg mouse	Detachment of synaptic terminals in selective NMJ subtypes	Pathological	[87,88]
	SOD1 tg mouse	Synaptic plasticity in selective NMJ subtypes	Compensatory	[87,88]
	SOD1 tg mouse	Neurotrophic support from muscle	Compensatory	[89]
	Mouse and Drosophila with mutant sodium channels	Homeostatic synaptic plasticity	Compensatory	[90]
	TDP-43 KO Drosophila	Altered synaptic function	Pathological	[91]
	C9orf72 mutant Drosophila	Homeostatic synaptic plasticity	Compensatory	[92]

Abbreviations: tg = transgenic; KO = knockout.