Blockade of dopamine D3 receptors improves hippocampal synaptic function and rescues age-related cognitive phenotype.

Dopamine D3 receptors (D3Rs) modulate neuronal activity in several brain regions including the hippocampus. Although previous studies reported that blocking D3Rs exerts pro-cognitive effects, their involvement in hippocampal synaptic function and memory in the healthy and aged brain has not been thoroughly investigated. We demonstrated that in adult wild type (WT) mice, D3R pharmacological blockade or genetic deletion as in D3 knock out (KO) mice, converted the weak form of long-term potentiation (LTP1) into the stronger long-lasting LTP (LTP2) via the cAMP/PKA pathway, and allowed the formation of long-term memory. D3R effects were mainly mediated by post-synaptic mechanisms as their blockade enhanced basal synaptic transmission (BST), AMPAR-mediated currents, mEPSC amplitude, and the expression of the post-synaptic proteins PSD-95, phospho(p)GluA1 and p-CREB. Consistently, electron microscopy revealed a prevalent expression of D3Rs in post-synaptic dendrites. Interestingly, with age, D3Rs decreased in axon terminals while maintaining their levels in post-synaptic dendrites. Indeed, in aged WT mice, blocking D3Rs reversed the impairment of LTP, BST, memory, post-synaptic protein expression, and PSD length. Notably, aged D3-KO mice did not exhibit synaptic and memory deficits. In conclusion, we demonstrated the fundamental role of D3Rs in hippocampal synaptic function and memory, and their potential as a therapeutic target to counteract the age-related hippocampal cognitive decline.

Nitric oxide/cGMP/CREB pathway and amyloid-beta crosstalk: From physiology to Alzheimer's disease.

The nitric oxide (NO)/cGMP pathway has been extensively studied for its pivotal role in synaptic plasticity and memory processes, resulting in an increase of cAMP response element-binding (CREB) phosphorylation, and consequent synthesis of plasticity-related proteins. The NO/cGMP/CREB signaling is downregulated during aging and neurodegenerative disorders and is affected by Amyloid-ß peptide (Aß) and tau protein, whose increase and deposition is considered the key pathogenic event of Alzheimer's disease (AD). On the other hand, in physiological conditions, the crosstalk between the NO/cGMP/PKG/CREB pathway and Aß ensures long-term potentiation and memory formation. This review summarizes the current knowledge on the interaction between the NO/cGMP/PKG/CREB pathway and Aß in the healthy and diseased brain, offering a new perspective to shed light on AD pathophysiology. We will focus on the synaptic mechanisms underlying Aß physiological interplay with cGMP pathway and how this balance is corrupted in AD, as high levels of Aß interfere with NO production and cGMP molecular signaling leading to cognitive impairment. Finally, we will discuss results from preclinical and clinical studies proposing the increase of cGMP signaling as a therapeutic strategy in the treatment of AD.

Application of 3D Printing Technology to Produce Hippocampal Customized Guide Cannulas.

Implantation of guide cannulas is a widely used technique to access specific brain areas. Although commercially available, the need to personalize these implants and the high cost prompted us to design open-source customized devices taking advantage of 3D printing technology. Our cannulas consisted in a 3D-printed head mount designed according to the Paxinos coordinates to reach the CA1 area of the hippocampus. To cut guide cannulas to the proper length, we designed and realized an original 3D-printed linear motion apparatus. Polylactic acid thermoplastic polymer was used as printing material. Homemade or commercial cannulas were implanted in 4- to 6-month-old wild-type mice and intrahippocampal injections of amyloid-ß peptide at different concentrations were performed. In vivo behavioral studies of novel object recognition indicated that results obtained with homemade versus commercial devices were comparable. Methylene blue injections and Nissl staining confirmed the correct localization of cannulas in the CA1 area of mouse hippocampus. Our method allows a fast manufacturing of hippocampal cannulas preserving the required precision at very low cost. Furthermore, this system can be easily modified to produce cannulas to target other brain areas. In conclusion, 3D printing might be used as a useful and versatile technology to realize open-source customized devices in neuroscience laboratories.