The Brain’s Extracellular Matrix and Its Role in Synaptic Plasticity

During development, the ECM and CSPGs regulate neuronal migration, axon outgrowth, synaptogenesis and synaptic maturation.

“During development, the ECM, and CSPGs in particular, regulate neuronal migration, axon outgrowth, synaptogenesis and synaptic maturation.23, 27, 28, 29, 30, 31”

Once formed, PNNs control neuronal access to growth and transcription factors, stabilize synaptic connectivity and compartmentalize the neuronal surface, regulating availability of glutamatergic receptors and neuronal firing properties.

“Once formed, and throughout adulthood, PNNs control neuronal access to growth and transcription factors, stabilize synaptic connectivity and compartmentalize the neuronal surface, regulating the availability of glutamatergic receptors to postsynaptic specializations and, thus, neuronal firing properties.23, 25, 38”

PNN maturation during late postnatal development contributes to the closure of critical periods of development, stabilizing successful synaptic connectivity and instating a restricted mode of synaptic plasticity characteristic of adulthood.

“PNN maturation during late postnatal development contributes to the closure of critical periods of development, stabilizing successful synaptic connectivity and instating a restricted mode of synaptic plasticity characteristic of adulthood.4, 23, 82, 83, 84”

Astrocytes form microdomains modulating glutamatergic synapses and extrasynaptic glutamate receptors, and CSPGs control lateral diffusion of cell surface receptors, extrasynaptic diffusion of negatively charged transmitters such as glutamate, and expression of glial transmitter transporters.

“This possibility is in line with growing evidence indicating that astrocytes form microdomains modulating glutamatergic synapses and extrasynaptic glutamate receptors, and that CSPGs (cell surface bound and as part of ECM) control (i) lateral diffusion of cell surface receptors, (ii) the extrasynaptic diffusion of negatively charged transmitters such as glutamate and (iii) the expression of glial”

PNNs form perisynaptic condensations of organized ECM that are an integral component of the functional synaptic complex.

“PNNs form perisynaptic condensations of organized ECM, which become an integral component of the functional synaptic complex.”

PNNs restrict the lateral diffusion of AMPA receptors and thus allow synaptic desensitization.

“This process, proposed to represent a fundamental mechanism for the maintenance of synaptic receptor pools, has been shown to controlled by PNNs, which restricted the lateral diffusion of AMPA receptors and thus allow synaptic desensitization (Frischknecht and Gundelfinger, 2012; Frischknecht et al., 2009; Heine et al., 2008).”

Metalloproteases are key in synaptic plasticity and memory by transiently relieving ECM constraints on plasticity and promoting synaptogenesis.

“Notably, metalloproteases play a key role in synaptic plasticity and memory, creating windows of opportunity for learning by temporarily releasing neurons from the ECM clamping effects on plasticity and increasing synaptogenesis (Frischknecht and Gundelfinger, 2012; Rivera et al., 2010; Van Hove et al., 2012; Wright and Harding, 2009).”

The ECM is continually remodeled in development and adulthood in response to stimuli including learning and memory, stress, and immune activation.

“Emerging evidence supports the intriguing idea that the ECM, both in its developmental and adult forms, is constantly remodeled in response to a broad variety of stimuli, which in adulthood include learning and memory, stress, and immune system activation (Frischknecht and Gundelfinger, 2012).”

These developmental changes include increases in synaptic pruning and myelination, as well as increases in the availability of dopamine in the limbic circuitry.

“These changes include increases in synaptic pruning and myelination107,171, as well as increases in the availability of dopamine in the limbic circuitry172,173.”