In whisker-trimmed mice versus controls, we analyzed the changes of excitatory and inhibitory neurons in the barrel cortices. After loss of whisker inputs for a week, the functions of excitatory neurons and synapses as well as the sites of receiving excitatory inputs are upregulated (Figures 2 and 5). On the other hand, the functions of GABAergic neurons and synapses as well as the processes of receiving synaptic inputs are downregulated (Figures 6 and 8). These changes elevate the activity levels of network neurons in the barrel cortices, which may prevent a loss of their functions due to idle whisker inputs and increase their sensitivity to sensory inputs, as well as be ready to attracting the innervations from other sensory cortices and/or peripheral nerves for the remained modalities during the cross-modal sensory plasticity [39–42].
In terms of physiological impacts for bidirectional changes in pyramidal neurons vs. GABAergic neurons from the barrel cortex after the loss of whisker inputs, the upregulation of excitatory units and the downregulation of inhibitory units will reset the balance of excitation versus inhibition toward the end of excitation. In addition to reducing the threshold to boost neuronal networks, this upregulated activity may maintain the sensitivity of pyramidal neurons to weak input, so that their functions are not lost. Moreover, their upregulated activities may attract the exogenous inputs to innervate the barrel cortices, such as from piriform cortex , for cross-modal sensory plasticity and rehabilitation. Upregulations in the frequency of excitatory synaptic events (Figure 3) and the sites of receiving synaptic inputs (Figures 4 and 5) grant the establishment of new excitatory innervations in the barrel cortices.
After a loss of whisker inputs, the capabilities of firing spikes and transmitting excitatory synaptic signals increase on pyramidal neurons in the barrel cortex (Figures 2 and 3). The capabilities of firing spikes on GABAergic cells and executing their synaptic outputs decrease (Figures 6 and 7). That is, the intrinsic property and synaptic transmission change coordinately for homogenous functions in experience-dependent neural plasticity. This coordinate change is also seen synaptic transmission and input structures, since excitatory synaptic events and dendritic spines increase in a loss of whisker inputs (Figures 3 and 5). The coordination in the neurons and synapses is critical for them to work in a common purpose, i.e., the increase of neuronal sensitivity to inputs boost the activity of neuronal networks for cross-modal sensory plasticity [41, 42]. In addition, we observed the bidirectional change between processes and their spines in apical and basal dendrites (Figures 4 and 5). This homeostasis in process density and spines saves the neuronal resources, a process similar to homeostasis by coordinating subcellular compartments and single molecules [43, 44]. Therefore, the coordination and homeostasis among the neurons and synapses are present in vivo, based on our studies, which expends this knowledge obtained from the studies in vitro.
In terms of the mechanism underlying the upregulation of excitatory units and the downregulation of inhibitory units after loss of sensory inputs in the barrel cortices, we assume that they use homeostatic mechanisms, which are seen in the studies in vitro. Neuronal activities undergo homeostatic upregulation after functional deficits by pharmacological or genetic manipulations [45, 46]. For instance, neuronal excitability rises when removing the treatment of TTX. The density of AMPA-type glutamate receptors is high when using CNQX. Neuronal excitability shows low and then recovery when potassium channels are over-expressed [47–49]. Such slowly developed homeostasis plays a role in functional compensation. The molecular mechanisms underlying neural homeostasis include glutamate/GABA receptors, voltage-gated sodium channels, brain-derived neurotrophic factors and α/β CaM-kinases [50–56]. It remains to be investigated how these molecules are coordinately initiated in vivo for the plasticity of the barrel cortices after loss of whisker inputs.
Excitatory synaptic transmission and dendritic spines increase on pyramidal neurons of the barrel cortex after loss of whisker inputs. As the strength of synaptic activities from the thalamus input deceases due to a lack of information from whisker-trigeminal ganglion-thalamus afferent pathway, these increased events and input-targeting units at excitatory synapses may be from cerebral cortices for other modalities, which is supported by our previous study . This point brings insight into the concept that the neurons are never to be the functional silent units under the physiological condition. After loss of excitatory synaptic inputs, the neurons call up through the homeostatic mechanism, attract synaptic inputs from other cortical areas and execute new functions, e.g., cross-modal plasticity for sensory compensation. How the substitution of other cortical inputs to thalamus inputs is temporally controlled by the molecular events remains to be studied.
Previous studies in the barrel cortices after trimming whiskers indicated the changes in synaptic transmission [25, 26], synaptic plasticity [27–30], dendritic reo rganization [31, 32], spine generation [33, 34] and zinc-containing neural circuit reorganization [35, 36]. These data indicate the important roles of synaptic plasticity and circuit rewire in experience-dependent neural plasticity. By labeling different neurons as well as studying their functions and morphology, we are able to see the coordination and homeostasis among the different types of neurons and synapses in the barrel cortices after experience-dependent neural plasticity. Our study brings new information for this subject.
In summary, we have investigated experience-dependent plasticity in the barrel cortices after loss of whisker inputs. The upregulation of excitatory neurons and synapses as well as the downregulation of inhibitory neurons and synapses are associated with the loss of sensory inputs. The upregulated activities of network neurons, after loss of their original sensory inputs, will prevent the loss of their functions and attract the inputs from other cortical areas and/or peripheral nerves for cross-modal compensation.