Brains use classic homoeostatic negative feedback mechanisms. These allows neurons and/or circuits sense how active they are and adjust their excitability to keep activity in range. Neurons must sense activity. When this measure deviates from a target value, force must be generated to adjust excitability to move neuronal activity back to target. If individual neurons can stabilise own firing then overall network activity can be stabilised.
There are 2 different ways neurons could homeostatically regulate excitability. 1) they can adjust synaptic strengths up or down in right direction to stabilise average neuronal firing rates. 2) Instead of regulating synaptic strength they could modulate intrinsic excitability to shift relationship between synaptic input and firing rate.
Neuron activity is determined by strength of excitatory and inhibitory synaptic inputs and by balance of inward and outward voltage-dependent conductances that regulate intrinsic excitability.
Neurons can compensate for reduced sensory drive by using synaptic mechanisms to modify balance between excitatory and inhibitory inputs or by using intrinsic mechanisms to modify balance of inward and outward voltage-dependent currents.
Homeostatic regulation of neuronal firing
Circuit activity is homeostatically regulated to maintain firing rates and/or firing patterns in boundaries. Central neurons in dissociated cultures can maintain average firing rates around a homeostatic set point. When cortical or hippocampal neurons are induced to fire more than normal over hours, firing returns to basline levels. If firing is reduced over time neurons compensate. Firing is restored to basline. Most homeostatic compensation in central neurons are slow and take hours to adys. This may prevent interference with info transfer.
In most networks, small changes in balance between excitation and ihbition (E/I balance) can affect ongoing activity. E/I balance appears to be tightly regulated. It is required that excitatory and inhibitory syanptic strengths are adjusted in a cell-type-specific manner.
Synaptic scaling of excitatory synapses
Several forms of homeostatic plasticity of excitatory synapses. Global mechanisms include synaptic scaling. It operates on all a neuron's synapses. Local mechanisms act on individual or small groups of synapses.
Some synaptic homeostasis involves persynaptic and others postsynaptic change in function.
Synaptic scaling was identified in cultured neocortical neurons. Pharmacological manipulations of activity induced compensatory and bidirectional changes in unit strength of glutamatergic synapses. By measuring miniature EPSCs mediated by AMPA and NMDAR, it was found that modulating network activity induced uniform increases or decreases in entire mini amplitude distribution. This scales postsynaptic strength up and down. Change in mini amplitude change amplitude of evoked transmission with little or no change in short-term synaptic dynamics.
This may stabilised activity without changing relative strength of synaptic inputs. Does not disrupt info-storage mechanisms that rely on differences in synaptic weights.
How do neurons sense perturbations in activity during synaptic scaling? Studies show that synaptic scaling is cell-autonomous. Neurons sense changes in own activity through changes in firing/depolarisation and Ca2+ influx. Selectively blocking firing in an individual cortical pyramidal neuron scales up that neurons' synaptic strengths to same degree as blockade of network activity. This process requires a drop in somatic Ca2+ influx reduced activation of CamKK and CaMKIV and transcription.
Signalling pathway causes increases accumulation of AMPAR in postsynaptic membrane at all excitatory synapses. This scales up mini amplitude and enhances evoked transmission. Global enhancement of AMPAR abundance in response to activity blockade requires sequences on C-terminal of GluR2 subunit on AMPAR. This distinguishes synaptic scaling from other forms of synaptic enhancement such as LTP that requires sequences on GluR1 subunit. Synaptic scaling up is different from LTP. It takes longer time (hours) and wider spatial scale (global). It uses trafficking steps that target GluR2 subunit to enhance AMPAR abundance at synapses.
Scaling down in hippocampal slice cultures responds to enhanced activity (using channel rhodopsin and optical stimulation). It can be induced by cell-autonomous changes in Ca2+ influx. This involves CamKK/CaMKIV signalling and transcription. It requires the GluR2 subunit for its expression. Unlike CaMKK, CaMKIV is required but not sufficient to trigger reduction in synaptic strength. CamKK may activate signalling pathways that reduce synaptic strength. In hippocampal neurons driving individual neurons to fire induces synapse loss and reduced quantal amplitude.
Several molecules are involved in synaptic scaling. They regulate AMPAR trafficking. Arc (an immediate early gene) interacts with endocytic machinery to remove AMPAR from membrane. TNFα increases synaptic AMPAR accumulation. Beta3 integrins regulate AMPAR surface expression.
Synapse-type specificity of excitatory synaptic scaling
Rules for scaling excitatory synapses are cell-type specific. In cultured cortical and hippocampal neurons, excitatory synapses onto pyramidal neurons are scaled up by activity blockade. Excitatory synapses onto GABA-ergic interneurons are unaffected or reduced. Enhancing network activity increases excitatory transmission onto GABAergic interneurons. This involves the activity-dependent regulation of the immediate early gene Narp. Narp seems to be secreted by presynaptic pyramidal neurons. It accumulates preferentially at excitatory synapses into parvalbumin-positive interneurons.
Not all excitatory neurons express synaptic scaling at all times during development. Activating blockade in hippocampal networks scales up CA1 but not CA3 excitatory synapses. This suggests that the rules for expression of scaling in hippocampus are cell-type specific. Probably synaptic scaling is specifically expressed when and where it is needed.
It is not known whether a postsynaptic neuron can preferentially scale one subtype of excitatory synapse without affecting others. As mini amplitude distribution is scaled up or down proportionally, it is thought all excitatory synapses are affected equally during synaptic scaling in response to activity drop. If a synapse type that is a small fraction of a neuron's synapses was not affected, not sensitive enough to detect deviation.
Homoeostatic regulation of inhibitory synapses
To stabilise network activity, reciprocally regulate relative strengths of excitatory and inhibitory synapses. Inhibition is regulated by long-lasting changes in activity and/or sensory drive.
Visual deprivation or inhibition of retinal activity with tetrodotoxin decreased immunoreactivity for GABA. It reduced inhibition and inhibitory synapse number in cortical and hippocampal cultures.
Amplitude of miniature inhibitory postsynaptic currents are scaled down. This can involve changes in accumulation of postsynaptic GABAAR and reduced presynpaptic GABAergic markers. Studies show homoeostatic regulation of inhibition can occur by changes in postsynaptic strength, synapse number, and GABA packaging and release in combinations.
Is regulation of inhibition is due to presynaptic inhbitory neuron or postsynpatic inhibitory neuron. In hippocampal cultures, firing was prevented in either postsnypatic pyramidal neuron or presyntaptic inhibitory neuron while measuring inhibitory synapses onto pyramidal neuron. Neither was enough to mimic effects of blocking network firing. unlike synaptic scaling of excitatory synapses, homeostatic regulation of inhibition if non-cell-autonomous process. It requires changes in both pre and postynaptic activity simultaneously or is triggered by global changes in network activity.
Homeostasis of intrinsic excitability
Changes in intrinsic excitability that alter a neurons' input-output function can affect network behaviour. Intrinsic plasticity can be destabilising or homeostatic.