Neuronal and astrocyte determinants of critical periods of plasticity.

Windows of plasticity allow environmental experiences to produce intense activity-dependent changes during postnatal development. The reordering and refinement of neural connections occurs during these periods, significantly influencing the formation of brain circuits and physiological processes in adults. Recent advances have shed light on factors that determine the onset and duration of sensitive and critical periods of plasticity. Although GABAergic inhibition has classically been implicated in closing windows of plasticity, astrocytes and adenosinergic inhibition have also emerged more recently as key determinants of the duration of these periods of plasticity. Here, we review novel aspects of the involvement of GABAergic inhibition, the possible role of presynaptic NMDARs, and the emerging roles of astrocytes and adenosinergic inhibition in determining the duration of windows of plasticity in different brain regions.

Adenosine and astrocytes determine the developmental dynamics of spike timing-dependent plasticity in the somatosensory cortex.

During development, critical periods of synaptic plasticity facilitate the reordering and refinement of neural connections, allowing the definitive synaptic circuits responsible for correct adult physiology to be established. The L4-L2/3 synapses in the somatosensory cortex (S1) exhibit a presynaptic form of spike timing-dependent long-term depression (t-LTD) that probably fulfills a role in synaptic refinement. This t-LTD persists until the 4rd postnatal week in mice, disappearing thereafter. When we investigated the mechanisms underlying this maturation-related loss of t-LTD in either sex mouse slices, we found that it could be completely recovered by antagonizing adenosine type 1 receptors (A1R). By contrast, an agonist of A1R impeded the induction of t-LTD at P13-27. Furthermore, we found that the adenosine that mediated the loss of t-LTD at the end of the 4th week of development is most probably supplied by astrocytes. At more mature stages (P38-60), we found that the protocol used to induce t-LTD provokes t-LTP. We characterized the mechanisms underlying the induction of this form of LTP and we found it to be expressed presynaptically, as witnessed by paired-pulse and coefficient of variation analysis. In addition, this form of presynaptic t-LTP requires the activation of NMDARs and mGlu1Rs, and the entry of Ca2+ into the postsynaptic neuron through L-type voltage-dependent Ca2+ channels. Nitric oxide is also required for t-LTP as a messenger in the postsynaptic neuron, as are the adenosine and glutamate that are released in association with astrocyte signaling. These results provide direct evidence of the mechanisms that close the window of plasticity associated with t-LTD and that drive the switch in synaptic transmission from t-LTD to t-LTP at L4-L2/3 synapses, in which astrocytes play a central role.SIGNIFICANCE STATEMENTDuring development, critical periods of plasticity facilitate the reordering and refining of neural connections, allowing correct adult physiology to be established. The L4-L2/3 synapses in the somatosensory cortex exhibit a presynaptic form plasticity (long-term depression -LTD) that probably fulfills a role in synaptic refinement. It is present until the 4rd postnatal week in mice, disappearing thereafter. The mechanisms that are responsible for this loss of plasticity are not clear. We describe here these mechanisms and those involved in the switch from LTD to LTP observed as the brain matures. Defining these events responsible for closing (and opening) plasticity windows may be important for brain repair, sensorial recovery, the treatment of neurodevelopmental disorders and for educational policy.

HERC1 Ubiquitin Ligase Is Required for Hippocampal Learning and Memory.

