Critical periods and local circuits

1. Instructive
   1. control of spiking
      1. 2. fast somatic inhibition (GABAA α1-subunit)

         Anmerkungen:

         • situated for suppression, or 'editing' of unwanted spikes, preventing them from back-propagating through the cell body into the dendritic tree 
         1. basket cells- feedforward inhibition (α1)

            Anmerkungen:

            • Fast-spiking, feedforward inhibition mediated by α1-subunit-containing receptors on the soma is then ideally situated to suppress back-propagation of unwanted spikes125 (Fig. 7a). The model incorporates the wide-reaching, horizontal axons of basket cells that receive input from one eye to inhibit targets of the other eye67
            1. PV+ cells (k3.1 channels)
      2. 1. well-timed spikes

         Anmerkungen:

         • in the soma itself might facilitate nuclear calcium entry for gene transcription (and growth) in response to waves of calcium arriving from synapses on dendritic spines
         1. uses STDP for activation

            Anmerkungen:

            • rely on precise millisecond time windows to allow such postsynaptic spikes to meet presynaptic input123, 
            1. need a molecular substrate

               Anmerkungen:

               • Identifying a molecular substrate that is unique to spike-timing dependent (as opposed to LFS or tetanus-induced126q) plasticity will be a prerequisite to testing this scheme in vivo
         2. sloppy gating

            Anmerkungen:

            • Sloppy gating by weak inhibition at the soma would prevent a competitive outcome by allowing excess back-propagation and spurious coincident activity with infrequent, deprived inputs from the retina125
         3. similar to LTP/ LTD
      3. 3. axonal inhibition (GABAA α2-subunit)
         1. Gad65-knockout mice/ immature mice
            1. controlled by chanderlier cells (α2-subunit )

               Anmerkungen:

               • Chandelier cell 'cartridge' synapses (which use α2 GABAA receptor subunits) can directly control this excessive spiking at the axon initial segment46, 
            2. excessive spiking

               Anmerkungen:

               • prolonged neuronal discharge that continues well after stimuli have passed through the receptive field of individual cells43, 
         2. failure

            Anmerkungen:

            • failure to regulate excess spiking at the axon initial segment can still be differentiated by fast-spiking inhibition at the cell body
2. Premissive
   1. Gap junctional coupling

      Anmerkungen:

      • Gap junctional coupling endows networks of parvalbumin-positive (PV+) interneurons with the ability to detect synchronous input
      1. involves PV+

         Anmerkungen:

         • Even in adulthood, basket cells can be coupled electrically into groups of 40 or 50 cells endowing the network with the ability to detect synchrony130
         1. GABAA α1-subunits
         2. detect synchrony
      2. nonsynchronous

         Anmerkungen:

         • Even a slight jitter in input timing (for example, between eyes) dampens network activity through reciprocal GABA-mediated contacts  α1-subunits
         1. inhibited by GABAA α1-subunits
      3. synchronous

         Anmerkungen:

         • Only synchronous open-eye (co-excite cells through gap junctions)  input will produce maximal, activity-dependent release or uptake of 'permissive' factors for neurite growth (for example, tissue-type plasminogen activator78, 86 and brain-derived neurotrophic factor). 
         1. allows passage
            1. tPA–plasmin/ BDNF release ?

               Anmerkungen:

               • possibly is one of the mediators
               1. monocular deprivation

                  Anmerkungen:

                  • Laminar motility of spines85 and their rapid pruning86 by brief periods of monocular deprivation could reflect activity-dependent secretion of proteases from the axons of fast-spiking cells themselves, in which parvalbumin is an important contributor to presynaptic calcium signals and synaptic integration139
               2. spines nearest the soma of layer 2/3 pyramidal cells

                  Anmerkungen:

                  • This might explain why spines nearest the soma of layer 2/3 pyramidal cells are most robustly lost during monocular deprivation86, as they lie nearest the parvalbumin-positive cell-rich layer59
      4. assumes
         1. different to LTP/LTD

            Anmerkungen:

            • extracellular locus of competition to be quite distinct from the intracellular mechanisms of LTP and LTD
      5. model
         1. less active/ deprived synapses
            1. release tPA/ don't release protease inhibitors
               1. spine pruning
         2. active/ open eye
            1. become insensitive to proteases

               Anmerkungen:

               • don't release tPA/ release inhibitors
               1. no pruning
            2. release other factors involved in growth e.g. BDNF
               1. neural growth
   2. future evidence
      1. conditional deletion of connexins

         Anmerkungen:

         • conditional deletion of connexins in cortical parvalbumin-positive cells alone, as the retina is also rich in gap junctions134

Anmerkungen:

•    Critical / sensitive periods: A window of opportunity in which learning is enhanced/ only possible in that window. It difficult to determine critical periods for high level cognitive processes in humans, however evidence for critical periods in sensory systems in several species has been found.   

