**5. Factors affecting hippocampal learning and memory**

### **5.1 LIS1**

An interesting candidate molecule supporting synaptic integrity is LIS1, which is related to lissencephaly [71, 72]. LIS1 deficits in specific hippocampal neuron populations significantly changed the excitatory synaptic transmission in adult-born Lis1+/− DG projection neurons and dendritic spine density and excitatory synaptic aggregation on hippocampal CA1 projection neurons that lost Lis1 expression from postnatal 20 days [73, 74]. Moreover, the loss of LIS1 after childhood destroys the structure and cell composition of the hippocampus, the connection with other brain regions, and the dependence on the cognition of hippocampal circuits [75, 76].

### **5.2 Fos**

Increasing evidence has shown that sparse neuron groups distributed in many areas of the brain constitute the neural matrix of various behaviors [22, 77]. One sign of these active neuron sets is the instantaneous expression of a group of genes called immediate early genes, one of which encodes the Fos transcription factor, composed of eight members with at least partial functional redundancy (Fos, Fosb, c-Fos, Fosl1, Fosl2, Jun, Junb, and Jund) [78–81]. A long-standing hypothesis is that once activated by a significant stimulation, the neurons expressing Fos will undergo modification, which is helpful to encode specific experience characteristics, so

that even if a subset of these neurons are subsequently reactivated, it is enough to trigger memories of the initial experience [82]. Compared with non-Fos-activated neurons, Fos-activated neurons in the hippocampal CA1 region have been shown to stably encode context information [77].

### **5.3 SynCAM 1**

The expression of the synaptic cell adhesion molecule, SynCAM 1, in forebrain neurons, which is also known as a cell adhesion molecule 1 (Cadm1) and Necl-2, is a candidate protein used to evaluate the role of different regions of synaptic tissue proteins [83]. SynCAM 1 belongs to four homophilic and heterophilic membrane protein families of the immunoglobulin superfamily, which are expressed at the peak of synaptic formation and exist until adulthood. This marks the edge of excitatory postsynaptic sites, which is sufficient to induce functional excitatory presynaptic specialization [84]. Studies on knockout and overexpression of the hippocampal CA1 region in mice have shown that SynCAM 1 is necessary to promote excitatory synaptic input of excitatory neurons in vivo [85]. SynCAM 1 also accelerated synapse maturation, which improved the stability of newly formed synapses and in turn increased the likelihood of survival of adult-born neurons [86]. SynCAM 1, therefore, regulates the input of excitatory mossy fibers into the interneurons and major neurons in the hippocampal CA3 region to balance network excitability [87].

### **5.4 Brain-derived neurotrophic factor (BDNF)**

BDNF is one of the most widely distributed and studied neurotrophic factors in mammalian brains. It has a direct impact on memory through various mechanisms. BDNF regulates many different cellular processes involved in the maintenance and development of normal brain function, by binding and activating the TrkB, which is a member of the larger family of Trk receptors [88]. For example, during embryogenesis, BDNF–TrkB signaling promotes the differentiation of cortical progenitor cells and then promotes differentiation of cortical progenitor cells into neurons (i.e., neurogenesis) [89]. The single nucleotide polymorphism of BDNF most likely affects memory through long-term potentiation (LTP), which is important for memory persistence [90]. In the human BDNF gene, a single nucleotide polymorphism leads to an amino acid substitution of valine (Val66Val) to methionine at amino acid residue 66 (Val66Met), which changes the secretion of the mature peptide. This alteration has been related to cognitive deficits among carriers [91]. The effects of BDNF on LTP are also mediated by the TrkB receptor. Especially in the hippocampus, this neurotrophin is thought to act on both pre and postsynaptic compartments, modulating synaptic efficacy, not only by changing the presynaptic transmitter release but also by increasing postsynaptic transmitter sensitivity to induce a long-lasting increase in synaptic plasticity [92, 93].

