Pathological studies of RTT brains have found evidence of decreased neuronal and brain size, defects in synaptogenesis, and reduced dendritic arborizations and spines. Some studies have also identified altered (mostly reduced) neurotransmitter levels 63–65. All of these are indicators of less mature and less complex neurons. Defects in synaptogenesis may lead to alterations in neuronal processes 66 such as learning, memory, and information retrieval. Reduced dendritic arborizations can be considered as sign of a less complex neuron. Similarly, spine density on excitatory glutamatergic neurons is a strong indicator of these neuron’s maturity and ability to potentiate synaptic connectivity, as dendrites with reduced number of spines can receive less inputs. Furthermore, spine formation, plasticity, and maintenance depend on contact mediated and long range signals that are in part genetically encoded and in part regulated by synaptic activity and can be modulated by one’s sensory experiences 67–69. Since the synaptic activity and sensory experiences are likely abnormal for RTT patients, this implies at some level a vicious cycle if RTT patients do in fact have reduced spines as pathological studies so far suggest. Gene expression profiling of post mortem RTT brains also hinted at specific deficits in expression of presynaptic markers 70.