Mutations in the human HERC1 E3 ubiquitin ligase protein develop intellectual disability. The tambaleante (tbl) mouse carries a HERC1 mutation characterized by cerebellar ataxia due of adult cerebellar Purkinje cells death by extensive autophagy. Our previous studies demonstrated that both the neuromuscular junction and the peripheral nerve myelin sheaths are also affected in this mutant. Moreover, there are signs of dysregulated autophagy in the central nervous system in the tbl mouse, affecting spinal cord motor neurons, and pyramidal neurons of the neocortex and the hippocampal CA3 region. The tbl mutation affects associative learning, with absence of short- and long-term potentiation in the lateral amygdala, altered spinogenesis in their neurons, and a dramatic decrease in their glutamatergic input. To assess whether other brain areas engaged in learning processes might be affected by the tbl mutation, we have studied the tbl hippocampus using behavioral tests, ex vivo electrophysiological recordings, immunohistochemistry, the Golgi-Cox method and transmission electron microscopy. The tbl mice performed poorly in the novel-object recognition, T-maze and Morris water maze tests. In addition, there was a decrease in glutamatergic input while the GABAergic one remains unaltered in the hippocampal CA1 region of tbl mice, accompanied by changes in the dendritic spines, and signs of cellular damage. Moreover, the proportions of immature and mature neurons in the dentate gyrus of the tbl hippocampus differ relative to the control mice. Together, these observations demonstrate the important role of HERC1 in regulating synaptic activity during learning.

Astrocyte-mediated switch in spike timing-dependent plasticity during hippocampal development.

Presynaptic spike timing-dependent long-term depression (t-LTD) at hippocampal CA3-CA1 synapses is evident until the 3rd postnatal week in mice, disappearing during the 4th week. At more mature stages, we found that the protocol that induced t-LTD induced t-LTP. We characterized this form of t-LTP and the mechanisms involved in its induction, as well as that driving this switch from t-LTD to t-LTP. We found that this t-LTP is expressed presynaptically at CA3-CA1 synapses, as witnessed by coefficient of variation, number of failures, paired-pulse ratio and miniature responses analysis. Additionally, this form of presynaptic t-LTP does not require NMDARs but the activation of mGluRs and the entry of Ca2+ into the postsynaptic neuron through L-type voltage-dependent Ca2+ channels and the release of Ca2+ from intracellular stores. Nitric oxide is also required as a messenger from the postsynaptic neuron. Crucially, the release of adenosine and glutamate by astrocytes is required for t-LTP induction and for the switch from t-LTD to t-LTP. Thus, we have discovered a developmental switch of synaptic transmission from t-LTD to t-LTP at hippocampal CA3-CA1 synapses in which astrocytes play a central role and revealed a form of presynaptic LTP and the rules for its induction.

Adenosine Receptor-Mediated Developmental Loss of Spike Timing-Dependent Depression in the Hippocampus.

Critical periods of synaptic plasticity facilitate the reordering and refining of neural connections during development, allowing the definitive synaptic circuits responsible for correct adult physiology to be established. Presynaptic spike timing-dependent long-term depression (t-LTD) exists in the hippocampus, which depends on the activation of NMDARs and that probably fulfills a role in synaptic refinement. This t-LTD is present until the third postnatal week in mice, disappearing in the fourth week of postnatal development. We were interested in the mechanisms underlying this maturation related loss of t-LTD and we found that at CA3-CA1 synapses, presynaptic NMDA receptors (pre-NMDARs) are tonically active between P13 and P21, mediating an increase in glutamate release during this critical period of plasticity. Conversely, at the end of this critical period (P22-P30) and coinciding with the loss of t-LTD, these pre-NMDARs are no longer tonically active. Using immunogold electron microscopy, we demonstrated the existence of pre-NMDARs at Schaffer collateral synaptic boutons, where a decrease in the number of pre-NMDARs during development coincides with the loss of both tonic pre-NMDAR activation and t-LTD. Interestingly, this t-LTD can be completely recovered by antagonizing adenosine type 1 receptors (A1R), which also recovers the tonic activation of pre-NMDARs at P22-P30. By contrast, the induction of t-LTD was prevented at P13-P21 by an agonist of A1R, as was tonic pre-NMDAR activation. Furthermore, we found that the adenosine that mediated the loss of t-LTD during the fourth week of development is supplied by astrocytes. These results provide direct evidence for the mechanism that closes the window of plasticity associated with t-LTD, revealing novel events probably involved in synaptic remodeling during development.