1. mechanisms
   1. GABA circuits
      1. Parvalbumin-positive- (PV+) innervate GABA interneurons

         Anmerkungen:

         • calcium-binding albumin proteins cells    
         1. disrupts nets of PV+ cells in adulthood

            Anmerkungen:

            • The disruption of nets of Parvalbumin-positive cells in adulthood can induce ocular dominance shifts using monocular deprivation, possibly due to resetting the original GABA-mediated trigger:  
            1. monocular deprivation

               Anmerkungen:

               • which should only work in the critical period
               1. can induce ocular dominance shifts
         2. large basket cell
         3. enwrapped in nets of extracellular matrix (ECM)

            Anmerkungen:

            • This might be the result of resetting and tapping the original GABA-mediated trigger, as perineuronal nets probably control the extracellular ionic milieu (for example, potassium concentration) that surrounds parvalbumin-positive cells, allowing them to establish their fast firing efficiency, or might otherwise sequester molecular regulators of parvalbumin-positive cell maturation.   
            1. distruption of ECM in adulthood
               1. monocular deprivation
      2. potassium channel (Kv3.1)

         Anmerkungen:

         • uniquely regulates the fidelity of FAST-SPIKING behaviour (and thereby GABA release) from parvalbumin-positive interneurons 
         1. Kv3.1 antagonist- slows ocular dominance plasticity
      3. GABA
         1. α1-subunit drive plasticity-
            1. knock-in

               Anmerkungen:

               • Systematic use of the mouse 'knock-in' mutation has shown that only one of these subtypes, the α1-subunit-containing circuits, drives cortical plasticity 
            2. determine benzodiazepine binding

               Anmerkungen:

               • through a single amino acid residue in their amino terminus
            3. Diazepam α1 in mutants

               Anmerkungen:

               • fails to trigger premature plasticity in α1-subunit-mutants, although they are fully capable of undergoing plasticity at the proper age (postnatal day (P) 25) even without drugs46, as they form normal α1- subunit-containing GABA receptors at the appropriate time
               1. fails to trigger premature plasticity
            4. inputs from PV+

               Anmerkungen:

               • The α1-subunit-containing GABAA receptors are instead localized to receive parvalbumin-positive (but not cholecystokinin-positive) synapses on the soma68, 69, further implicating these large basket cell circuits in the control of the critical period
         2. α2-subunit are not involved in plasticity
            1. immuno-electron microscopy

               Anmerkungen:

               • indicated that individual GABAA receptor α-subunits are trafficked to discrete postsynaptic sites on the pyramidal cell axon, soma and dendrites 
            2. regulate neuronal firing- but not induction of plasticity
   2. structural
   3. Proteases

      Anmerkungen:

      • The extracellular matrix (ECM) is increasingly being recognized as a potent site for critical period plasticity73. Proteases are ideally suited to clear the way for growing neurites74
      1. tPA

         Anmerkungen:

         • TISSUE-TYPE PLASMINOGEN ACTIVATOR is the main serine protease in the postnatal mammalian brain75, 
         1. monocular deprivation during critical period
            1. tPA upregulated

               Anmerkungen:

               • Proteolysis by tPA is gradually upregulated in V1 
            2. not upregulated in Gad65 knockouts/ adults

               Anmerkungen:

               • Gad65 knockout blocks the critical period by disrupting the GABAergic circuits
         2. blocking tPA
            1. ocular dominance plasticity is impaired
               1. rescued by exogenous tPA(but not diazepam)
         3. is part of a molecular cascade linked with ocular dominance plasticity
         4. contribute to anatomical rewiring
   4. Second messengers

      Anmerkungen:

      • PKA Extracellular Signal-regulated kinase (ERK) CaMKIICREB Plasmin system- tPA  
      1. BDNF
         1. early role in plasticity
         2. cleaved from pro-BDNF by tPA
            1. positive feedback

               Anmerkungen:

               • BDNF stimulates the expression and release of tPA
         3. contribute to anatomical rewiring

            Anmerkungen:

