## 4 Discussion
### The Cerebellar Transcriptome Profile of ATM-Null Mice at 12 Months of Age
While extending our notions about a glutamate-focused ATM role, this transcriptomic approach permitted the additional insight that ATM loss also upregulates receptors in the inhibitory GABA-pathways (_Gabra3_, _Gabra5_, _Gabra2_, _Gabrg1_, _Gabrg3_, _Gabrg2_, _Gabrq_, _Gabrb1_, _Gabrap1_ (contrasted by downregulation only for _Gabra6_), together with upregulation of GABA-transporters _Slc6a11_ and _Slc3a1_, as well as receptors in the inhibitory glycine (_Glr1_, _Gla3_, _Glr2a_, _Glr4_), and in the dopamine (_Drd2_, _Drd5_), acetylcholine (_Clrm2_, _Chrna4_, _Clrm3_, _Chrna7_, _Chrna6_, _Chrnm5_, _Clrmb4_, _Clrmb3_) systems. These data suggest that ATM plays a main role in the stress adaptation of synaptic vesicles not only for excitatory but also for inhibitory signalling, possibly via the regulation of vesicle availability/loading/release/recycling. Regarding neuropeptides and their receptors, additional general affection of these signalling pathways was documented, with upregulates of somatostatin (_Sst_, _Sstr1_, _Sstr2_), neurotensin (_Nts_, _Ntsr1_, _Ntsr2_), tachykinin (_Tac1_, _Tacr1_, _Tacr3_), neuropeptides-Y (_Npy_, _Npy1r_, _Npy4r_) mRNAs, and _Resp18_ mRNA encoding a factor responsible for neuropeptide packing in dense core vesicles [127; 128; 129], as well as _Qpct_ encoding a factor responsible for the N-terminal pyroglutamyl residues of neuropeptides and cytokines [130]. In addition, _Oprn1_ as mu-type (morphin-type), _Opr1_ as kappa3-type (nociception-type), and _Oprk1_ as kappa1-type (for alpha-neoendorphins and dynorphins) of opioid receptors showed upregulated transcripts. These cerebellar findings identify molecular mechanisms that show how ATM deficits trigger not only excessive changes in neurotransmission, but may come to impact vasodilation/telangiectasia and inflammatory oedema (via tachykinins, _Ecel1_), growth and fertility (via somatostatin and neuropeptide-Y), immunity and lipid metabolism (via neurotensin), as well as pain perception (via opioids). As one of the strongest upregulated transcripts, _Rgs4_ is a known regulator of G-protein signalling downstream from mu- and kappa-opioid signalling [131; 132; 133; 134]. Even the neuropeptide activator _Pcsk1_ and its inhibitor _Pcsk1n_, as well as neuropeptide activators like _Mme_ (which is responsible for Spinocerebellar Ataxia type 43 [101]) and _Ecel1_ were upregulated. These data suggest that ATM plays a stress adaptor role in general also for dense core vesicles where neuropeptides are stored. Regarding the atrophy of the aged cerebellum in A-T, it is plausible to pay attention to neurotrophins and other cytokines, which are stored in large dense core vesicles (LCDV) before their release and where ATM might play a similar role as for neuropeptides. Indeed, upregulation of neurotrophin receptors _Gfra1_ and _Gfra2_[135; 136], inhibitory neurite growth modulators _Slitrk3_[137; 138], _Slitrk5_[139] and _Slitrk6_[140], neuronal sorting receptors _Sorcs1_ and _Sorcs2_[141; 142; 143; 144], stress-dependent transcription factor _Jun_ with its kinase _Mapk9_/_Jnk2_[145; 146], and heavy-metal-toicity-inducible death executor _Ngfrap1_[147; 148] suggest at first glance that LCDV pathology might contribute to a trophic imbalance in the cerebellum. Furthermore, a downregulation of the ligands _Nrg1_ and _Nrg3_ with converse upregulation of their receptor _Erbb3_ and _Erbb4_ transcripts was observed [149]. Crucial downregulations of neurotrophin _Ntf3_ with its receptor _Ntrk3_, as well as the sorting receptor _Sor11_[150], have to be noted. However, while the systematic interrogation of neurotrophins confirmed mostly upregulation as in neurotransmission and neuropeptide pathways, a similar systematic interrogation of cytokine receptors and their ligands did not reveal a similarly uniform effect.