In the elderly with normal cognition, the presence of BDNF Val66Met is associated with greater hippocampal atrophy and faster cognitive decline [94]. BDNF polymorphism is associated with larger DG volumes within the anterior hippocampus (head) in Met-carriers compared to Val/Val homozygotes. The total hippocampal volume predicted the performance on visuospatial memory tasks in Met-carriers [95]. Although little is known about the process of memory consolidation, it is known that a hippocampal BDNF-positive autoregulatory feedback loop is necessary to mediate memory consolidation via the CCAAT-enhancer-binding protein β (C/EBPβ) [96].

BDNF also mediates the influence of many factors on memory. First, TLQP62, which is a neuropeptide derived from the neurotrophin-inducible VGF (nonacronymic) protein, is capable of inducing increased memory in the mouse *Neural Circuits and Some New Factors Involved in Hippocampal Memory DOI: http://dx.doi.org/10.5772/intechopen.101309*

hippocampus by promoting neurogenesis and synaptic plasticity through BDNF and its receptor tyrosine receptor kinase B (TrkB) [97, 98]. When TLQP62 promotes BDNF expression, which in turn activates the BDNF/TrkB/CREB (cAMP response element-binding protein) pathway that upregulates VGF expression, there is a VGF-BDNF regulatory loop that appears to regulate neurogenesis [99]. In addition, as is well known, exercise can promote the formation of memory, which is also inseparable from BDNF levels. Lactate, a metabolite released during exercise by muscles, crosses the blood–brain barrier and accumulates in the hippocampus, where it promotes the formation of learning and memory by inducing BDNF expression through silent information regulator 1-dependent induction of the PGC1a/FNDC5 pathway [100]. In addition, the increase of the microglia-dependent proBDNF/ BDNF ratio following persistent inflammatory pain leads to cell death of the CA1 and DG neurons. Then, this subsequently causes a cognitive deficit in learning and spatial memory functions [29]. Furthermore, in postmenopausal women, the lower plasma BDNF levels are associated with significantly worse memory performance and changes in the function of the working memory circuit [101].

### **5.5 Smad3**

Smad3 is an intracellular molecule involved in the transforming growth factor-β signaling cascade, which is strongly expressed by granulosa cells of the DG of adult mice [102]. Smad3 deficiency promotes dopaminergic neurodegeneration and α-synuclein aggregation in substantia nigra striatum [103]. Endogenous Smad3 signaling plays important role in neurogenesis and LTP induction of adult DG, which are two forms of hippocampal plasticity related to learning and memory, and which decrease with age and neurological diseases [102].

### **5.6 Oxytocin**

Oxytocin is a brain plasticity regulator of neuronal growth factors, cytoskeleton proteins, and behavioral changes, and is important for short-term hippocampaldependent memory [104] and regulates neuronal excitability, network oscillatory activity, synaptic plasticity, and society memory [105]. In the SH3 domain and ankyrin repeat-containing, the protein 3 (SHANK3) deficient model related to autism, abnormal neuronal morphology and altered synaptic protein levels are recovered by oxytocin [106]. Early changes of the oxytocin signal may interfere with the maturation of neurons and could have both short-term and long-term pathological consequences [107]. At the molecular level, neurodevelopmental disorders include numerous changes in cytoskeleton rearrangement and neurogenesis, leading to various synaptic diseases [108].

### **5.7 Disrupted-in-schizophrenia 1 (DISC1)**

DISC1 is a strong candidate susceptibility gene for a series of neuropsychiatric diseases [109, 110]. Reports of both DISC1 point mutations (L100P and Q31L) heterozygotes and DISC1 transgenic mice [111, 112] found that the combination of adolescent isolation (from 5 to 8 weeks) and DISC1 L100P mutation damaged the social memory of adults. In addition, adolescent isolation aggravates adult neurogenesis defects in the hippocampus of L100P mice, but has no similar effect on WT mice, and leads to long-term continuous changes in synaptic transmission and plasticity of the hippocampal network of DISC1 L100P mice [113, 114]. There is also a possible sex-dependent effect of DICS1. In the test of significant gene–environment interactions in the amphetamine-induced anxiety in male animals and the

amphetamine-induced locomotion in female animals, we surprisingly found that gene–environment interactions improved social memory in not only male but also female animals, but JIA alone disrupted spatial memory and recognition memory only in male animals [115].