            • Both tPA and BDNF can then contribute sequentially to the final anatomical rewiring of the cortical circuits
         4. may contribute to the elongation of neurites
2. Sensory
   1. V1
      1. Ocular dominance
         1. Occluding an eye during development

            Anmerkungen:

            • leads to expansion of the columns of that eye, and reduction (in size and afferent complexity) to the columns serving the other eye
         2. Normal developing ocular dominance columns
            1. results from activity dependent rules

               Anmerkungen:

               •    Theory-  the segregation of columns by normal vision during the critical period has been thought to result from similar activity-dependent rules acting on an initially overlapping continuum of THALAMOCORTICAL AFFERENTS.   
         3. Evidence
            1. Shared environment- siblings
               1. Similar visual maps

                  Anmerkungen:

                  •    ·         siblings show substantial similarity of visual maps, which supports the idea that molecular cues establish columnar architecture15.   
            2. Partial deprivation

               Anmerkungen:

               • Even the focal patterns of deprivation that are produced by shadows of blood vessels in a single eye are embossed onto the primary visual cortex16
            3. Computational models- lateral inhibition

               Anmerkungen:

               • lateral inhibition can establish narrow or wide columns in computer simulations of column formation by adjusting the contrast between inputs that would lead to winding or narrowing of the columns>> This is probably what happens during development- the ratio in lateral inhibition in the critical period can determine the size of the column
               • local imbalances of neuronal activity influence columnar architecture during normal development, and this cannot be explained solely by genetic instruction. 
               1. GABAA agonists during critical periods of kittens - increase lateral inhibition
                  1. 30% increase in column width
                  2. inverse agonist- column shrinkage
                     1. Diazepam
                  3. benzodiazepine
               2. Strabismus

                  Anmerkungen:

                  •    Strabismus also known as squint-eye and crossed-eye, is a condition in which the eyes are not properly aligned with each other   
                  1. exotropic deviation during critical period
                     1. increase column width
      2. spines
         1. during the critical period
            1. motility transiently elevated by 2 days of monocular deprivation
               1. tPA

                  Anmerkungen:

                  • This occludes the motility that can be induced by the direct application of tPA to naive brain slices, which indicates that tPA and its substrate, plasminogen, might be the endogenous mediators of experience-dependent spine motility
               2. only layers 2, 3 and 5
         2. tPA- can induce motility of spines
         3. monocular deprivation in adulthood or in mice that lack tPA or GAD65
            1. spine density is not reduced
               1. restored b exogenous tPA or diazepam infusiony
   2. S1
   3. A1
   4. Sensory experience-individualizes maps

      Anmerkungen:

      • it is agreed that sensory experience is important for individualizing ocular dominance maps during the critical period
3. Pathology
   1. amblyopia
4. Onset
   1. monocular deprivation

      Anmerkungen:

      • Based on the fact that monocular deprivation and affect ocular dominance shifts only during the critical period- it's possible to use to to test whether alterations to a specific target can 'reset' this period, delay or accelerate the onset of it
      1. temporal properties

         Anmerkungen:

         • Sensitivity to monocular deprivation is restricted to a critical period that begins, in mice, about 1 week after the eyes open (at postnatal day 13) and peaks 1 month after birth38
      2. amblyopia- only during critical period
      3. Sensitivity to monocular deprivation is restricted to a critical period
      4. -

         Anmerkungen:

         • Excessive emphasis on LTP/LTD alone (which is all-or-none at single synapses107) ignores the gradual, long-lasting changes that are the hallmark of critical period plasticity. One day of monocular deprivation does not occlude homosynaptic depression by single LFS94, and these early forms of synaptic change, which persist in the presence of protein synthesis inhibitors108, are insufficient to shift ocular dominance in vivo87. 
   2. preventing maturation of GABA transmission

      Anmerkungen:

      • by gene-targeted deletion of Gad65, which encodes a GABA-synthetic enzyme43, or by dark-rearing from birth 
      1. delays onset of critical period
      2. Gad65-knockout mice

         Anmerkungen:

         • Baseline receptive field properties are normal in the absence of GAD65, but ocular dominance plasticity is prevented until inhibition is acutely restored with diazepam43
         1. rescue of plasticity

            Anmerkungen:

            • possible at any age in Gad65-knockout mice, which indicates that the critical period is dependent on the proper level of inhibitory transmission 
   3. enhancing GABA transmission

      Anmerkungen:

      • directly with benzodiazepines just after eye-opening, or by promoting the rapid maturation of interneurons through excess brain-derived neurotrophic factor (BDNF) expression 
      1. accelerating onset